Polymorphisms of the FAS and FAS Ligand Genes Associated with Risk of Cutaneous Malignant Melanoma

Pharmacogenetics and Genomics. Apr, 2006  |  Pubmed ID: 16538172

The FAS/FAS ligand (FASLG) system has a key role in regulating cell growth and thus tumorigenesis. Functional promoter polymorphisms of the FAS and FASLG genes alter the transcriptional activities, but no published study has investigated the role of these polymorphisms in the etiology of cutaneous malignant melanoma (CMM). In a hospital-based, case-control study of 602 non-Hispanic white CMM patients and 603 cancer-free age- and sex-matched control subjects, we genotyped FAS-1377G>A, FAS-670A>G, FASLG-844T>C and FASLG-IVS2nt-124G>A polymorphisms and assessed their respective associations with CMM risk. We found that an increased risk of CMM was associated with the FAS-1377GG [adjusted odds ratio (OR)=1.32; 95% confidence interval (CI)=1.00-1.75 for -1377GG] and -670AA (adjusted OR=1.28; 95% CI=1.00-1.65 for -670AA) genotypes compared to the -1377AA/AG and -670AG/GG genotypes, respectively; an increased risk of CMM was associated with the FASLG-IVS2nt-124AG+GG (OR=1.54; 95% CI=1.18-2.01) genotype compared to the AA genotype, but no evident risk was associated with any of the FAS-844T>C genotypes. In the combined analysis of these four variant alleles, we found that, compared to those having 0-3 variants, those having 4-8 variant alleles had a significantly increased risk for CMM (OR=1.38; 95% CI=1.10-1.73), and this risk was more pronounced in subgroups of old (>50 years) males, and those who were at low risk of sunlight-induced CMM, except for having fair skin colour, moles, dysplastic nevi and a family history of cancer. In conclusion, genetic variants in the FAS and FASLG genes may contribute to the etiology of CMM in the general population, particularly in those with a low risk of sunlight-induced CMM.

Metastatic Melanoma to Lymph Nodes in Patients with Unknown Primary Sites

Cancer. May, 2006  |  Pubmed ID: 16568458

The natural history of metastatic melanoma in lymph nodes in the absence of a known primary site (MUP) has been defined poorly; thus, treatment guidelines for patients with MUP are not clear-cut.

Genetic Variants of the ADPRT, XRCC1 and APE1 Genes and Risk of Cutaneous Melanoma

Carcinogenesis. Sep, 2006  |  Pubmed ID: 16621887

Sunlight causes various kinds of DNA damage, including oxidative lesions that are removed effectively by the base excision repair (BER) pathway, in which ADPRT, XRCC1 and APE1 play a key role. However, genetic variation in these genes may alter their functions. We hypothesized that ADPRT, XRCC1 and APE1 polymorphisms are associated with risk of cutaneous melanoma (CM). In a hospital-based case-control study of 602 CM patients and 603 cancer-free control subjects frequency matched on age, sex and ethnicity, we genotyped for three non-synonymous single nucleotide polymorphisms (SNPs) (i.e. the ADPRT Val762Ala, XRCC1 Arg399Gln and APE1Asp148Glu) and assessed their associations with risk of CM. We found no significant difference in the allele frequencies between cases and controls for any of these three SNPs. However, we found that, compared with the APE1 Asp/Asp genotype, a significantly decreased risk of CM was associated with the APE1 Asp/Glu [adjusted odds ratio (OR), 0.60; 95% confidence interval (CI), 0.41-0.86], Glu/Glu (OR, 0.58; 95% CI, 0.38-0.88) and combined APE1 Asp/Glu+Glu/Glu (OR, 0.59; 95% CI, 0.42-0.83) genotypes, but not for other XRCC1 variant genotypes. Moreover, there was evidence for a possible gene-gene interaction between XRCC1 and APE1 variants in the association with risk of CM (P=0.030). We conclude that the APE1 Glu variant may have an effect or interact with XRCC1 in the etiology of CM or in linkage disequilibrium with other untyped protective alleles. Larger studies with more SNPs in the BER genes are needed to verify these findings.

Invasive Squamous Cell Carcinoma of the Skin: Defining a High-risk Group

Annals of Surgical Oncology. Jul, 2006  |  Pubmed ID: 16788750

Unlike its more common non-invasive form, invasive squamous cell carcinoma (SCC) of the skin can be biologically aggressive and is prone to recur. The objectives of this study were to identify relevant clinicopathologic prognostic factors associated with the outcomes of patients with invasive SCC in order to define a high-risk group.

Polymorphisms in the DNA Repair Genes XPC, XPD, and XPG and Risk of Cutaneous Melanoma: a Case-control Analysis

Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology. Dec, 2006  |  Pubmed ID: 17164380

Sunlight causes DNA damage, including bulky lesions that are removed effectively by the nucleotide-excision repair (NER) pathway. There are at least eight core NER proteins participating in the pathway, and genetic variations in their genes may alter NER functions. We hypothesized that some NER variants are associated with risk of cutaneous melanoma. In a hospital-based case-control study of 602 non-Hispanic White patients with cutaneous melanoma and 603 age- and sex-matched cancer-free controls, we genotyped five common non-synonymous single-nucleotide polymorphisms identified to date and assessed their associations with risk of cutaneous melanoma. We found that a significantly increased risk of cutaneous melanoma was associated with XPD 751Lys/Gln [adjusted odds ratio (OR), 1.55 and 95% confidence interval (95% CI), 1.12-2.16] and XPD 751Gln/Gln (OR, 1.66; 95% CI, 1.03-2.68) genotypes compared with the XPD 751Lys/Lys genotype as well as XPD312Asp/Asn (OR, 1.54; 95% CI, 1.11-2.12) and XPD312Asn/Asn (OR, 1.75; 95% CI, 1.05-2.90) genotypes compared with the XPD 312Asp/Asp genotype. This increased risk was not observed in the other three XPC and XPG single-nucleotide polymorphisms. Moreover, the number of the observed XPD at-risk genotypes (i.e., 312Asn/Asn+Asn/Asp and 751Gln/Gln+Lys/Gln) was associated with cutaneous melanoma risk in a dose-response manner (OR, 1.47; 95% CI, 0.97-2.23 for one at-risk genotype; OR, 1.83; 95% CI, 1.29-2.61 for two at-risk genotypes; P(trend) < 0.001). However, we found no evidence of any interaction between XPD genotypes with XPC and XPG genotypes or the known risk factors. We concluded that genetic variants of the XPD gene might serve as biomarkers for susceptibility to cutaneous melanoma.

Polymorphisms of the Neuronal and Inducible Nitric Oxide Synthase Genes and the Risk of Cutaneous Melanoma: a Case-control Study

Cancer. Apr, 2007  |  Pubmed ID: 17328085

Nitric oxide (NO) is a multifunctional molecule that is produced by both neuronal NO synthase (nNOS) and inducible NO synthase (iNOS), and the expression of nNOS and iNOS is up-regulated in various cancer cells, including cutaneous melanoma (CM). The authors hypothesized that selected functional single-nucleotide polymorphisms (SNPs) in the nNOS and iNOS genes are associated with the risk of CM.

Genetic Variants of the Vitamin D Receptor Gene Alter Risk of Cutaneous Melanoma

The Journal of Investigative Dermatology. Feb, 2007  |  Pubmed ID: 16990805

Sunlight causes DNA damage but also induces production of vitamin D whose metabolite 1,25-(OH)2D3 has antiproliferative and pro-differentiative effects in both melanocytes and cutaneous melanoma (CM) cells mediated through the vitamin D receptor (VDR). We hypothesized that genetic polymorphisms of VDR are associated with risk of CM. In a hospital-based case-control study of 602 non-Hispanic white CM patients and 603 cancer-free control subjects frequency matched by age and sex, we genotyped two VDR polymorphisms (TaqI and FokI) and assessed their association with CM risk. We found that a significantly decreased risk was associated with VDR-TaqI Tt (adjusted odds ratio (OR), 0.70; 95% confidence interval (CI), 0.54-0.90) and Tt+tt (OR=0.70; 95% CI, 0.55-0.89) genotypes, compared with the VDR-TaqI TT genotype, whereas an increased risk was associated with VDR-FokI Ff genotype (OR=1.32; 95% CI, 1.03-1.68), and a borderline significantly increased risk was associated with Ff+ff (OR=1.26; 95% CI, 1.00-1.59) genotypes, compared with the VDR-FokI FF genotype. In conclusion, genetic variants (i.e., TaqI t protective allele and FokI f risk allele) in VDR may alter risk of CM.

Haplotype and Genotypes of the VDR Gene and Cutaneous Melanoma Risk in Non-Hispanic Whites in Texas: a Case-control Study

International Journal of Cancer. Journal International Du Cancer. May, 2008  |  Pubmed ID: 18183598

In a hospital-based case-control study of 805 non-Hispanic whites with cutaneous melanoma and 841 cancer-free age-, sex- and ethnicity-matched control subjects, 3 VDR polymorphisms (i.e., TaqI, BsmI and FokI) were genotyped using blood samples collected between 1994 and 2006. We tested the hypothesis that the haplotypes and combined genotypes of these polymorphisms were associated with melanoma risk by interacting with known risk factors. Haplotypes t-B-F (adjusted odds ratio [OR], 0.52; 95% confidence interval [CI], 0.34-0.80) and t-B-f (adjusted OR, 0.51; CI, 0.27-0.94) were associated with a reduced risk when compared to T-b-f. The combined genotypes Tt+tt/Bb+BB/Ff+ff (adjusted OR, 0.69; CI, 0.52, 0.90) and Tt+tt/Bb+BB/FF (adjusted OR, 0.58; CI, 0.43, 0.78) were also associated with reduced risk, whereas the combined genotype TT/Bb+BB/Ff+ff genotype (adjusted OR, 2.35; CI, 1.13, 4.98) was associated with increased risk when compared to TT/bb/Ff+ff genotypes. On multivariate analysis, only the TaqI polymorphism was an independent risk factor, while the FokI polymorphism interacted with skin color (p = 0.029), moles (p = 0.017) and first-degree relatives with any cancer (p = 0.013) in modifying risk. Together, these findings suggest that VDR polymorphisms may directly affect or modify the risk associated with known melanoma risk factors. Larger, population-based studies are needed to replicate our findings.

Adjuvant High-dose Interferon for Cutaneous Melanoma is Most Beneficial for Patients with Early Stage III Disease

Cancer. May, 2008  |  Pubmed ID: 18320602

Evidence from randomized trials in the pre-sentinel lymph node biopsy era indicate that adjuvant treatment with high-dose interferon-alpha (IFN) increases recurrence-free survival (RFS) in patients with high-risk melanoma. However, to the authors' knowledge, the role of this treatment in selected patients with early stage III disease has not been well studied.

Parathyroid Exploration in the Reoperative Neck: Improved Preoperative Localization with 4D-computed Tomography

Journal of the American College of Surgeons. May, 2008  |  Pubmed ID: 18471717

Reoperation for hyperparathyroidism (HPT) carries an increased risk for morbidity and failure to cure. Accurate preoperative localization minimizes operative risk but is often difficult to achieve in the reoperative setting. Four-dimensional computed tomography (4D-CT) is an emerging technique that uses functional parathyroid anatomy for precise preoperative localization. We evaluated 4D-CT as a tool for localization of hyperfunctioning parathyroid tissue in the reoperative setting.

Genetic Variants and Haplotypes of the Caspase-8 and Caspase-10 Genes Contribute to Susceptibility to Cutaneous Melanoma

Human Mutation. Dec, 2008  |  Pubmed ID: 18563783

Caspase-8 (CASP8) and caspase-10 (CASP10) play key roles in regulating apoptosis, and their functional polymorphisms may alter apoptosis and cancer risk. However, no reported studies have investigated the association between such polymorphisms and the risk of cutaneous melanoma (CM). In a hospital-based study of 805 non-Hispanic white patients with CM and 835 cancer-free age-, sex-, and ethnicity-matched controls, we genotyped three reported putatively functional polymorphisms of CASP8 and CASP10-CASP8 D302 H (rs1045485:G>C), CASP8 -652 6N del (rs3834129:-/CTTACT), and CASP10 I522L (rs13006529:A>T)-and assessed their associations with risk of CM and interactions with known risk factors for CM. We also calculated the false-positive report probability (FPRP) for significant findings. CASP8 302 H variant genotypes (DH: adjusted odds ratio [OR], 0.70; 95% confidence interval [CI], 0.50-0.98; DH+HH: unadjusted OR, 0.78; 95% CI, 0.62-0.98; FPRP, 0.79) and CASP8 -652 6N del variant genotypes (ins/del: OR, 0.74; 95% CI, 0.57-0.97; ins/del+del/del: OR, 0.76; 95% CI, 0.61-0.95; FPRP, 0.61) were associated with significantly lower CM risk than were the DD and ins/ins genotypes, respectively. However, the CASP10 522L variant genotypes were not associated with significantly altered CM risk. Also, the D-del-I haplotype was associated with a significantly lower CM risk (OR, 0.52; 95% CI, 0.37-0.74; FPRP, 0.04) than was the most common haplotype, D-ins-I. Furthermore, multivariate logistic regression analysis revealed that CASP8 D302 H, CASP8 -652 6N del, and CASP10 I522L were independent risk factors for CM. Therefore, these CASP8 and CASP10 polymorphisms may be biomarkers for susceptibility to CM.

Polymorphisms of TP53 Arg72Pro, but Not P73 G4C14>A4TA4 and P21 Ser31Arg, Contribute to Risk of Cutaneous Melanoma

The Journal of Investigative Dermatology. Jun, 2008  |  Pubmed ID: 18049450

Preoperative Vitamin D Replacement Therapy in Primary Hyperparathyroidism: Safe and Beneficial?

Surgery. Dec, 2008  |  Pubmed ID: 19040987

The significance of vitamin D deficiency with primary hyperparathyroidism (PHPT) remains unclear. The safety and value of preoperative vitamin D (Vit D) replacement is unknown.

Genome-wide Association Study Identifies a New Melanoma Susceptibility Locus at 1q21.3

Nature Genetics. Nov, 2011  |  Pubmed ID: 21983785

We performed a genome-wide association study of melanoma in a discovery cohort of 2,168 Australian individuals with melanoma and 4,387 control individuals. In this discovery phase, we confirm several previously characterized melanoma-associated loci at MC1R, ASIP and MTAP-CDKN2A. We selected variants at nine loci for replication in three independent case-control studies (Europe: 2,804 subjects with melanoma, 7,618 control subjects; United States 1: 1,804 subjects with melanoma, 1,026 control subjects; United States 2: 585 subjects with melanoma, 6,500 control subjects). The combined meta-analysis of all case-control studies identified a new susceptibility locus at 1q21.3 (rs7412746, P = 9.0 × 10(-11), OR in combined replication cohorts of 0.89 (95% CI 0.85-0.95)). We also show evidence suggesting that melanoma associates with 1q42.12 (rs3219090, P = 9.3 × 10(-8)). The associated variants at the 1q21.3 locus span a region with ten genes, and plausible candidate genes for melanoma susceptibility include ARNT and SETDB1. Variants at the 1q21.3 locus do not seem to be associated with human pigmentation or measures of nevus density.