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Find video protocols related to scientific articles indexed in Pubmed.
EGFR as a potential therapeutic target for a subset of muscle-invasive bladder cancers presenting a basal-like phenotype.
Sci Transl Med
PUBLISHED: 07-11-2014
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Muscle-invasive bladder carcinoma (MIBC) constitutes a heterogeneous group of tumors with a poor outcome. Molecular stratification of MIBC may identify clinically relevant tumor subgroups and help to provide effective targeted therapies. From seven series of large-scale transcriptomic data (383 tumors), we identified an MIBC subgroup accounting for 23.5% of MIBC, associated with shorter survival and displaying a basal-like phenotype, as shown by the expression of epithelial basal cell markers. Basal-like tumors presented an activation of the epidermal growth factor receptor (EGFR) pathway linked to frequent EGFR gains and activation of an EGFR autocrine loop. We used a 40-gene expression classifier derived from human tumors to identify human bladder cancer cell lines and a chemically induced mouse model of bladder cancer corresponding to human basal-like bladder cancer. We showed, in both models, that tumor cells were sensitive to anti-EGFR therapy. Our findings provide preclinical proof of concept that anti-EGFR therapy can be used to target a subset of particularly aggressive MIBC tumors expressing basal cell markers and provide diagnostic tools for identifying these tumors.
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Rare variants of large effect in BRCA2 and CHEK2 affect risk of lung cancer.
Nat. Genet.
PUBLISHED: 05-08-2014
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We conducted imputation to the 1000 Genomes Project of four genome-wide association studies of lung cancer in populations of European ancestry (11,348 cases and 15,861 controls) and genotyped an additional 10,246 cases and 38,295 controls for follow-up. We identified large-effect genome-wide associations for squamous lung cancer with the rare variants BRCA2 p.Lys3326X (rs11571833, odds ratio (OR) = 2.47, P = 4.74 × 10(-20)) and CHEK2 p.Ile157Thr (rs17879961, OR = 0.38, P = 1.27 × 10(-13)). We also showed an association between common variation at 3q28 (TP63, rs13314271, OR = 1.13, P = 7.22 × 10(-10)) and lung adenocarcinoma that had been previously reported only in Asians. These findings provide further evidence for inherited genetic susceptibility to lung cancer and its biological basis. Additionally, our analysis demonstrates that imputation can identify rare disease-causing variants with substantive effects on cancer risk from preexisting genome-wide association study data.
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Repair of ionizing radiation-induced DNA damage and risk of second cancer in childhood cancer survivors.
Carcinogenesis
PUBLISHED: 03-26-2014
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The study's purpose was to assess whether individuals who developed a second malignant neoplasm (SMN) after treatment for a first malignant neoplasm (FMN) had a lower ability to repair DNA double-strand breaks (DSBs) using a bioassay with ?H2AX intensity as a surrogate endpoint. In a case-control study nested in a cohort of childhood cancer survivors, lymphoblastoid cell lines (LCLs) were established from blood samples collected from 94 cases (SMN) and 94 matched controls (FMN). LCLs were irradiated with ionizing radiation (2 and 5 Gy) and ?H2AX intensities measured 1, 3, 5 and 24h post-irradiation. Differences in mean ?H2AX intensity between cases and controls were compared using Kruskal-Wallis tests. Generalized linear models for repeated measures and conditional logistic regressions for SMN risk estimates were performed. The mean baseline ?H2AX intensity measured without irradiation was 9.1 [95% confidence interval (95% CI): 8.5-9.7] in the LCLs from cases and 6.4 (95% CI: 6.0-6.8) from controls (P < 0.001). Markedly higher ?H2AX intensity, particularly at 1 h post-irradiation, was also found in the LCLs from the cases compared with the controls for all FMNs and for different types of FMN. Chemotherapy and radiation doses received by bone marrow and thymus for FMN treatment showed a non-significant effect on ?H2AX intensity. This case-control study shows that higher baseline and post-irradiation levels of DNA DSBs, as measured by ?H2AX intensity, are associated with the risk of SMN in childhood cancer survivors. Further investigations in a prospective setting are warranted to confirm this association.
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Genome-wide interaction study of smoking and bladder cancer risk.
Carcinogenesis
PUBLISHED: 03-24-2014
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Bladder cancer is a complex disease with known environmental and genetic risk factors. We performed a genome-wide interaction study (GWAS) of smoking and bladder cancer risk based on primary scan data from 3002 cases and 4411 controls from the National Cancer Institute Bladder Cancer GWAS. Alternative methods were used to evaluate both additive and multiplicative interactions between individual single nucleotide polymorphisms (SNPs) and smoking exposure. SNPs with interaction P values < 5 × 10(-) (5) were evaluated further in an independent dataset of 2422 bladder cancer cases and 5751 controls. We identified 10 SNPs that showed association in a consistent manner with the initial dataset and in the combined dataset, providing evidence of interaction with tobacco use. Further, two of these novel SNPs showed strong evidence of association with bladder cancer in tobacco use subgroups that approached genome-wide significance. Specifically, rs1711973 (FOXF2) on 6p25.3 was a susceptibility SNP for never smokers [combined odds ratio (OR) = 1.34, 95% confidence interval (CI) = 1.20-1.50, P value = 5.18 × 10(-) (7)]; and rs12216499 (RSPH3-TAGAP-EZR) on 6q25.3 was a susceptibility SNP for ever smokers (combined OR = 0.75, 95% CI = 0.67-0.84, P value = 6.35 × 10(-) (7)). In our analysis of smoking and bladder cancer, the tests for multiplicative interaction seemed to more commonly identify susceptibility loci with associations in never smokers, whereas the additive interaction analysis identified more loci with associations among smokers-including the known smoking and NAT2 acetylation interaction. Our findings provide additional evidence of gene-environment interactions for tobacco and bladder cancer.
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Genetic variants in DNA repair pathways and risk of upper aerodigestive tract cancers: combined analysis of data from two genome-wide association studies in European populations.
Carcinogenesis
PUBLISHED: 03-21-2014
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DNA repair pathways are good candidates for upper aerodigestive tract cancer susceptibility because of their critical role in maintaining genome integrity. We have selected 13 pathways involved in DNA repair representing 212 autosomal genes. To assess the role of these pathways and their associated genes, two European data sets from the International Head and Neck Cancer Epidemiology consortium were pooled, totaling 1954 cases and 3121 controls, with documented demographic, lifetime alcohol and tobacco consumption information. We applied an innovative approach that tests single nucleotide polymorphism (SNP)-sets within DNA repair pathways and then within genes belonging to the significant pathways. We showed an association between the polymerase pathway and oral cavity/pharynx cancers (P-corrected = 4.45 × 10(-) (2)), explained entirely by the association with one SNP, rs1494961 (P = 2.65 × 10(-) (4)), a missense mutation V306I in the second exon of HELQ gene. We also found an association between the cell cycle regulation pathway and esophagus cancer (P-corrected = 1.48 × 10(-) (2)), explained by three SNPs located within or near CSNK1E gene: rs1534891 (P = 1.27 × 10(-) (4)), rs7289981 (P = 3.37 × 10(-) (3)) and rs13054361 (P = 4.09 × 10(-) (3)). As a first attempt to investigate pathway-level associations, our results suggest a role of specific DNA repair genes/pathways in specific upper aerodigestive tract cancer sites.
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Determinants of genetic counseling uptake and its impact on breast cancer outcome: a population-based study.
Breast Cancer Res. Treat.
PUBLISHED: 01-27-2014
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Genetic counseling and BRCA1/BRCA2 genes testing are routinely offered in a clinical setting. However, no data are available on the proportion of breast cancer patients with a positive family history undergoing genetic counseling. By linking databases of the Oncogenetics and Cancer Prevention Unit at the Geneva University Hospitals and the population-based Geneva Cancer Registry, we evaluated the uptake of genetic counseling among 1709 breast cancer patients with familial risk of breast cancer and the determinants of such a consultation process. We also studied the impact of genetic counseling on contralateral breast cancer occurrence and survival. Overall, 191 (11.2 %) breast cancer patients had genetic counseling; this proportion was 25.1 % within the high familial risk group. Recent period of diagnosis, early-onset breast cancer, female offspring, high familial risk, tumor size, and chemotherapy treatment were statistically significantly associated with genetic counseling uptake in multivariate analysis. More than 2 % of patients had developed contralateral metachronous breast cancer. An increased risk of contralateral breast cancer of borderline significance was found for patients who had genetic counseling versus those who had not (Cox model adjusted hazard ratio 2.2, 95 % confidence intervals 1.0-5.2, P = 0.063). Stratification by BRCA1/BRCA2 mutation status showed that the occurrence of contralateral breast cancer was 8-fold higher among mutation carriers compared with non-carriers. Age-adjusted overall survival and breast cancer-specific survival were not significantly different between patients who underwent genetic counseling and those who did not. In conclusion, we observed a significant increase in the use of genetic counseling over time and found that breast cancer patients with high familial risk had more often genetic counseling than those with moderate familial risk. A more thorough evaluation of sociodemographic and clinical predictors to attend the cancer genetic unit may help improving the use of genetic counseling services for at-risk individuals at a population level.
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Cancer registries can provide evidence-based data to improve quality of care and prevent cancer deaths.
Ecancermedicalscience
PUBLISHED: 01-01-2014
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Today, many countries are increasing their efforts to ensure that all cancer patients receive the best possible care. Population-based cancer registries have adapted their registration to collect additional clinical variables to provide clinicians with unbiased population data on cancer treatment and survival. Taking several examples of epidemiological cancer research performed at the Geneva Cancer Registry, we aim to illustrate how cancer registries oversee the treatment and outcomes of cancer patients to help clinicians continually improve quality of care and prevent cancer deaths in the population.
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Impact of family history of breast cancer on tumour characteristics, treatment, risk of second cancer and survival among men with breast cancer.
Swiss Med Wkly
PUBLISHED: 11-14-2013
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Male breast cancer patients have a higher risk of developing a second primary cancer, but whether this risk differs according to the family history of breast or ovarian cancers remains to be elucidated. We aimed to determine the effect of a positive family history among men diagnosed with breast cancer on tumour characteristics, treatment, second cancer occurrence and overall survival.
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Genome-wide association study identifies multiple loci associated with bladder cancer risk.
Jonine D Figueroa, Yuanqing Ye, Afshan Siddiq, Montserrat Garcia-Closas, Nilanjan Chatterjee, Ludmila Prokunina-Olsson, Victoria K Cortessis, Charles Kooperberg, Olivier Cussenot, Simone Benhamou, Jennifer Prescott, Stefano Porru, Colin P Dinney, Nuria Malats, Dalsu Baris, Mark Purdue, Eric J Jacobs, Demetrius Albanes, Zhaoming Wang, Xiang Deng, Charles C Chung, Wei Tang, H Bas Bueno-de-Mesquita, Dimitrios Trichopoulos, Börje Ljungberg, Francoise Clavel-Chapelon, Elisabete Weiderpass, Vittorio Krogh, Miren Dorronsoro, Ruth Travis, Anne Tjønneland, Paul Brenan, Jenny Chang-Claude, Elio Riboli, David Conti, Manuela Gago-Dominguez, Mariana C Stern, Malcolm C Pike, David Van Den Berg, Jian-Min Yuan, Chancellor Hohensee, Rebecca Rodabough, Géraldine Cancel-Tassin, Morgan Rouprêt, Eva Compérat, Constance Chen, Immaculata De Vivo, Edward Giovannucci, David J Hunter, Peter Kraft, Sara Lindstrom, Angela Carta, Sofia Pavanello, Cecilia Arici, Giuseppe Mastrangelo, Ashish M Kamat, Seth P Lerner, H Barton Grossman, Jie Lin, Jian Gu, Xia Pu, Amy Hutchinson, Laurie Burdette, William Wheeler, Manolis Kogevinas, Adonina Tardón, Consol Serra, Alfredo Carrato, Reina Garcia-Closas, Josep Lloreta, Molly Schwenn, Margaret R Karagas, Alison Johnson, Alan Schned, Karla R Armenti, G M Hosain, Gerald Andriole, Robert Grubb, Amanda Black, W Ryan Diver, Susan M Gapstur, Stephanie J Weinstein, Jarmo Virtamo, Chris A Haiman, Maria T Landi, Neil Caporaso, Joseph F Fraumeni, Paolo Vineis, Xifeng Wu, Debra T Silverman, Stephen Chanock, Nathaniel Rothman.
Hum. Mol. Genet.
PUBLISHED: 10-24-2013
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Candidate gene and genome-wide association studies (GWAS) have identified 11 independent susceptibility loci associated with bladder cancer risk. To discover additional risk variants, we conducted a new GWAS of 2422 bladder cancer cases and 5751 controls, followed by a meta-analysis with two independently published bladder cancer GWAS, resulting in a combined analysis of 6911 cases and 11 814 controls of European descent. TaqMan genotyping of 13 promising single nucleotide polymorphisms with P < 1 × 10(-5) was pursued in a follow-up set of 801 cases and 1307 controls. Two new loci achieved genome-wide statistical significance: rs10936599 on 3q26.2 (P = 4.53 × 10(-9)) and rs907611 on 11p15.5 (P = 4.11 × 10(-8)). Two notable loci were also identified that approached genome-wide statistical significance: rs6104690 on 20p12.2 (P = 7.13 × 10(-7)) and rs4510656 on 6p22.3 (P = 6.98 × 10(-7)); these require further studies for confirmation. In conclusion, our study has identified new susceptibility alleles for bladder cancer risk that require fine-mapping and laboratory investigation, which could further understanding into the biological underpinnings of bladder carcinogenesis.
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Hierarchical modeling identifies novel lung cancer susceptibility variants in inflammation pathways among 10,140 cases and 11,012 controls.
Hum. Genet.
PUBLISHED: 01-14-2013
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Recent evidence suggests that inflammation plays a pivotal role in the development of lung cancer. In this study, we used a two-stage approach to investigate associations between genetic variants in inflammation pathways and lung cancer risk based on genome-wide association study (GWAS) data. A total of 7,650 sequence variants from 720 genes relevant to inflammation pathways were identified using keyword and pathway searches from Gene Cards and Gene Ontology databases. In Stage 1, six GWAS datasets from the International Lung Cancer Consortium were pooled (4,441 cases and 5,094 controls of European ancestry), and a hierarchical modeling (HM) approach was used to incorporate prior information for each of the variants into the analysis. The prior matrix was constructed using (1) role of genes in the inflammation and immune pathways; (2) physical properties of the variants including the location of the variants, their conservation scores and amino acid coding; (3) LD with other functional variants and (4) measures of heterogeneity across the studies. HM affected the priority ranking of variants particularly among those having low prior weights, imprecise estimates and/or heterogeneity across studies. In Stage 2, we used an independent NCI lung cancer GWAS study (5,699 cases and 5,818 controls) for in silico replication. We identified one novel variant at the level corrected for multiple comparisons (rs2741354 in EPHX2 at 8q21.1 with p value = 7.4 × 10(-6)), and confirmed the associations between TERT (rs2736100) and the HLA region and lung cancer risk. HM allows for prior knowledge such as from bioinformatic sources to be incorporated into the analysis systematically, and it represents a complementary analytical approach to the conventional GWAS analysis.
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A genome-wide association study identifies a novel susceptibility locus for renal cell carcinoma on 12p11.23.
Xifeng Wu, Ghislaine Scelo, Mark P Purdue, Nathaniel Rothman, Mattias Johansson, Yuanqing Ye, Zhaoming Wang, Diana Zelenika, Lee E Moore, Christopher G Wood, Egor Prokhortchouk, Valerie Gaborieau, Kevin B Jacobs, Wong-Ho Chow, Jorge R Toro, David Zaridze, Jie Lin, Jan Lubiński, Joanna Trubicka, Neonilia Szeszenia-Dabrowska, Jolanta Lissowska, Peter Rudnai, Eleonóra Fabiánová, Dana Mates, Viorel Jinga, Vladimír Bencko, Alena Slamova, Ivana Holcatova, Marie Navratilova, Vladimir Janout, Paolo Boffetta, Joanne S Colt, Faith G Davis, Kendra L Schwartz, Rosamonde E Banks, Peter J Selby, Patricia Harnden, Christine D Berg, Ann W Hsing, Robert L Grubb, Heiner Boeing, Paolo Vineis, Francoise Clavel-Chapelon, Domenico Palli, Rosario Tumino, Vittorio Krogh, Salvatore Panico, Eric J Duell, José Ramón Quirós, Maria-Jose Sanchez, Carmen Navarro, Eva Ardanaz, Miren Dorronsoro, Kay-Tee Khaw, Naomi E Allen, H Bas Bueno-de-Mesquita, Petra H M Peeters, Dimitrios Trichopoulos, Jakob Linseisen, Börje Ljungberg, Kim Overvad, Anne Tjønneland, Isabelle Romieu, Elio Riboli, Victoria L Stevens, Michael J Thun, W Ryan Diver, Susan M Gapstur, Paul D Pharoah, Douglas F Easton, Demetrius Albanes, Jarmo Virtamo, Lars Vatten, Kristian Hveem, Tony Fletcher, Kvetoslava Koppova, Olivier Cussenot, Géraldine Cancel-Tassin, Simone Benhamou, Michelle A Hildebrandt, Xia Pu, Mario Foglio, Doris Lechner, Amy Hutchinson, Meredith Yeager, Joseph F Fraumeni, Mark Lathrop, Konstantin G Skryabin, James D McKay, Jian Gu, Paul Brennan, Stephen J Chanock.
Hum. Mol. Genet.
PUBLISHED: 10-18-2011
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Renal cell carcinoma (RCC) is the most lethal urologic cancer. Only two common susceptibility loci for RCC have been confirmed to date. To identify additional RCC common susceptibility loci, we conducted an independent genome-wide association study (GWAS). We analyzed 533 191 single nucleotide polymorphisms (SNPs) for association with RCC in 894 cases and 1516 controls of European descent recruited from MD Anderson Cancer Center in the primary scan, and validated the top 500 SNPs in silico in 3772 cases and 8505 controls of European descent involved in the only published GWAS of RCC. We identified two common variants in linkage disequilibrium, rs718314 and rs1049380 (r(2) = 0.64, D? = 0.84), in the inositol 1,4,5-triphosphate receptor, type 2 (ITPR2) gene on 12p11.23 as novel susceptibility loci for RCC (P = 8.89 × 10(-10) and P = 6.07 × 10(-9), respectively, in meta-analysis) with an allelic odds ratio of 1.19 [95% confidence interval (CI): 1.13-1.26] for rs718314 and 1.18 (95% CI: 1.12-1.25) for rs1049380. It has been recently identified that rs718314 in ITPR2 is associated with waist-hip ratio (WHR) phenotype. To our knowledge, this is the first genetic locus associated with both cancer risk and WHR.
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Antiestrogen therapy for breast cancer modifies the risk of subsequent cutaneous melanoma.
Cancer Prev Res (Phila)
PUBLISHED: 09-20-2011
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Increased risk of secondary melanoma after breast cancer has been reported. Several lines of evidence suggest that elevated estrogen levels may be implicated in melanoma etiology. Accordingly, use of antiestrogens should be associated with decreased risk of melanoma. We compared melanoma incidence among a cohort of breast cancer patients with and without antiestrogen therapy, with data from the Geneva Cancer Registry. The cohort consisted of 7,360 women diagnosed with breast cancer between 1980 and 2005. About 54% of these patients received antiestrogens. All women were followed until December 2008. We compared cutaneous melanoma incidence rates among patients with and without antiestrogens with those expected in the general population by age and period standardized incidence ratios (SIR). A total of 34 women developed a melanoma during the follow-up period. Compared with the general population, the risk of melanoma was higher for patients who did not receive antiestrogens (SIR: 1.60, 95% CI: 1.08-2.12, P = 0.02). On the contrary, the risk was close to 1 (SIR: 0.98, 95% CI: 0.40-1.56, P = 0.57) for patients who received antiestrogen therapy. This study suggests that antiestrogen therapy modifies the risk of melanoma after breast cancer. Although our results are in agreement with the hypothesis that estrogens could play a role in melanoma occurrence, they need to be replicated in a larger study with data on potential confounders. .
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Occupational exposure to organic dust increases lung cancer risk in the general population.
Thorax
PUBLISHED: 08-19-2011
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Organic dust is a complex mixture of particulate matter from microbial, plant or animal origin. Occupations with exposure to animal products have been associated with an increased lung cancer risk, while exposure to microbial components (eg, endotoxin) has been associated with a decreased risk. To date there has not been a comprehensive evaluation of the possible association between occupational organic dust exposure (and its specific constituents) and lung cancer risk in the general population.
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Diet and the risk of head and neck cancer: a pooled analysis in the INHANCE consortium.
Cancer Causes Control
PUBLISHED: 05-11-2011
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We investigated the association between diet and head and neck cancer (HNC) risk using data from the International Head and Neck Cancer Epidemiology (INHANCE) consortium. The INHANCE pooled data included 22 case-control studies with 14,520 cases and 22,737 controls. Center-specific quartiles among the controls were used for food groups, and frequencies per week were used for single food items. A dietary pattern score combining high fruit and vegetable intake and low red meat intake was created. Odds ratios (OR) and 95% confidence intervals (CI) for the dietary items on the risk of HNC were estimated with a two-stage random-effects logistic regression model. An inverse association was observed for higher-frequency intake of fruit (4th vs. 1st quartile OR = 0.52, 95% CI = 0.43-0.62, p (trend) < 0.01) and vegetables (OR = 0.66, 95% CI = 0.49-0.90, p (trend) = 0.01). Intake of red meat (OR = 1.40, 95% CI = 1.13-1.74, p (trend) = 0.13) and processed meat (OR = 1.37, 95% CI = 1.14-1.65, p (trend) < 0.01) was positively associated with HNC risk. Higher dietary pattern scores, reflecting high fruit/vegetable and low red meat intake, were associated with reduced HNC risk (per score increment OR = 0.90, 95% CI = 0.84-0.97).
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Sequence Variants and the Risk of Head and Neck Cancer: Pooled Analysis in the INHANCE Consortium.
Front Oncol
PUBLISHED: 03-20-2011
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Previous molecular epidemiological studies on head and neck cancer have examined various single nucleotide polymorphisms (SNPs), but there are very few documented associations. In the International head and neck cancer epidemiology (INHANCE) consortium, we evaluated associations between SNPs in the metabolism, cell cycle, and DNA repair pathways and the risk of head and neck cancer. We analyzed individual-level pooled data from 14 European, North American, Central American, and Asia case-control studies (5,915 head and neck cancer cases and 10,644 controls) participating in the INHANCE consortium. Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for SNP effects, adjusting for age, sex, race, and country. We observed an association between head and neck cancer risk and MGMT Leu84Phe heterozygotes (OR?=?0.79, 95% CI?=?0.68-0.93), XRCC1 Arg194Trp homozygotes Arg/Arg (OR?=?2.3, 95% CI?=?1.1-4.7), ADH1B Arg48His homozygotes Arg/Arg (OR?=?2.7, 95% CI?=?1.9-4.0), ADH1C Ile350Val homozygotes Ile/Ile (OR?=?1.2, 95% CI?=?1.1-1.4), and the GSTM1 null genotype (OR?=?1.1, 95% CI?=?1.0-1.2). Among these results, MGMT Leu84Phe, ADH1B Arg48His, ADH1C Ile350Arg, and the GSTM1 null genotype had fairly low false positive report probabilities (<20%). We observed associations between ADH1B Arg48His, ADH1C Ile350Arg, and GSTM1 null genotype and head and neck cancer risk. No functional study currently supports the observed association for MGMT Leu84Phe, and the association with XRCC1 Arg194Trp may be a chance finding.
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A sex-specific association between a 15q25 variant and upper aerodigestive tract cancers.
Cancer Epidemiol. Biomarkers Prev.
PUBLISHED: 02-18-2011
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Sequence variants located at 15q25 have been associated with lung cancer and propensity to smoke. We recently reported an association between rs16969968 and risk of upper aerodigestive tract (UADT) cancers (oral cavity, oropharynx, hypopharynx, larynx, and esophagus) in women (OR = 1.24, P = 0.003) with little effect in men (OR = 1.04, P = 0.35).
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A genome-wide association study of upper aerodigestive tract cancers conducted within the INHANCE consortium.
James D McKay, Thérèse Truong, Valerie Gaborieau, Amélie Chabrier, Shu-Chun Chuang, Graham Byrnes, David Zaridze, Oxana Shangina, Neonila Szeszenia-Dabrowska, Jolanta Lissowska, Peter Rudnai, Eleonóra Fabiánová, Alexandru Bucur, Vladimír Bencko, Ivana Holcatova, Vladimir Janout, Lenka Foretova, Pagona Lagiou, Dimitrios Trichopoulos, Simone Benhamou, Christine Bouchardy, Wolfgang Ahrens, Franco Merletti, Lorenzo Richiardi, Renato Talamini, Luigi Barzan, Kristina Kjaerheim, Gary J Macfarlane, Tatiana V Macfarlane, Lorenzo Simonato, Cristina Canova, Antonio Agudo, Xavier Castellsague, Ray Lowry, David I Conway, Patricia A McKinney, Claire M Healy, Mary E Toner, Ariana Znaor, María Paula Curado, Sergio Koifman, Ana Menezes, Victor Wünsch-Filho, Jose Eluf Neto, Leticia Fernández Garrote, Stefania Boccia, Gabriella Cadoni, Dario Arzani, Andrew F Olshan, Mark C Weissler, William K Funkhouser, Jingchun Luo, Jan Lubiński, Joanna Trubicka, Marcin Lener, Dorota Oszutowska, Stephen M Schwartz, Chu Chen, Sherianne Fish, David R Doody, Joshua E Muscat, Philip Lazarus, Carla J Gallagher, Shen-Chih Chang, Zuo-Feng Zhang, Qingyi Wei, Erich M Sturgis, Li-E Wang, Silvia Franceschi, Rolando Herrero, Karl T Kelsey, Michael D McClean, Carmen J Marsit, Heather H Nelson, Marjorie Romkes, Shama Buch, Tomoko Nukui, Shilong Zhong, Martin Lacko, Johannes J Manni, Wilbert H M Peters, Rayjean J Hung, John Mclaughlin, Lars Vatten, Inger Njølstad, Gary E Goodman, John K Field, Triantafillos Liloglou, Paolo Vineis, Francoise Clavel-Chapelon, Domenico Palli, Rosario Tumino, Vittorio Krogh, Salvatore Panico, Carlos A González, J Ramon Quiros, Carmen Martínez, Carmen Navarro, Eva Ardanaz, Nerea Larranaga, Kay-Tee Khaw, Timothy Key, H Bas Bueno-de-Mesquita, Petra H M Peeters, Antonia Trichopoulou, Jakob Linseisen, Heiner Boeing, Göran Hallmans, Kim Overvad, Anne Tjønneland, Merethe Kumle, Elio Riboli, Kristjan Välk, Tõnu Vooder, Tõnu Voodern, Andres Metspalu, Diana Zelenika, Anne Boland, Marc Delepine, Mario Foglio, Doris Lechner, Hélène Blanché, Ivo G Gut, Pilar Galán, Simon Heath, Mia Hashibe, Richard B Hayes, Paolo Boffetta, Mark Lathrop, Paul Brennan.
PLoS Genet.
PUBLISHED: 02-11-2011
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Genome-wide association studies (GWAS) have been successful in identifying common genetic variation involved in susceptibility to etiologically complex disease. We conducted a GWAS to identify common genetic variation involved in susceptibility to upper aero-digestive tract (UADT) cancers. Genome-wide genotyping was carried out using the Illumina HumanHap300 beadchips in 2,091 UADT cancer cases and 3,513 controls from two large European multi-centre UADT cancer studies, as well as 4,821 generic controls. The 19 top-ranked variants were investigated further in an additional 6,514 UADT cancer cases and 7,892 controls of European descent from an additional 13 UADT cancer studies participating in the INHANCE consortium. Five common variants presented evidence for significant association in the combined analysis (p ? 5 × 10??). Two novel variants were identified, a 4q21 variant (rs1494961, p?=?1×10??) located near DNA repair related genes HEL308 and FAM175A (or Abraxas) and a 12q24 variant (rs4767364, p =2 × 10??) located in an extended linkage disequilibrium region that contains multiple genes including the aldehyde dehydrogenase 2 (ALDH2) gene. Three remaining variants are located in the ADH gene cluster and were identified previously in a candidate gene study involving some of these samples. The association between these three variants and UADT cancers was independently replicated in 5,092 UADT cancer cases and 6,794 controls non-overlapping samples presented here (rs1573496-ADH7, p = 5 × 10??); rs1229984-ADH1B, p = 7 × 10??; and rs698-ADH1C, p = 0.02). These results implicate two variants at 4q21 and 12q24 and further highlight three ADH variants in UADT cancer susceptibility.
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Breast cancer prognosis is inherited independently of patient, tumor and treatment characteristics.
Int. J. Cancer
PUBLISHED: 02-01-2011
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Population-based studies have shown a concordance of breast cancer survival among first-degree relatives (FDRs), suggesting a heritable component. Reasons for such heritability remain to be elucidated. We aimed to determine whether association of breast cancer survival among FDRs is linked to shared patient and tumor characteristics or type of treatment. At the population-based Geneva Breast Cancer Registry, we identified 162 FDR pairs diagnosed with breast cancer. We categorized FDRs into poor, medium and good familial survival risk groups according to breast cancer-specific survival of their proband (mother or sister). We compared patient, tumor and treatment characteristics between categories and calculated standardized mortality ratios (SMRs) and adjusted disease-specific mortality for each group. Breast cancer patients in the poor familial survival risk group were more likely to be diagnosed at later stages than those in the good familial survival risk group. Similarly, they had higher SMRs than those in the medium and good survival risk groups (18.7, 95% confidence interval [CI]: 9.4-33.5 vs. 16.5, 95% CI: 7.5-31.3 and 9.4, 95% CI: 3.4-20.4, respectively). After adjustment for patient and tumor characteristics and type of treatment, women in the poor familial survival risk group were almost five times more likely to die of breast cancer than those in the good familial survival risk group (adjusted hazard ratio 4.8, 95% CI: 1.4-16.4). Our study shows that breast cancer prognosis clusters within families and suggests that the hereditary component is independent of patient and tumor characteristics and type of treatment.
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Lung cancer mortality risk among breast cancer patients treated with anti-estrogens.
Cancer
PUBLISHED: 01-24-2011
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The Womens Health Initiative randomized clinical trial reported that menopausal hormone therapy increases lung cancer mortality risk. If this is true, use of anti-estrogens should be associated with decreased lung cancer mortality risk. The authors compared lung cancer incidence and mortality among breast cancer patients with and without anti-estrogen therapy.
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Occupation and risk of upper aerodigestive tract cancer: the ARCAGE study.
Int. J. Cancer
PUBLISHED: 01-16-2011
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We investigated the association between occupational history and upper aerodigestive tract (UADT) cancer risk in the ARCAGE European case-control study. The study included 1,851 patients with incident cancer of the oral cavity, oropharynx, hypopharynx, larynx or esophagus and 1,949 controls. We estimated odds ratios (OR) and 95% confidence intervals (CI) for ever employment in 283 occupations and 172 industries, adjusting for smoking and alcohol. Men (1,457 cases) and women (394 cases) were analyzed separately and we incorporated a semi-Bayes adjustment approach for multiple comparisons. Among men, we found increased risks for occupational categories previously reported to be associated with at least one type of UADT cancer, including painters (OR = 1.74, 95% CI: 1.01-3.00), bricklayers (1.58, 1.05-2.37), workers employed in the erection of roofs and frames (2.62, 1.08-6.36), reinforced concreters (3.46, 1.11-10.8), dockers (2.91, 1.05-8.05) and workers employed in the construction of roads (3.03, 1.23-7.46), general construction of buildings (1.44, 1.12-1.85) and cargo handling (2.60, 1.17-5.75). With the exception of the first three categories, risks both increased when restricting to long duration of employment and remained elevated after semi-Bayes adjustment. Increased risks were also found for loggers (3.56, 1.20-10.5) and cattle and dairy farming (3.60, 1.15-11.2). Among women, there was no clear evidence of increased risks of UADT cancer in association with occupations or industrial activities. This study provides evidence of an association between some occupational categories and UADT cancer risk among men. The most consistent findings, also supported by previous studies, were obtained for specific workers employed in the construction industry.
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A novel epigenetic phenotype associated with the most aggressive pathway of bladder tumor progression.
J. Natl. Cancer Inst.
PUBLISHED: 12-20-2010
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Epigenetic silencing can extend to whole chromosomal regions in cancer. There have been few genome-wide studies exploring its involvement in tumorigenesis.
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The aetiology of upper aerodigestive tract cancers among young adults in Europe: the ARCAGE study.
Cancer Causes Control
PUBLISHED: 08-26-2010
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The incidence of cancers of the upper aerodigestive tract (UADT) is increasing throughout the world. To date the increases have been proportionally greatest among young people. Several reports have suggested that they often do not have a history of tobacco smoking or heavy alcohol consumption.
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Replication of lung cancer susceptibility loci at chromosomes 15q25, 5p15, and 6p21: a pooled analysis from the International Lung Cancer Consortium.
J. Natl. Cancer Inst.
PUBLISHED: 06-14-2010
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Genome-wide association studies have identified three chromosomal regions at 15q25, 5p15, and 6p21 as being associated with the risk of lung cancer. To confirm these associations in independent studies and investigate heterogeneity of these associations within specific subgroups, we conducted a coordinated genotyping study within the International Lung Cancer Consortium based on independent studies that were not included in previous genome-wide association studies.
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A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci.
Nathaniel Rothman, Montserrat Garcia-Closas, Nilanjan Chatterjee, Nuria Malats, Xifeng Wu, Jonine D Figueroa, Francisco X Real, David Van Den Berg, Giuseppe Matullo, Dalsu Baris, Michael Thun, Lambertus A Kiemeney, Paolo Vineis, Immaculata De Vivo, Demetrius Albanes, Mark P Purdue, Thorunn Rafnar, Michelle A T Hildebrandt, Anne E Kiltie, Olivier Cussenot, Klaus Golka, Rajiv Kumar, Jack A Taylor, Jose I Mayordomo, Kevin B Jacobs, Manolis Kogevinas, Amy Hutchinson, Zhaoming Wang, Yi-Ping Fu, Ludmila Prokunina-Olsson, Laurie Burdett, Meredith Yeager, William Wheeler, Adonina Tardón, Consol Serra, Alfredo Carrato, Reina Garcia-Closas, Josep Lloreta, Alison Johnson, Molly Schwenn, Margaret R Karagas, Alan Schned, Gerald Andriole, Robert Grubb, Amanda Black, Eric J Jacobs, W Ryan Diver, Susan M Gapstur, Stephanie J Weinstein, Jarmo Virtamo, Victoria K Cortessis, Manuela Gago-Dominguez, Malcolm C Pike, Mariana C Stern, Jian-Min Yuan, David J Hunter, Monica McGrath, Colin P Dinney, Bogdan Czerniak, Meng Chen, Hushan Yang, Sita H Vermeulen, Katja K Aben, J Alfred Witjes, Remco R Makkinje, Patrick Sulem, Soren Besenbacher, Kari Stefansson, Elio Riboli, Paul Brennan, Salvatore Panico, Carmen Navarro, Naomi E Allen, H Bas Bueno-de-Mesquita, Dimitrios Trichopoulos, Neil Caporaso, Maria Teresa Landi, Federico Canzian, Börje Ljungberg, Anne Tjonneland, Francoise Clavel-Chapelon, David T Bishop, Mark T W Teo, Margaret A Knowles, Simonetta Guarrera, Silvia Polidoro, Fulvio Ricceri, Carlotta Sacerdote, Alessandra Allione, Géraldine Cancel-Tassin, Silvia Selinski, Jan G Hengstler, Holger Dietrich, Tony Fletcher, Peter Rudnai, Eugen Gurzau, Kvetoslava Koppova, Sophia C E Bolick, Ashley Godfrey, Zongli Xu, José I Sanz-Velez, María D García-Prats, Manuel Sánchez, Gabriel Valdivia, Stefano Porru, Simone Benhamou, Robert N Hoover, Joseph F Fraumeni, Debra T Silverman, Stephen J Chanock.
Nat. Genet.
PUBLISHED: 05-10-2010
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We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 × 10?¹²) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 × 10?¹¹) on 19q12 maps to CCNE1 and rs11892031 (P = 1 × 10??) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 × 10?¹¹) and a tag SNP for NAT2 acetylation status (P = 4 × 10?¹¹), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis.
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Genome-wide association study of renal cell carcinoma identifies two susceptibility loci on 2p21 and 11q13.3.
Mark P Purdue, Mattias Johansson, Diana Zelenika, Jorge R Toro, Ghislaine Scelo, Lee E Moore, Egor Prokhortchouk, Xifeng Wu, Lambertus A Kiemeney, Valerie Gaborieau, Kevin B Jacobs, Wong-Ho Chow, David Zaridze, Vsevolod Matveev, Jan Lubiński, Joanna Trubicka, Neonila Szeszenia-Dabrowska, Jolanta Lissowska, Peter Rudnai, Eleonóra Fabiánová, Alexandru Bucur, Vladimír Bencko, Lenka Foretova, Vladimir Janout, Paolo Boffetta, Joanne S Colt, Faith G Davis, Kendra L Schwartz, Rosamonde E Banks, Peter J Selby, Patricia Harnden, Christine D Berg, Ann W Hsing, Robert L Grubb, Heiner Boeing, Paolo Vineis, Francoise Clavel-Chapelon, Domenico Palli, Rosario Tumino, Vittorio Krogh, Salvatore Panico, Eric J Duell, José Ramón Quirós, Maria-Jose Sanchez, Carmen Navarro, Eva Ardanaz, Miren Dorronsoro, Kay-Tee Khaw, Naomi E Allen, H Bas Bueno-de-Mesquita, Petra H M Peeters, Dimitrios Trichopoulos, Jakob Linseisen, Börje Ljungberg, Kim Overvad, Anne Tjønneland, Isabelle Romieu, Elio Riboli, Anush Mukeria, Oxana Shangina, Victoria L Stevens, Michael J Thun, W Ryan Diver, Susan M Gapstur, Paul D Pharoah, Douglas F Easton, Demetrius Albanes, Stephanie J Weinstein, Jarmo Virtamo, Lars Vatten, Kristian Hveem, Inger Njølstad, Grethe S Tell, Camilla Stoltenberg, Rajiv Kumar, Kvetoslava Koppova, Olivier Cussenot, Simone Benhamou, Egbert Oosterwijk, Sita H Vermeulen, Katja K H Aben, Saskia L van der Marel, Yuanqing Ye, Christopher G Wood, Xia Pu, Alexander M Mazur, Eugenia S Boulygina, Nikolai N Chekanov, Mario Foglio, Doris Lechner, Ivo Gut, Simon Heath, Hélène Blanché, Amy Hutchinson, Gilles Thomas, Zhaoming Wang, Meredith Yeager, Joseph F Fraumeni, Konstantin G Skryabin, James D McKay, Nathaniel Rothman, Stephen J Chanock, Mark Lathrop, Paul Brennan.
Nat. Genet.
PUBLISHED: 05-03-2010
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We conducted a two-stage genome-wide association study of renal cell carcinoma (RCC) in 3,772 affected individuals (cases) and 8,505 controls of European background from 11 studies and followed up 6 SNPs in 3 replication studies of 2,198 cases and 4,918 controls. Two loci on the regions of 2p21 and 11q13.3 were associated with RCC susceptibility below genome-wide significance. Two correlated variants (r² = 0.99 in controls), rs11894252 (P = 1.8 × 10??) and rs7579899 (P = 2.3 × 10??), map to EPAS1 on 2p21, which encodes hypoxia-inducible-factor-2 alpha, a transcription factor previously implicated in RCC. The second locus, rs7105934, at 11q13.3, contains no characterized genes (P = 7.8 × 10?¹?). In addition, we observed a promising association on 12q24.31 for rs4765623, which maps to SCARB1, the scavenger receptor class B, member 1 gene (P = 2.6 × 10??). Our study reports previously unidentified genomic regions associated with RCC risk that may lead to new etiological insights.
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Risk of second breast cancer according to estrogen receptor status and family history.
Breast Cancer Res. Treat.
PUBLISHED: 02-18-2010
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A recent study reported an increased risk of contralateral estrogen-negative breast cancer after a first primary estrogen-negative breast cancer. Our study aims to confirm this result and to evaluate how the risk of second breast cancer occurrence is affected by family history of breast cancer and anti-estrogen treatment. We included all 4,152 women diagnosed with breast cancer between 1995 and 2007, using data from the population-based Geneva Cancer Registry. We compared the incidence of second breast cancer among patients according to estrogen receptor (ER) status with that expected in the general population by age-period Standardized Incidence Ratios (SIRs). Among the cohort, 63 women developed second breast cancer. Patients with ER-positive first tumors had a decreased risk of second breast cancer occurrence (SIR: 0.67, 95% CI: 0.48-0.90), whereas patients with ER-negative primary tumors had an increased risk (SIR: 1.98, 95% CI: 1.19-3.09) limited to ER-negative second tumors (SIR: 7.94, 95% CI: 3.81-14.60). Patients with positive family history had a tenfold (SIR: 9.74, 95% CI: 3.57-21.12) higher risk of ER-negative second tumor which increased to nearly 50-fold (SIR: 46.18, 95% CI: 12.58-118.22) when the first tumor was ER-negative. Treatment with anti-estrogen decreased the risk of second ER-positive tumors but not ER-negative tumors. The risk of second ER-negative breast cancer is very high after a first ER-negative tumor, in particular among women with strong family history. Surveillance and prevention of second cancer occurrence should consider both ER status of the first tumor and family history.
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Active and involuntary tobacco smoking and upper aerodigestive tract cancer risks in a multicenter case-control study.
Cancer Epidemiol. Biomarkers Prev.
PUBLISHED: 12-05-2009
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Several important issues for the established association between tobacco smoking and upper aerodigestive tract (UADT) cancer risks include the associations with smoking by cancer subsite, by type of tobacco, and among never alcohol drinkers and the associations with involuntary smoking among nonsmokers. Our aim was to examine these specific issues in a large-scale case-control study in Europe.
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Polymorphisms in DNA repair genes, smoking, and bladder cancer risk: findings from the international consortium of bladder cancer.
Cancer Res.
PUBLISHED: 08-25-2009
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Tobacco smoking is the most important and well-established bladder cancer risk factor and a rich source of chemical carcinogens and reactive oxygen species that can induce damage to DNA in urothelial cells. Therefore, common variation in DNA repair genes might modify bladder cancer risk. In this study, we present results from meta-analyses and pooled analyses conducted as part of the International Consortium of Bladder Cancer. We included data on 10 single nucleotide polymorphisms corresponding to seven DNA repair genes from 13 studies. Pooled analyses and meta-analyses included 5,282 cases and 5,954 controls of non-Latino white origin. We found evidence for weak but consistent associations with ERCC2 D312N [rs1799793; per-allele odds ratio (OR), 1.10; 95% confidence interval (95% CI), 1.01-1.19; P = 0.021], NBN E185Q (rs1805794; per-allele OR, 1.09; 95% CI, 1.01-1.18; P = 0.028), and XPC A499V (rs2228000; per-allele OR, 1.10; 95% CI, 1.00-1.21; P = 0.044). The association with NBN E185Q was limited to ever smokers (interaction P = 0.002) and was strongest for the highest levels of smoking dose and smoking duration. Overall, our study provides the strongest evidence to date for a role of common variants in DNA repair genes in bladder carcinogenesis.
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Changing pattern of age-specific breast cancer incidence in the Swiss canton of Geneva.
Breast Cancer Res. Treat.
PUBLISHED: 07-08-2009
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Hormone replacement therapy (HRT) use declined sharply after mid-2002, when the Womens Health Initiative trial reported an association between breast cancer occurrence and HRT. Hypothesized mechanism behind this association is that HRT promotes growth of pre-existing small tumors, leading to earlier tumor detection. We evaluated the impact of the sudden decline in HRT use on age distribution of breast cancer in Geneva. We included all incident breast cancer cases recorded from 1975 to 2006 at the Geneva cancer registry. We calculated mean annual incidence rates per 100,000 for 2 year periods for three age groups and assessed temporal changes by joinpoint regression. We compared age-specific incidence curves for different periods, reflecting different prevalence rates of HRT use. After increasing constantly between 1986 and 2002 among women aged 50-69 years [annual percent change (APC): +4.4, P < 0.0001], rates declined sharply after 2003 (APC: -6.0; P = 0.0264). Age-specific breast cancer rates changed dramatically with changes in prevalence of HRT use. During low HRT prevalence, breast cancer incidence increased progressively with age, when HRT prevalence was reaching its maximum (1995-2002), higher rates were seen in 60- to 64-year-old women, with a concomitant decrease in risk among elderly. After the sudden decline in HRT use, the incidence peak diminished significantly and incidence increased again with age. Following the abrupt decline in HRT use in Geneva, breast cancer incidence rates among post-menopausal women decreased considerably with striking changes in age-specific incidence rates before, during and after the peak in HRT prevalence.
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A genome-wide association study of lung cancer identifies a region of chromosome 5p15 associated with risk for adenocarcinoma.
Am. J. Hum. Genet.
PUBLISHED: 07-03-2009
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Three genetic loci for lung cancer risk have been identified by genome-wide association studies (GWAS), but inherited susceptibility to specific histologic types of lung cancer is not well established. We conducted a GWAS of lung cancer and its major histologic types, genotyping 515,922 single-nucleotide polymorphisms (SNPs) in 5739 lung cancer cases and 5848 controls from one population-based case-control study and three cohort studies. Results were combined with summary data from ten additional studies, for a total of 13,300 cases and 19,666 controls of European descent. Four studies also provided histology data for replication, resulting in 3333 adenocarcinomas (AD), 2589 squamous cell carcinomas (SQ), and 1418 small cell carcinomas (SC). In analyses by histology, rs2736100 (TERT), on chromosome 5p15.33, was associated with risk of adenocarcinoma (odds ratio [OR]=1.23, 95% confidence interval [CI]=1.13-1.33, p=3.02x10(-7)), but not with other histologic types (OR=1.01, p=0.84 and OR=1.00, p=0.93 for SQ and SC, respectively). This finding was confirmed in each replication study and overall meta-analysis (OR=1.24, 95% CI=1.17-1.31, p=3.74x10(-14) for AD; OR=0.99, p=0.69 and OR=0.97, p=0.48 for SQ and SC, respectively). Other previously reported association signals on 15q25 and 6p21 were also refined, but no additional loci reached genome-wide significance. In conclusion, a lung cancer GWAS identified a distinct hereditary contribution to adenocarcinoma.
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Genetic associations of 115 polymorphisms with cancers of the upper aerodigestive tract across 10 European countries: the ARCAGE project.
Cancer Res.
PUBLISHED: 04-03-2009
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Cancers of the upper aerodigestive tract (UADT) include malignant tumors of the oral cavity, pharynx, larynx, and esophagus and account for 6.4% of all new cancers in Europe. In the context of a multicenter case-control study conducted in 14 centers within 10 European countries and comprising 1,511 cases and 1,457 controls (ARCAGE study), 115 single nucleotide polymorphisms (SNP) from 62 a priori-selected genes were studied in relation to UADT cancer. We found 11 SNPs that were statistically associated with UADT cancers overall (5.75 expected). Considering the possibility of false-positive results, we focused on SNPs in CYP2A6, MDM2, tumor necrosis factor (TNF), and gene amplified in squamous cell carcinoma 1 (GASC1), for which low P values for trend (P trend<0.01) were observed in the main effects analyses of UADT cancer overall or by subsite. The rare variant of CYP2A6 -47A>C (rs28399433), a phase I metabolism gene, was associated with reduced UADT cancer risk (P trend=0.01). Three SNPs in the MDM2 gene, involved in cell cycle control, were associated with UADT cancer. MDM2 IVS5+1285A>G (rs3730536) showed a strong codominant effect (P trend=0.007). The rare variants of two SNPs in the TNF gene were associated with a decreased risk; for TNF IVS1+123G>A (rs1800610), the P trend was 0.007. Variants in two SNPs of GASC1 were found to be strongly associated with increased UADT cancer risk (for both, P trend=0.008). This study is the largest genetic epidemiologic study on UADT cancers in Europe. Our analysis points to potentially relevant genes in various pathways.
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Meta- and pooled analysis of GSTP1 polymorphism and lung cancer: a HuGE-GSEC review.
Am. J. Epidemiol.
PUBLISHED: 02-24-2009
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Lung cancer is the most common cancer worldwide. Polymorphisms in genes associated with carcinogen metabolism may modulate risk of disease. Glutathione S-transferase pi (GSTP1) detoxifies polycyclic aromatic hydrocarbons found in cigarette smoke and is the most highly expressed glutathione S-transferase in lung tissue. A polymorphism in the GSTP1 gene, an A-to-G transition in exon 5 (Ile105Val, 313A --> 313G), results in lower activity among individuals who carry the valine allele. The authors present a meta- and a pooled analysis of case-control studies that examined the association between this polymorphism in GSTP1 and lung cancer risk (27 studies, 8,322 cases and 8,844 controls and 15 studies, 4,282 cases and 5,032 controls, respectively). Overall, the meta-analysis found no significant association between lung cancer risk and the GSTP1 exon 5 polymorphism. In the pooled analysis, there was an overall association (odds ratio = 1.11, 95% confidence interval: 1.03, 1.21) between lung cancer and carriage of the GSTP1 Val/Val or Ile/Val genotype compared with those carrying the Ile/Ile genotype. Increased risk varied by histologic type in Asians. There appears to be evidence for interaction between amount of smoking, the GSTP1 exon 5 polymorphism, and risk of lung cancer in whites.
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Genetic polymorphisms in 85 DNA repair genes and bladder cancer risk.
Carcinogenesis
PUBLISHED: 02-23-2009
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Several defense mechanisms have been developed and maintained during the evolution to protect human cells against damage produced from exogenous or endogenous sources. We examined the associations between bladder cancer and a panel of 652 polymorphisms from 85 genes involved in maintenance of genetic stability [base excision repair, nucleotide excision repair, double-strand break repair (DSBR) and mismatch repair, as well as DNA synthesis and cell cycle regulation pathways] in 201 incident bladder cancer cases and 326 hospital controls. Score statistics were used to test differences in haplotype frequencies between cases and controls in an unconditional logistic regression model. To account for multiple testing, we associated to each P-value the expected proportion of false discoveries (q-value). Haplotype analysis revealed significant associations (P < 0.01) between bladder cancer and two genes (POLB and FANCA) with an associated q-value of 24%. A permutation test was also used to determine whether, in each pathway analyzed, there are more variants whose allelic frequencies are different between cases and controls as compared with what would be expected by chance. Differences were found for cell cycle regulation (P = 0.02) and to a lesser extent for DSBR (P = 0.05) pathways. These results hint to a few potential candidate genes; however, our study was limited by the small sample size and therefore low statistical power to detect associations. It is anticipated that genome-wide association studies will open new perspectives for interpretation of the results of extensive candidate gene studies such as ours.
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Diet and upper-aerodigestive tract cancer in Europe: the ARCAGE study.
Int. J. Cancer
PUBLISHED: 02-21-2009
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There is suggestive, but inconclusive, evidence that dietary factors may affect risk of cancers of the upper aerodigestive tract (UADT). In the context of the alcohol-related cancers and genetic susceptibility in Europe study, we have examined the association of dietary factors with UADT cancer risk. We have analyzed data from 2,304 patients with UADT cancer and 2,227 control subjects recruited in 14 centers in 10 European countries. Dietary data were collected through a semi-quantitative food frequency questionnaire that also assessed preferred temperature of hot beverages. Statistical analyses were conducted through multiple logistic regression controlling for potential confounding variables, including alcohol intake and smoking habits. Consumption of red meat (OR per increasing tertile = 1.14, 95% CI: 1.05-1.25), but not poultry, was significantly associated with increased UADT cancer risk and the association was somewhat stronger for esophageal cancer. Consumption of fruits (OR per increasing tertile = 0.68, 95% CI: 0.62-0.75) and vegetables (OR per increasing tertile = 0.73, 95% CI: 0.66-0.81) as well as of olive oil (OR for above versus below median = 0.78, 95% CI 0.67-0.90) and tea (OR for above versus below median = 0.83, 95% CI 0.69-0.98) were significantly associated with reduced risk of UADT cancer. There was no indication that an increase in tea or coffee temperature was associated with increased risk of UADT overall or cancer of the esophagus; in fact, the association was, if anything, inverse. In conclusion, the results of this large multicentric study indicate that diet plays an important role in the etiology of UADT cancer.
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Alcohol-related cancers and genetic susceptibility in Europe: the ARCAGE project: study samples and data collection.
Eur. J. Cancer Prev.
PUBLISHED: 02-20-2009
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Cancers of the upper aerodigestive tract (UADT) include those of the oral cavity, pharynx (other than nasopharynx), larynx, and esophagus. Tobacco smoking and consumption of alcoholic beverages are established causes of UADT cancers, whereas reduced intake of vegetables and fruits are likely causes. The role of genetic predisposition and possible interactions of genetic with exogenous factors, however, have not been adequately studied. Moreover, the role of pattern of smoking and drinking, as well as the exact nature of the implicated dietary variables, has not been clarified. To address these issues, the International Agency for Research on Cancer initiated in 2002 the alcohol-related cancers and genetic susceptibility (ARCAGE) in Europe project, with the participation of 15 centers in 11 European countries. Information and biological data from a total of 2304 cases and 2227 controls have been collected and will be used in a series of analyses. A total of 166 single nucleotide polymorphisms of 76 genes are being studied for genetic associations with UADT cancers. We report here the methodology of the ARCAGE project, main demographic and lifestyle characteristics of the cases and controls, as well as the distribution of cases by histology and subsite. About 80% of cases were males and fewer than 20% of all cases occurred before the age of 50 years. Overall, the most common subsite was larynx, followed by oral cavity, oropharynx, esophagus and hypopharynx. Close to 90% of UADT cancers were squamous cell carcinomas. A clear preponderance of smokers and alcohol drinkers among UADT cases compared with controls was observed.
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Type of alcoholic beverage and risk of head and neck cancer--a pooled analysis within the INHANCE Consortium.
Am. J. Epidemiol.
PUBLISHED: 02-10-2009
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The authors pooled data from 15 case-control studies of head and neck cancer (9,107 cases, 14,219 controls) to investigate the independent associations with consumption of beer, wine, and liquor. In particular, they calculated associations with different measures of beverage consumption separately for subjects who drank beer only (858 cases, 986 controls), for liquor-only drinkers (499 cases, 527 controls), and for wine-only drinkers (1,021 cases, 2,460 controls), with alcohol never drinkers (1,124 cases, 3,487 controls) used as a common reference group. The authors observed similar associations with ethanol-standardized consumption frequency for beer-only drinkers (odds ratios (ORs) = 1.6, 1.9, 2.2, and 5.4 for < or =5, 6-15, 16-30, and >30 drinks per week, respectively; P(trend) < 0.0001) and liquor-only drinkers (ORs = 1.6, 1.5, 2.3, and 3.6; P < 0.0001). Among wine-only drinkers, the odds ratios for moderate levels of consumption frequency approached the null, whereas those for higher consumption levels were comparable to those of drinkers of other beverage types (ORs = 1.1, 1.2, 1.9, and 6.3; P < 0.0001). Study findings suggest that the relative risks of head and neck cancer for beer and liquor are comparable. The authors observed weaker associations with moderate wine consumption, although they cannot rule out confounding from diet and other lifestyle factors as an explanation for this finding. Given the presence of heterogeneity in study-specific results, their findings should be interpreted with caution.
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A meta-analysis of the relationship between FGFR3 and TP53 mutations in bladder cancer.
PLoS ONE
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TP53 and FGFR3 mutations are the most common mutations in bladder cancers. FGFR3 mutations are most frequent in low-grade low-stage tumours, whereas TP53 mutations are most frequent in high-grade high-stage tumours. Several studies have reported FGFR3 and TP53 mutations to be mutually exclusive events, whereas others have reported them to be independent. We carried out a meta-analysis of published findings for FGFR3 and TP53 mutations in bladder cancer (535 tumours, 6 publications) and additional unpublished data for 382 tumours. TP53 and FGFR3 mutations were not independent events for all tumours considered together (OR?=?0.25 [0.18-0.37], p?=?0.0001) or for pT1 tumours alone (OR?=?0.47 [0.28-0.79], p?=?0.0009). However, if the analysis was restricted to pTa tumours or to muscle-invasive tumours alone, FGFR3 and TP53 mutations were independent events (OR?=?0.56 [0.23-1.36] (p?=?0.12) and OR?=?0.99 [0.37-2.7] (p?=?0.35), respectively). After stratification of the tumours by stage and grade, no dependence was detected in the five tumour groups considered (pTaG1 and pTaG2 together, pTaG3, pT1G2, pT1G3, pT2-4). These differences in findings can be attributed to the putative existence of two different pathways of tumour progression in bladder cancer: the CIS pathway, in which FGFR3 mutations are rare, and the Ta pathway, in which FGFR3 mutations are frequent. TP53 mutations occur at the earliest stage of the CIS pathway, whereas they occur would much later in the Ta pathway, at the T1G3 or muscle-invasive stage.
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Influence of common genetic variation on lung cancer risk: meta-analysis of 14 900 cases and 29 485 controls.
Hum. Mol. Genet.
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Recent genome-wide association studies (GWASs) have identified common genetic variants at 5p15.33, 6p21-6p22 and 15q25.1 associated with lung cancer risk. Several other genetic regions including variants of CHEK2 (22q12), TP53BP1 (15q15) and RAD52 (12p13) have been demonstrated to influence lung cancer risk in candidate- or pathway-based analyses. To identify novel risk variants for lung cancer, we performed a meta-analysis of 16 GWASs, totaling 14 900 cases and 29 485 controls of European descent. Our data provided increased support for previously identified risk loci at 5p15 (P = 7.2 × 10(-16)), 6p21 (P = 2.3 × 10(-14)) and 15q25 (P = 2.2 × 10(-63)). Furthermore, we demonstrated histology-specific effects for 5p15, 6p21 and 12p13 loci but not for the 15q25 region. Subgroup analysis also identified a novel disease locus for squamous cell carcinoma at 9p21 (CDKN2A/p16(INK4A)/p14(ARF)/CDKN2B/p15(INK4B)/ANRIL; rs1333040, P = 3.0 × 10(-7)) which was replicated in a series of 5415 Han Chinese (P = 0.03; combined analysis, P = 2.3 × 10(-8)). This large analysis provides additional evidence for the role of inherited genetic susceptibility to lung cancer and insight into biological differences in the development of the different histological types of lung cancer.
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Deregulation of Rab and Rab effector genes in bladder cancer.
PLoS ONE
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Growing evidence indicates that Rab GTPases, key regulators of intracellular transport in eukaryotic cells, play an important role in cancer. We analysed the deregulation at the transcriptional level of the genes encoding Rab proteins and Rab-interacting proteins in bladder cancer pathogenesis, distinguishing between the two main progression pathways so far identified in bladder cancer: the Ta pathway characterized by a high frequency of FGFR3 mutation and the carcinoma in situ pathway where no or infrequent FGFR3 mutations have been identified. A systematic literature search identified 61 genes encoding Rab proteins and 223 genes encoding Rab-interacting proteins. Transcriptomic data were obtained for normal urothelium samples and for two independent bladder cancer data sets corresponding to 152 and 75 tumors. Gene deregulation was analysed with the SAM (significant analysis of microarray) test or the binomial test. Overall, 30 genes were down-regulated, and 13 were up-regulated in the tumor samples. Five of these deregulated genes (LEPRE1, MICAL2, RAB23, STXBP1, SYTL1) were specifically deregulated in FGFR3-non-mutated muscle-invasive tumors. No gene encoding a Rab or Rab-interacting protein was found to be specifically deregulated in FGFR3-mutated tumors. Cluster analysis showed that the RAB27 gene cluster (comprising the genes encoding RAB27 and its interacting partners) was deregulated and that this deregulation was associated with both pathways of bladder cancer pathogenesis. Finally, we found that the expression of KIF20A and ZWINT was associated with that of proliferation markers and that the expression of MLPH, MYO5B, RAB11A, RAB11FIP1, RAB20 and SYTL2 was associated with that of urothelial cell differentiation markers. This systematic analysis of Rab and Rab effector gene deregulation in bladder cancer, taking relevant tumor subgroups into account, provides insight into the possible roles of Rab proteins and their effectors in bladder cancer pathogenesis. This approach is applicable to other group of genes and types of cancer.
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Risk of upper aerodigestive tract cancer and type of alcoholic beverage: a European multicenter case-control study.
Eur. J. Epidemiol.
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The general relationship between cancers of the upper aerodigestive tract (UADT) and alcohol drinking is established. Nevertheless, it is uncertain whether different types of alcoholic beverages (wine, beer and liquor) carry different UADT cancer risks. Our study included 2,001 UADT cancer cases and 2,125 controls from 14 centres in 10 European countries. All cases were histologically or cytologically confirmed squamous cell carcinomas. Controls were frequency matched by sex, age and centre. Logistic regression models were used to estimate odds ratios (OR) and 95 % confidence intervals (95 %CI) adjusted for age, sex, centre, education level, vegetable and fruit intake, tobacco smoking and alcohol drinking, where appropriate. Risk of beverage-specific alcohol consumption were calculated among pure drinker who consumed one beverage type exclusively, among predominant drinkers who consumed one beverage type to more than 66 % and among mixed drinkers who consumed more than one beverage type to similar proportions. Compared to never drinkers and adjusted for cumulative alcohol consumption, the OR and 95 %CI for wine, beer and liquor drinking, respectively, were 1.24 (0.86, 1.78), 1.54 (1.05, 2.27) and 0.94 (0.53, 1.64) among pure drinkers (p value for heterogeneity across beverage types = 0.306), 1.05 (0.76,1.47), 1.25 (0.87,1.79) and 1.43 (0.95, 2.16) among predominant drinkers (p value = 0.456), and 1.09 (0.79, 1.50), 1.20 (0.88, 1.63) and 1.12 (0.82, 1.53) among mixed drinkers (p value = 0.889). Risk of UADT cancer increased with increasing consumption of all three alcohol beverage types. Our findings underscore the strong and comparable carcinogenic effect of ethanol in wine, beer and liquor on organs of the UADT.
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Risk, characteristics, and prognosis of breast cancer after Hodgkins lymphoma.
Oncologist
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To assess breast cancer (BC) risk after Hodgkins lymphoma (HL) and compare characteristics, risk of second BC, and prognosis of patients with these BCs with patients with first primary BC.
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CDKN2A homozygous deletion is associated with muscle invasion in FGFR3-mutated urothelial bladder carcinoma.
J. Pathol.
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The gene cyclin-dependent kinase inhibitor 2A (CDKN2A) is frequently inactivated by deletion in bladder carcinoma. However, its role in bladder tumourigenesis remains unclear. We investigated the role of CDKN2A deletion in urothelial carcinogenesis, as a function of FGFR3 mutation status, a marker for one of the two pathways of bladder tumour progression, the Ta pathway. We studied 288 bladder carcinomas: 177 non-muscle-invasive (123 Ta, 54 T1) and 111 muscle-invasive (T2-4) tumours. CDKN2A copy number was determined by multiplex ligation-dependent probe amplification, and FGFR3 mutations by SNaPshot analysis. FGFR3 mutation was detected in 124 tumours (43.1%) and CDKN2A homozygous deletion in 56 tumours (19.4%). CDKN2A homozygous deletion was significantly more frequent in FGFR3-mutated tumours than in wild-type FGFR3 tumours (p = 0.0015). This event was associated with muscle-invasive tumours within the FGFR3-mutated subgroup (p < 0.0001) but not in wild-type FGFR3 tumours. Similar findings were obtained for an independent series of 101 bladder carcinomas. The impact of CDKN2A deletions on recurrence-free and progression-free survival was then analysed in 89 patients with non-muscle-invasive FGFR3-mutated tumours. Kaplan-Meier survival analysis showed that CDKN2A losses (hemizygous and homozygous) were associated with progression (p = 0.0002), but not with recurrence, in these tumours. Multivariate Cox regression analysis identified CDKN2A loss as a predictor of progression independent of stage and grade. These findings highlight the crucial role of CDKN2A loss in the progression of non-muscle-invasive FGFR3-mutated bladder carcinomas and provide a potentially useful clinical marker for adapting the treatment of such tumours, which account for about 50% of cases at initial clinical presentation.
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Lung cancer and DNA repair genes: multilevel association analysis from the International Lung Cancer Consortium.
Carcinogenesis
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Lung cancer (LC) is the leading cause of cancer-related death worldwide and tobacco smoking is the major associated risk factor. DNA repair is an important process, maintaining genome integrity and polymorphisms in DNA repair genes may contribute to susceptibility to LC. To explore the role of DNA repair genes in LC, we conducted a multilevel association study with 1655 single nucleotide polymorphisms (SNPs) in 211 DNA repair genes using 6911 individuals pooled from four genome-wide case-control studies. Single SNP association corroborates previous reports of association with rs3131379, located on the gene MSH5 (P = 3.57 × 10-5) and returns a similar risk estimate. The effect of this SNP is modulated by histological subtype. On the log-additive scale, the odds ratio per allele is 1.04 (0.84-1.30) for adenocarcinomas, 1.52 (1.28-1.80) for squamous cell carcinomas and 1.31 (1.09-1.57) for other histologies (heterogeneity test: P = 9.1 × 10(-)(3)). Gene-based association analysis identifies three repair genes associated with LC (P < 0.01): UBE2N, structural maintenance of chromosomes 1L2 and POLB. Two additional genes (RAD52 and POLN) are borderline significant. Pathway-based association analysis identifies five repair pathways associated with LC (P < 0.01): chromatin structure, DNA polymerases, homologous recombination, genes involved in human diseases with sensitivity to DNA-damaging agents and Rad6 pathway and ubiquitination. This first international pooled analysis of a large dataset unravels the role of specific DNA repair pathways in LC and highlights the importance of accounting for gene and pathway effects when studying LC.
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Similar DNA methylation pattern in lung tumours from smokers and never-smokers with second-hand tobacco smoke exposure.
Mutagenesis
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Tobacco smoke causes lung cancer in smokers and in never-smokers exposed to second-hand tobacco smoke (SHS). Nonetheless, molecular mechanisms of lung cancer in SHS-exposed never-smokers are still elusive. We studied lung cancers from current smokers (n = 109), former smokers (n = 56) and never-smokers (n = 47) for promoter hypermethylation of five tumour suppressor genes--p16, RARB, RASSF1, MGMT and DAPK1--using methylation-specific polymerase chain reaction. Lung tumours from ever-smokers suggested an increased risk of p16 hypermethylation as compared to never-smokers (P = 0.073), with former smokers having the highest frequency of p16 hypermethylation (P = 0.044 versus current smokers and P = 0.009 versus never-smokers). In the never-smoking group, p16 hypermethylation was seen in lung tumours from SHS-exposed individuals (4/33; 12%) but in none of the non-exposed individuals (0/9). The overall occurrence of hypermethylation (measured both as methylation index and as number of genes affected) was similar in those ever exposed to tobacco smoke (smokers, SHS-exposed never-smokers) and differed from non-exposed never-smokers. In multivariate analysis, p16 hypermethylation was more prevalent in lung tumours from male than female patients (P = 0.018) and in squamous cell carcinomas than in adenocarcinomas (P = 0.025). Occurrence of TP53 mutation in the tumour was associated with hypermethylation of at least one gene (P = 0.027). In all, our data suggest that promoter hypermethylation pattern in SHS-exposed never-smokers resembles that observed in smokers. Association between TP53 mutation, a hallmark of smokers lung cancer, and methylation of one or more of the lung cancer-related genes studied, provides further evidence for common tobacco smoke-related origin for both types of molecular alterations.
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