JoVE Visualize What is visualize?
Stop Reading. Start Watching.
Advanced Search
Stop Reading. Start Watching.
Regular Search
Find video protocols related to scientific articles indexed in Pubmed.
Identification and characterization of novel associations in the CASP8/ALS2CR12 region on chromosome 2 with breast cancer risk.
Wei-Yu Lin, Nicola J Camp, Maya Ghoussaini, Jonathan Beesley, Kyriaki Michailidou, John L Hopper, Carmel Apicella, Melissa C Southey, Jennifer Stone, Marjanka K Schmidt, Annegien Broeks, Laura J Van't Veer, Emiel J Th Rutgers, Kenneth Muir, Artitaya Lophatananon, Sarah Stewart-Brown, Pornthep Siriwanarangsan, Peter A Fasching, Lothar Haeberle, Arif B Ekici, Matthias W Beckmann, Julian Peto, Isabel Dos-Santos-Silva, Olivia Fletcher, Nichola Johnson, Manjeet K Bolla, Qin Wang, Joe Dennis, Elinor J Sawyer, Timothy Cheng, Ian Tomlinson, Michael J Kerin, Nicola Miller, Frederik Marme, Harald M Surowy, Barbara Burwinkel, Pascal Guénel, Thérèse Truong, Florence Menegaux, Claire Mulot, Stig E Bojesen, Børge G Nordestgaard, Sune F Nielsen, Henrik Flyger, Javier Benitez, M Pilar Zamora, José Ignacio Arias Perez, Primitiva Menéndez, Anna González-Neira, Guillermo Pita, M Rosario Alonso, Nuria Alvarez, Daniel Herrero, Hoda Anton-Culver, Hermann Brenner, Aida Karina Dieffenbach, Volker Arndt, Christa Stegmaier, Alfons Meindl, Peter Lichtner, Rita K Schmutzler, Bertram Müller-Myhsok, Hiltrud Brauch, Thomas Brüning, Yon-Dschun Ko, , Daniel C Tessier, Daniel Vincent, Francois Bacot, Heli Nevanlinna, Kristiina Aittomäki, Carl Blomqvist, Sofia Khan, Keitaro Matsuo, Hidemi Ito, Hiroji Iwata, Akiyo Horio, Natalia V Bogdanova, Natalia N Antonenkova, Thilo Dörk, Annika Lindblom, Sara Margolin, Arto Mannermaa, Vesa Kataja, Veli-Matti Kosma, Jaana M Hartikainen, Anna H Wu, Chiu-Chen Tseng, David Van Den Berg, Daniel O Stram, Patrick Neven, Els Wauters, Hans Wildiers, Diether Lambrechts, Jenny Chang-Claude, Anja Rudolph, Petra Seibold, Dieter Flesch-Janys, Paolo Radice, Paolo Peterlongo, Siranoush Manoukian, Bernardo Bonanni, Fergus J Couch, Xianshu Wang, Celine Vachon, Kristen Purrington, Graham G Giles, Roger L Milne, Catriona McLean, Christopher A Haiman, Brian E Henderson, Fredrick Schumacher, Loic Le Marchand, Jacques Simard, Mark S Goldberg, France Labrèche, Martine Dumont, Soo Hwang Teo, Cheng Har Yip, Norhashimah Hassan, Eranga Nishanthie Vithana, Vessela Kristensen, Wei Zheng, Sandra Deming-Halverson, Martha J Shrubsole, Jirong Long, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Saila Kauppila, Irene L Andrulis, Julia A Knight, Gord Glendon, Sandrine Tchatchou, Peter Devilee, Robert A E M Tollenaar, Caroline Seynaeve, Christi J van Asperen, Montserrat Garcia-Closas, Jonine Figueroa, Jolanta Lissowska, Louise Brinton, Kamila Czene, Hatef Darabi, Mikael Eriksson, Judith S Brand, Maartje J Hooning, Antoinette Hollestelle, Ans M W van den Ouweland, Agnes Jager, Jingmei Li, Jianjun Liu, Keith Humphreys, Xiao-Ou Shu, Wei Lu, Yu-Tang Gao, Hui Cai, Simon S Cross, Malcolm W R Reed, William Blot, Lisa B Signorello, Qiuyin Cai, Paul D P Pharoah, Barbara Perkins, Mitul Shah, Fiona M Blows, Daehee Kang, Keun-Young Yoo, Dong-Young Noh, Mikael Hartman, Hui Miao, Kee Seng Chia, Thomas Choudary Putti, Ute Hamann, Craig Luccarini, Caroline Baynes, Shahana Ahmed, Mel Maranian, Catherine S Healey, Anna Jakubowska, Jan Lubiński, Katarzyna Jaworska-Bieniek, Katarzyna Durda, Suleeporn Sangrajrang, Valerie Gaborieau, Paul Brennan, James McKay, Susan Slager, Amanda E Toland, Drakoulis Yannoukakos, Chen-Yang Shen, Chia-Ni Hsiung, Pei-Ei Wu, Shian-Ling Ding, Alan Ashworth, Michael Jones, Nick Orr, Anthony J Swerdlow, Helen Tsimiklis, Enes Makalic, Daniel F Schmidt, Quang M Bui, Stephen J Chanock, David J Hunter, Rebecca Hein, Norbert Dahmen, Lars Beckmann, Kirsimari Aaltonen, Taru A Muranen, Tuomas Heikkinen, Astrid Irwanto, Nazneen Rahman, Clare A Turnbull, Quinten Waisfisz, Hanne E J Meijers-Heijboer, Muriel A Adank, Rob B van der Luijt, Per Hall, Georgia Chenevix-Trench, Alison Dunning, Douglas F Easton, Angela Cox.
Hum. Mol. Genet.
PUBLISHED: 08-28-2014
Show Abstract
Hide Abstract
Previous studies have suggested that polymorphisms in CASP8 on chromosome 2 are associated with breast cancer risk. To clarify the role of CASP8 in breast cancer susceptibility, we carried out dense genotyping of this region in the Breast Cancer Association Consortium (BCAC). Single-nucleotide polymorphisms (SNPs) spanning a 1 Mb region around CASP8 were genotyped in 46 450 breast cancer cases and 42 600 controls of European origin from 41 studies participating in the BCAC as part of a custom genotyping array experiment (iCOGS). Missing genotypes and SNPs were imputed and, after quality exclusions, 501 typed and 1232 imputed SNPs were included in logistic regression models adjusting for study and ancestry principal components. The SNPs retained in the final model were investigated further in data from nine genome-wide association studies (GWAS) comprising in total 10 052 case and 12 575 control subjects. The most significant association signal observed in European subjects was for the imputed intronic SNP rs1830298 in ALS2CR12 (telomeric to CASP8), with per allele odds ratio and 95% confidence interval [OR (95% confidence interval, CI)] for the minor allele of 1.05 (1.03-1.07), P = 1 × 10(-5). Three additional independent signals from intronic SNPs were identified, in CASP8 (rs36043647), ALS2CR11 (rs59278883) and CFLAR (rs7558475). The association with rs1830298 was replicated in the imputed results from the combined GWAS (P = 3 × 10(-6)), yielding a combined OR (95% CI) of 1.06 (1.04-1.08), P = 1 × 10(-9). Analyses of gene expression associations in peripheral blood and normal breast tissue indicate that CASP8 might be the target gene, suggesting a mechanism involving apoptosis.
Related JoVE Video
First steps in exploring prospective exome sequencing of consanguineous couples.
Eur J Med Genet
PUBLISHED: 06-19-2014
Show Abstract
Hide Abstract
Consanguinity is one of the most frequent risk factors for congenital disorders. In theory, prospective exome sequencing of consanguineous couples could identify couples who both are carriers of autosomal recessive diseases, and empower such couples to make informed reproductive decisions. To investigate this, we sent blood samples to our laboratory of four pairs of consanguineous parents having one or more children affected by an autosomal recessive disorder, without revealing any diagnostic information. The study was restricted to find identical, previously described, or evidently pathogenic mutations in both parents of each couple, in over 400 genes known to result in severe autosomal recessive disorders. Out of the six autosomal recessive disorders known to the four couples studied, two were correctly identified. Carrier status of one not previously known autosomal recessive disorder was discovered. As expected, given the pipeline used, large deletions, mutations in genes not present in the gene list, mutations outside the exons and consensus splice sites, and mutations that were not evidently pathogenic and previously not reported, were not identified. The restriction to detecting only couples with identical mutations diminishes the risk of revealing unsolicited findings and shortens the time needed for analysis, but also results in missing couples with different mutations in the same gene. In addition to the proposed pipeline, couples should be offered testing for carrier status of frequent disorders that can present themselves by large deletions, non-exonic mutations or compound heterozygous mutations (e.g. thalassemia, spinal muscular atrophy, cystic fibrosis). Even though sensitivity is reduced, offering exome sequencing prospectively will increase reproductive options for consanguineous couples.
Related JoVE Video
Hypomyelination with atrophy of the basal ganglia and cerebellum: further delineation of the phenotype and genotype-phenotype correlation.
Brain
PUBLISHED: 04-30-2014
Show Abstract
Hide Abstract
Hypomyelination with atrophy of the basal ganglia and cerebellum is a rare leukoencephalopathy that was identified using magnetic resonance imaging in 2002. In 2013, whole exome sequencing of 11 patients with the disease revealed that they all had the same de novo mutation in TUBB4A, which encodes tubulin ?-4A. We investigated the mutation spectrum in a cohort of 42 patients and the relationship between genotype and phenotype. Patients were selected on the basis of clinical and magnetic resonance imaging abnormalities that are indicative of hypomyelination with atrophy of the basal ganglia and cerebellum. Genetic testing and a clinical inventory were performed, and sequential magnetic resonance images were evaluated using a standard protocol. The heterozygous TUBB4A mutation observed in the first 11 patients was the most common (25 patients). Additionally, 13 other heterozygous mutations were identified, located in different structural domains of tubulin ?-4A. We confirmed that the mutations were de novo in all but three patients. In two of these three cases we lacked parental DNA and in one the mutation was also found in the mother, most likely due to mosaicism. Patients showed a phenotypic continuum ranging from neonatal to childhood disease onset, normal to delayed early development and slow to more rapid neurological deterioration. Neurological symptomatology consisted of extrapyramidal movement abnormalities, spasticity, ataxia, cognitive deficit and sometimes epilepsy. Three patients died and the oldest living patient was 29 years of age. The patients' magnetic resonance images showed an absent or disappearing putamen, variable cerebellar atrophy and highly variable cerebral atrophy. Apart from hypomyelination, myelin loss was evident in several cases. Three severely affected patients had similar, somewhat atypical magnetic resonance image abnormalities. The study results were strongly suggestive of a genotype-phenotype correlation. The 25 patients with the common c.745G>A mutation generally had a less rapidly progressive disease course than the 17 cases with other TUBB4A mutations. Overall, this work demonstrates that the distinctive magnetic resonance imaging pattern for hypomyelination with atrophy of the basal ganglia and cerebellum defines a homogeneous clinical phenotype of variable severity. Patients almost invariably have prominent extrapyramidal movement abnormalities, which are rarely seen in patients with hypomyelination of different origin. A dominant TUBB4A mutation is also associated with dystonia type 4, in which magnetic resonance images of the brain seem normal. It is highly likely that there is a disease continuum associated with TUBB4A mutations, of which hypomyelination with atrophy of the basal ganglia and cerebellum and dystonia type 4 are the extremes. This would indicate that extrapyramidal movement abnormalities constitute the core feature of the disease spectrum related to dominant TUBB4A mutations and that all other features are variable.
Related JoVE Video
Mutations in RARS cause hypomyelination.
Ann. Neurol.
PUBLISHED: 02-18-2014
Show Abstract
Hide Abstract
Hypomyelinating disorders of the central nervous system are still a diagnostic challenge, as many patients remain without genetic diagnosis. Using magnetic resonance imaging (MRI) pattern recognition and whole exome sequencing, we could ascertain compound heterozygous mutations in RARS in 4 patients with hypomyelination. Clinical features included severe spasticity and nystagmus. RARS encodes the cytoplasmic arginyl-tRNA synthetase, an enzyme essential for RNA translation. This protein is among the subunits of the multisynthetase complex, which emerges as a key player in myelination.
Related JoVE Video
A novel splice site mutation in the noncoding region of BRCA2: implications for Fanconi anemia and familial breast cancer diagnostics.
Hum. Mutat.
PUBLISHED: 02-15-2014
Show Abstract
Hide Abstract
Fanconi anemia (FA) is a rare recessive disorder with chromosomal instability, congenital abnormalities, and a high cancer risk. The breast cancer susceptibility gene BRCA2 (FANCD1) is one of the 16 genes involved in this recessive disease. We have identified a novel mutation of the splice donor site of intron 1 in the noncoding region of BRCA2 in a Japanese FA family. This mutation may account for the FA phenotype in a patient originally reported to have biallelic mutations in BRCA2. Subsequent functional studies revealed that one of the mutations, K2729N, was a neutral change. As reported here, a more careful analysis resulted in the identification of a novel splice site mutation. Functional analysis using a mouse embryonic stem cell-based assay revealed that it causes aberrant splicing, reduced transcript levels and hypersensitivity to DNA damaging agents, suggesting that it is likely to be pathogenic. Although similar pathogenic variants in the noncoding region of BRCA1 and 2 were not identified in a cohort of 752 familial breast cancer cases, we still think this finding is relevant for mutation analysis in Hereditary Breast and Ovarian Cancer Syndrome families in a diagnostic setting.
Related JoVE Video
A genome-wide association study of early-onset breast cancer identifies PFKM as a novel breast cancer gene and supports a common genetic spectrum for breast cancer at any age.
Cancer Epidemiol. Biomarkers Prev.
PUBLISHED: 02-03-2014
Show Abstract
Hide Abstract
Early-onset breast cancer (EOBC) causes substantial loss of life and productivity, creating a major burden among women worldwide. We analyzed 1,265,548 Hapmap3 single-nucleotide polymorphisms (SNP) among a discovery set of 3,523 EOBC incident cases and 2,702 population control women ages ? 51 years. The SNPs with smallest P values were examined in a replication set of 3,470 EOBC cases and 5,475 control women. We also tested EOBC association with 19,684 genes by annotating each gene with putative functional SNPs, and then combining their P values to obtain a gene-based P value. We examined the gene with smallest P value for replication in 1,145 breast cancer cases and 1,142 control women. The combined discovery and replication sets identified 72 new SNPs associated with EOBC (P < 4 × 10(-8)) located in six genomic regions previously reported to contain SNPs associated largely with later-onset breast cancer (LOBC). SNP rs2229882 and 10 other SNPs on chromosome 5q11.2 remained associated (P < 6 × 10(-4)) after adjustment for the strongest published SNPs in the region. Thirty-two of the 82 currently known LOBC SNPs were associated with EOBC (P < 0.05). Low power is likely responsible for the remaining 50 unassociated known LOBC SNPs. The gene-based analysis identified an association between breast cancer and the phosphofructokinase-muscle (PFKM) gene on chromosome 12q13.11 that met the genome-wide gene-based threshold of 2.5 × 10(-6). In conclusion, EOBC and LOBC seem to have similar genetic etiologies; the 5q11.2 region may contain multiple distinct breast cancer loci; and the PFKM gene region is worthy of further investigation. These findings should enhance our understanding of the etiology of breast cancer.
Related JoVE Video
MicroRNA Related Polymorphisms and Breast Cancer Risk.
Sofia Khan, Dario Greco, Kyriaki Michailidou, Roger L Milne, Taru A Muranen, Tuomas Heikkinen, Kirsimari Aaltonen, Joe Dennis, Manjeet K Bolla, Jianjun Liu, Per Hall, Astrid Irwanto, Keith Humphreys, Jingmei Li, Kamila Czene, Jenny Chang-Claude, Rebecca Hein, Anja Rudolph, Petra Seibold, Dieter Flesch-Janys, Olivia Fletcher, Julian Peto, Isabel Dos Santos Silva, Nichola Johnson, Lorna Gibson, Zoe Aitken, John L Hopper, Helen Tsimiklis, Minh Bui, Enes Makalic, Daniel F Schmidt, Melissa C Southey, Carmel Apicella, Jennifer Stone, Quinten Waisfisz, Hanne Meijers-Heijboer, Muriel A Adank, Rob B van der Luijt, Alfons Meindl, Rita K Schmutzler, Bertram Müller-Myhsok, Peter Lichtner, Clare Turnbull, Nazneen Rahman, Stephen J Chanock, David J Hunter, Angela Cox, Simon S Cross, Malcolm W R Reed, Marjanka K Schmidt, Annegien Broeks, Laura J V A N't Veer, Frans B Hogervorst, Peter A Fasching, Michael G Schrauder, Arif B Ekici, Matthias W Beckmann, Stig E Bojesen, Børge G Nordestgaard, Sune F Nielsen, Henrik Flyger, Javier Benitez, Pilar M Zamora, Jose I A Perez, Christopher A Haiman, Brian E Henderson, Fredrick Schumacher, Loic Le Marchand, Paul D P Pharoah, Alison M Dunning, Mitul Shah, Robert Luben, Judith Brown, Fergus J Couch, Xianshu Wang, Celine Vachon, Janet E Olson, Diether Lambrechts, Matthieu Moisse, Robert Paridaens, Marie-Rose Christiaens, Pascal Guénel, Thérèse Truong, Pierre Laurent-Puig, Claire Mulot, Frederick Marme, Barbara Burwinkel, Andreas Schneeweiss, Christof Sohn, Elinor J Sawyer, Ian Tomlinson, Michael J Kerin, Nicola Miller, Irene L Andrulis, Julia A Knight, Sandrine Tchatchou, Anna Marie Mulligan, Thilo Dörk, Natalia V Bogdanova, Natalia N Antonenkova, Hoda Anton-Culver, Hatef Darabi, Mikael Eriksson, Montserrat Garcia-Closas, Jonine Figueroa, Jolanta Lissowska, Louise Brinton, Peter Devilee, Robert A E M Tollenaar, Caroline Seynaeve, Christi J van Asperen, Vessela N Kristensen, , Susan Slager, Amanda E Toland, Christine B Ambrosone, Drakoulis Yannoukakos, Annika Lindblom, Sara Margolin, Paolo Radice, Paolo Peterlongo, Monica Barile, Paolo Mariani, Maartje J Hooning, John W M Martens, J Margriet Collée, Agnes Jager, Anna Jakubowska, Jan Lubiński, Katarzyna Jaworska-Bieniek, Katarzyna Durda, Graham G Giles, Catriona McLean, Hiltrud Brauch, Thomas Brüning, Yon-Dschun Ko, Hermann Brenner, Aida Karina Dieffenbach, Volker Arndt, Christa Stegmaier, Anthony Swerdlow, Alan Ashworth, Nick Orr, Michael Jones, Jacques Simard, Mark S Goldberg, France Labrèche, Martine Dumont, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Mervi Grip, Vesa Kataja, Veli-Matti Kosma, Jaana M Hartikainen, Arto Mannermaa, Ute Hamann, Georgia Chenevix-Trench, Carl Blomqvist, Kristiina Aittomäki, Douglas F Easton, Heli Nevanlinna.
PLoS ONE
PUBLISHED: 01-01-2014
Show Abstract
Hide Abstract
Genetic variations, such as single nucleotide polymorphisms (SNPs) in microRNAs (miRNA) or in the miRNA binding sites may affect the miRNA dependent gene expression regulation, which has been implicated in various cancers, including breast cancer, and may alter individual susceptibility to cancer. We investigated associations between miRNA related SNPs and breast cancer risk. First we evaluated 2,196 SNPs in a case-control study combining nine genome wide association studies (GWAS). Second, we further investigated 42 SNPs with suggestive evidence for association using 41,785 cases and 41,880 controls from 41 studies included in the Breast Cancer Association Consortium (BCAC). Combining the GWAS and BCAC data within a meta-analysis, we estimated main effects on breast cancer risk as well as risks for estrogen receptor (ER) and age defined subgroups. Five miRNA binding site SNPs associated significantly with breast cancer risk: rs1045494 (odds ratio (OR) 0.92; 95% confidence interval (CI): 0.88-0.96), rs1052532 (OR 0.97; 95% CI: 0.95-0.99), rs10719 (OR 0.97; 95% CI: 0.94-0.99), rs4687554 (OR 0.97; 95% CI: 0.95-0.99, and rs3134615 (OR 1.03; 95% CI: 1.01-1.05) located in the 3' UTR of CASP8, HDDC3, DROSHA, MUSTN1, and MYCL1, respectively. DROSHA belongs to miRNA machinery genes and has a central role in initial miRNA processing. The remaining genes are involved in different molecular functions, including apoptosis and gene expression regulation. Further studies are warranted to elucidate whether the miRNA binding site SNPs are the causative variants for the observed risk effects.
Related JoVE Video
PLS3 mutations in X-linked osteoporosis with fractures.
N. Engl. J. Med.
PUBLISHED: 10-02-2013
Show Abstract
Hide Abstract
Plastin 3 (PLS3), a protein involved in the formation of filamentous actin (F-actin) bundles, appears to be important in human bone health, on the basis of pathogenic variants in PLS3 in five families with X-linked osteoporosis and osteoporotic fractures that we report here. The bone-regulatory properties of PLS3 were supported by in vivo analyses in zebrafish. Furthermore, in an additional five families (described in less detail) referred for diagnosis or ruling out of osteogenesis imperfecta type I, a rare variant (rs140121121) in PLS3 was found. This variant was also associated with a risk of fracture among elderly heterozygous women that was two times as high as that among noncarriers, which indicates that genetic variation in PLS3 is a novel etiologic factor involved in common, multi-factorial osteoporosis.
Related JoVE Video
A de novo FLCN mutation in a patient with spontaneous pneumothorax and renal cancer; a clinical and molecular evaluation.
Fam. Cancer
PUBLISHED: 09-18-2013
Show Abstract
Hide Abstract
Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant condition due to germline FLCN (folliculin) mutations, characterized by skin fibrofolliculomas, lung cysts, pneumothorax and renal cancer. We identified a de novo FLCN mutation, c.499C>T (p.Gln167X), in a patient who presented with spontaneous pneumothorax. Subsequently, typical skin features and asymptomatic renal cancer were diagnosed. Probably, de novo FLCN mutations are rare. However, they may be under-diagnosed if BHD is not considered in sporadic patients who present with one or more of the syndromic features. Genetic and immunohistochemical analysis of the renal tumour indicated features compatible with a tumour suppressor role of FLCN. The finding that mutant FLCN was expressed in the tumour might indicate residual functionality of mutant FLCN, a notion which will be explored in future studies.
Related JoVE Video
Best practice guidelines for the use of next-generation sequencing applications in genome diagnostics: a national collaborative study of dutch genome diagnostic laboratories.
Hum. Mutat.
PUBLISHED: 03-30-2013
Show Abstract
Hide Abstract
Next-generation sequencing (NGS) methods are being adopted by genome diagnostics laboratories worldwide. However, implementing NGS-based tests according to diagnostic standards is a challenge for individual laboratories. To facilitate the implementation of NGS in Dutch laboratories, the Dutch Society for Clinical Genetic Laboratory Diagnostics (VKGL) set up a working group in 2012. The results of their discussions are presented here. We provide best practice guidelines and criteria for implementing and validating NGS applications in a clinical setting. We introduce the concept of "diagnostic yield" as the main performance characteristic for evaluating diagnostic tests. We recommend that the laboratory procedures, including the tested genes, should be recorded in a publicly available document describing the complete "diagnostic routing." We also propose that laboratories should use a list of "core disease genes" for specific genetic diseases. This core list contains the essential genes for each disease, and they should all be included in a diagnostic test to establish a reliable and accurate molecular diagnosis. The guidelines will ensure a clear and standardized quality of care provided by genetic diagnostic laboratories. The best practice guidelines and criteria that are presented here were adopted by the VKGL in January 2013.
Related JoVE Video
Inactivating Mutations in GT198 in Familial and Early-Onset Breast and Ovarian Cancers.
Genes Cancer
PUBLISHED: 03-16-2013
Show Abstract
Hide Abstract
The human GT198 gene (gene symbol PSMC3IP) is located at chromosome 17q21, 470 kb proximal to BRCA1, a locus previously linked to breast and ovarian cancer predisposition. Its protein product (also known as TBPIP and Hop2) has been shown to regulate steroid hormone receptor-mediated gene activation and to stimulate homologous recombination in DNA repair. Here, we screened germline mutations in GT198 in familial and early-onset breast and ovarian cancer patients. We have identified 8 germline variants in a total of 212 index patients including reoccurring nonsense mutation c.310C>T (p.Q104X) and 5 UTR mutation c.-37A>T, each found in 2 unrelated families. Most identified index patients from cancer families had early onsets with a median age of 35 years. c.310C>T was absent in a total of 564 control individuals analyzed. GT198 gene amplification with an imbalanced mutant copy gain was identified in the blood DNA of one of the patients carrying c.310C>T. When tested, this truncating mutation abolished DNA damage-induced Rad51 foci formation. In addition, we have identified 15 somatic mutations in 2 tumors from 1 patient carrying germline mutation c.-37A>T. The presence of a somatic mutation on the wild-type allele showed that GT198 was biallelically mutated in the tumor. The somatic mutations identified near a splicing junction site caused defective alternative splicing and truncated the open reading frame. Therefore, distinct mutations may cause a similar consequence by truncating the full-length protein and inducing a loss of the wild type. Our study provides the first evidence of the presence of inactivating mutations in GT198 in familial and early-onset breast and ovarian cancer patients. Mutations in GT198, a gene regulating DNA repair, potentially contribute to an increased risk in familial breast and ovarian cancers.
Related JoVE Video
Exome sequencing reveals mutated SLC19A3 in patients with an early-infantile, lethal encephalopathy.
Brain
PUBLISHED: 03-12-2013
Show Abstract
Hide Abstract
To accomplish a diagnosis in patients with a rare unclassified disorder is difficult. In this study, we used magnetic resonance imaging pattern recognition analysis to identify patients with the same novel heritable disorder. Whole-exome sequencing was performed to discover the mutated gene. We identified seven patients sharing a previously undescribed magnetic resonance imaging pattern, characterized by initial swelling with T2 hyperintensity of the basal nuclei, thalami, cerebral white matter and cortex, pons and midbrain, followed by rarefaction or cystic degeneration of the white matter and, eventually, by progressive cerebral, cerebellar and brainstem atrophy. All patients developed a severe encephalopathy with rapid deterioration of neurological functions a few weeks after birth, followed by respiratory failure and death. Lactate was elevated in body fluids and on magnetic resonance spectroscopy in most patients. Whole-exome sequencing in a single patient revealed two predicted pathogenic, heterozygous missense mutations in the SLC19A3 gene, encoding the second thiamine transporter. Additional predicted pathogenic mutations and deletions were detected by Sanger sequencing in all six other patients. Pathology of brain tissue of two patients demonstrated severe cerebral atrophy and microscopic brain lesions similar to Leighs syndrome. Although the localization of SLC19A3 expression in brain was similar in the two investigated patients compared to age-matched control subjects, the intensity of the immunoreactivity was increased. Previously published patients with SLC19A3 mutations have a milder clinical phenotype, no laboratory evidence of mitochondrial dysfunction and more limited lesions on magnetic resonance imaging. In some, cerebral atrophy has been reported. The identification of this new, severe, lethal phenotype characterized by subtotal brain degeneration broadens the phenotypic spectrum of SLC19A3 mutations. Recognition of the associated magnetic resonance imaging pattern allows a fast diagnosis in affected infants.
Related JoVE Video
Large-scale genotyping identifies 41 new loci associated with breast cancer risk.
Kyriaki Michailidou, Per Hall, Anna González-Neira, Maya Ghoussaini, Joe Dennis, Roger L Milne, Marjanka K Schmidt, Jenny Chang-Claude, Stig E Bojesen, Manjeet K Bolla, Qin Wang, Ed Dicks, Andrew Lee, Clare Turnbull, Nazneen Rahman, , Olivia Fletcher, Julian Peto, Lorna Gibson, Isabel Dos Santos Silva, Heli Nevanlinna, Taru A Muranen, Kristiina Aittomäki, Carl Blomqvist, Kamila Czene, Astrid Irwanto, Jianjun Liu, Quinten Waisfisz, Hanne Meijers-Heijboer, Muriel Adank, Rob B van der Luijt, Rebecca Hein, Norbert Dahmen, Lars Beckman, Alfons Meindl, Rita K Schmutzler, Bertram Müller-Myhsok, Peter Lichtner, John L Hopper, Melissa C Southey, Enes Makalic, Daniel F Schmidt, André G Uitterlinden, Albert Hofman, David J Hunter, Stephen J Chanock, Daniel Vincent, Francois Bacot, Daniel C Tessier, Sander Canisius, Lodewyk F A Wessels, Christopher A Haiman, Mitul Shah, Robert Luben, Judith Brown, Craig Luccarini, Nils Schoof, Keith Humphreys, Jingmei Li, Børge G Nordestgaard, Sune F Nielsen, Henrik Flyger, Fergus J Couch, Xianshu Wang, Celine Vachon, Kristen N Stevens, Diether Lambrechts, Matthieu Moisse, Robert Paridaens, Marie-Rose Christiaens, Anja Rudolph, Stefan Nickels, Dieter Flesch-Janys, Nichola Johnson, Zoe Aitken, Kirsimari Aaltonen, Tuomas Heikkinen, Annegien Broeks, Laura J Van't Veer, C Ellen van der Schoot, Pascal Guénel, Thérèse Truong, Pierre Laurent-Puig, Florence Menegaux, Frederik Marme, Andreas Schneeweiss, Christof Sohn, Barbara Burwinkel, M Pilar Zamora, Jose Ignacio Arias Perez, Guillermo Pita, M Rosario Alonso, Angela Cox, Ian W Brock, Simon S Cross, Malcolm W R Reed, Elinor J Sawyer, Ian Tomlinson, Michael J Kerin, Nicola Miller, Brian E Henderson, Fredrick Schumacher, Loic Le Marchand, Irene L Andrulis, Julia A Knight, Gord Glendon, Anna Marie Mulligan, Annika Lindblom, Sara Margolin, Maartje J Hooning, Antoinette Hollestelle, Ans M W van den Ouweland, Agnes Jager, Quang M Bui, Jennifer Stone, Gillian S Dite, Carmel Apicella, Helen Tsimiklis, Graham G Giles, Gianluca Severi, Laura Baglietto, Peter A Fasching, Lothar Haeberle, Arif B Ekici, Matthias W Beckmann, Hermann Brenner, Heiko Muller, Volker Arndt, Christa Stegmaier, Anthony Swerdlow, Alan Ashworth, Nick Orr, Michael Jones, Jonine Figueroa, Jolanta Lissowska, Louise Brinton, Mark S Goldberg, France Labrèche, Martine Dumont, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Mervi Grip, Hiltrud Brauch, Ute Hamann, Thomas Brüning, Paolo Radice, Paolo Peterlongo, Siranoush Manoukian, Bernardo Bonanni, Peter Devilee, Rob A E M Tollenaar, Caroline Seynaeve, Christi J van Asperen, Anna Jakubowska, Jan Lubiński, Katarzyna Jaworska, Katarzyna Durda, Arto Mannermaa, Vesa Kataja, Veli-Matti Kosma, Jaana M Hartikainen, Natalia V Bogdanova, Natalia N Antonenkova, Thilo Dörk, Vessela N Kristensen, Hoda Anton-Culver, Susan Slager, Amanda E Toland, Stephen Edge, Florentia Fostira, Daehee Kang, Keun-Young Yoo, Dong-Young Noh, Keitaro Matsuo, Hidemi Ito, Hiroji Iwata, Aiko Sueta, Anna H Wu, Chiu-Chen Tseng, David Van Den Berg, Daniel O Stram, Xiao-Ou Shu, Wei Lu, Yu-Tang Gao, Hui Cai, Soo Hwang Teo, Cheng Har Yip, Sze Yee Phuah, Belinda K Cornes, Mikael Hartman, Hui Miao, Wei Yen Lim, Jen-Hwei Sng, Kenneth Muir, Artitaya Lophatananon, Sarah Stewart-Brown, Pornthep Siriwanarangsan, Chen-Yang Shen, Chia-Ni Hsiung, Pei-Ei Wu, Shian-Ling Ding, Suleeporn Sangrajrang, Valerie Gaborieau, Paul Brennan, James McKay, William J Blot, Lisa B Signorello, Qiuyin Cai, Wei Zheng, Sandra Deming-Halverson, Martha Shrubsole, Jirong Long, Jacques Simard, Montse Garcia-Closas, Paul D P Pharoah, Georgia Chenevix-Trench, Alison M Dunning, Javier Benitez, Douglas F Easton.
Nat. Genet.
PUBLISHED: 01-30-2013
Show Abstract
Hide Abstract
Breast cancer is the most common cancer among women. Common variants at 27 loci have been identified as associated with susceptibility to breast cancer, and these account for ?9% of the familial risk of the disease. We report here a meta-analysis of 9 genome-wide association studies, including 10,052 breast cancer cases and 12,575 controls of European ancestry, from which we selected 29,807 SNPs for further genotyping. These SNPs were genotyped in 45,290 cases and 41,880 controls of European ancestry from 41 studies in the Breast Cancer Association Consortium (BCAC). The SNPs were genotyped as part of a collaborative genotyping experiment involving four consortia (Collaborative Oncological Gene-environment Study, COGS) and used a custom Illumina iSelect genotyping array, iCOGS, comprising more than 200,000 SNPs. We identified SNPs at 41 new breast cancer susceptibility loci at genome-wide significance (P < 5 × 10(-8)). Further analyses suggest that more than 1,000 additional loci are involved in breast cancer susceptibility.
Related JoVE Video
Genome-wide association studies identify four ER negative-specific breast cancer risk loci.
Montserrat Garcia-Closas, Fergus J Couch, Sara Lindstrom, Kyriaki Michailidou, Marjanka K Schmidt, Mark N Brook, Nick Orr, Suhn Kyong Rhie, Elio Riboli, Heather S Feigelson, Loic Le Marchand, Julie E Buring, Diana Eccles, Penelope Miron, Peter A Fasching, Hiltrud Brauch, Jenny Chang-Claude, Jane Carpenter, Andrew K Godwin, Heli Nevanlinna, Graham G Giles, Angela Cox, John L Hopper, Manjeet K Bolla, Qin Wang, Joe Dennis, Ed Dicks, Will J Howat, Nils Schoof, Stig E Bojesen, Diether Lambrechts, Annegien Broeks, Irene L Andrulis, Pascal Guénel, Barbara Burwinkel, Elinor J Sawyer, Antoinette Hollestelle, Olivia Fletcher, Robert Winqvist, Hermann Brenner, Arto Mannermaa, Ute Hamann, Alfons Meindl, Annika Lindblom, Wei Zheng, Peter Devillee, Mark S Goldberg, Jan Lubiński, Vessela Kristensen, Anthony Swerdlow, Hoda Anton-Culver, Thilo Dörk, Kenneth Muir, Keitaro Matsuo, Anna H Wu, Paolo Radice, Soo Hwang Teo, Xiao-Ou Shu, William Blot, Daehee Kang, Mikael Hartman, Suleeporn Sangrajrang, Chen-Yang Shen, Melissa C Southey, Daniel J Park, Fleur Hammet, Jennifer Stone, Laura J Van't Veer, Emiel J Rutgers, Artitaya Lophatananon, Sarah Stewart-Brown, Pornthep Siriwanarangsan, Julian Peto, Michael G Schrauder, Arif B Ekici, Matthias W Beckmann, Isabel Dos Santos Silva, Nichola Johnson, Helen Warren, Ian Tomlinson, Michael J Kerin, Nicola Miller, Federick Marme, Andreas Schneeweiss, Christof Sohn, Thérèse Truong, Pierre Laurent-Puig, Pierre Kerbrat, Børge G Nordestgaard, Sune F Nielsen, Henrik Flyger, Roger L Milne, Jose Ignacio Arias Perez, Primitiva Menéndez, Heiko Muller, Volker Arndt, Christa Stegmaier, Peter Lichtner, Magdalena Lochmann, Christina Justenhoven, Yon-Dschun Ko, , Taru A Muranen, Kristiina Aittomäki, Carl Blomqvist, Dario Greco, Tuomas Heikkinen, Hidemi Ito, Hiroji Iwata, Yasushi Yatabe, Natalia N Antonenkova, Sara Margolin, Vesa Kataja, Veli-Matti Kosma, Jaana M Hartikainen, Rosemary Balleine, Chiu-Chen Tseng, David Van Den Berg, Daniel O Stram, Patrick Neven, Anne-Sophie Dieudonné, Karin Leunen, Anja Rudolph, Stefan Nickels, Dieter Flesch-Janys, Paolo Peterlongo, Bernard Peissel, Loris Bernard, Janet E Olson, Xianshu Wang, Kristen Stevens, Gianluca Severi, Laura Baglietto, Catriona McLean, Gerhard A Coetzee, Ye Feng, Brian E Henderson, Fredrick Schumacher, Natalia V Bogdanova, France Labrèche, Martine Dumont, Cheng Har Yip, Nur Aishah Mohd Taib, Ching-Yu Cheng, Martha Shrubsole, Jirong Long, Katri Pylkäs, Arja Jukkola-Vuorinen, Saila Kauppila, Julia A Knight, Gord Glendon, Anna Marie Mulligan, Robertus A E M Tollenaar, Caroline M Seynaeve, Mieke Kriege, Maartje J Hooning, Ans M W van den Ouweland, Carolien H M van Deurzen, Wei Lu, Yu-Tang Gao, Hui Cai, Sabapathy P Balasubramanian, Simon S Cross, Malcolm W R Reed, Lisa Signorello, Qiuyin Cai, Mitul Shah, Hui Miao, Ching Wan Chan, Kee Seng Chia, Anna Jakubowska, Katarzyna Jaworska, Katarzyna Durda, Chia-Ni Hsiung, Pei-Ei Wu, Jyh-Cherng Yu, Alan Ashworth, Michael Jones, Daniel C Tessier, Anna González-Neira, Guillermo Pita, M Rosario Alonso, Daniel Vincent, Francois Bacot, Christine B Ambrosone, Elisa V Bandera, Esther M John, Gary K Chen, Jennifer J Hu, Jorge L Rodriguez-Gil, Leslie Bernstein, Michael F Press, Regina G Ziegler, Robert M Millikan, Sandra L Deming-Halverson, Sarah Nyante, Sue A Ingles, Quinten Waisfisz, Helen Tsimiklis, Enes Makalic, Daniel Schmidt, Minh Bui, Lorna Gibson, Bertram Müller-Myhsok, Rita K Schmutzler, Rebecca Hein, Norbert Dahmen, Lars Beckmann, Kirsimari Aaltonen, Kamila Czene, Astrid Irwanto, Jianjun Liu, Clare Turnbull, Nazneen Rahman, Hanne Meijers-Heijboer, André G Uitterlinden, Fernando Rivadeneira, Curtis Olswold, Susan Slager, Robert Pilarski, Foluso Ademuyiwa, Irene Konstantopoulou, Nicholas G Martin, Grant W Montgomery, Dennis J Slamon, Claudia Rauh, Michael P Lux, Sebastian M Jud, Thomas Brüning, Joellen Weaver, Priyanka Sharma, Harsh Pathak, Will Tapper, Sue Gerty, Lorraine Durcan, Dimitrios Trichopoulos, Rosario Tumino, Petra H Peeters, Rudolf Kaaks, Daniele Campa, Federico Canzian, Elisabete Weiderpass, Mattias Johansson, Kay-Tee Khaw, Ruth Travis, Francoise Clavel-Chapelon, Laurence N Kolonel, Constance Chen, Andy Beck, Susan E Hankinson, Christine D Berg, Robert N Hoover, Jolanta Lissowska, Jonine D Figueroa, Daniel I Chasman, Mia M Gaudet, W Ryan Diver, Walter C Willett, David J Hunter, Jacques Simard, Javier Benitez, Alison M Dunning, Mark E Sherman, Georgia Chenevix-Trench, Stephen J Chanock, Per Hall, Paul D P Pharoah, Celine Vachon, Douglas F Easton, Christopher A Haiman, Peter Kraft.
Nat. Genet.
PUBLISHED: 01-29-2013
Show Abstract
Hide Abstract
Estrogen receptor (ER)-negative tumors represent 20-30% of all breast cancers, with a higher proportion occurring in younger women and women of African ancestry. The etiology and clinical behavior of ER-negative tumors are different from those of tumors expressing ER (ER positive), including differences in genetic predisposition. To identify susceptibility loci specific to ER-negative disease, we combined in a meta-analysis 3 genome-wide association studies of 4,193 ER-negative breast cancer cases and 35,194 controls with a series of 40 follow-up studies (6,514 cases and 41,455 controls), genotyped using a custom Illumina array, iCOGS, developed by the Collaborative Oncological Gene-environment Study (COGS). SNPs at four loci, 1q32.1 (MDM4, P = 2.1 × 10(-12) and LGR6, P = 1.4 × 10(-8)), 2p24.1 (P = 4.6 × 10(-8)) and 16q12.2 (FTO, P = 4.0 × 10(-8)), were associated with ER-negative but not ER-positive breast cancer (P > 0.05). These findings provide further evidence for distinct etiological pathways associated with invasive ER-positive and ER-negative breast cancers.
Related JoVE Video
Excess breast cancer risk in first degree relatives of CHEK2?1100delC positive familial breast cancer cases.
Eur. J. Cancer
PUBLISHED: 01-14-2013
Show Abstract
Hide Abstract
The CHEK2?1100delC mutation confers a relative risk of two for breast cancer (BC) in the general population. This study aims to explore the excess cancer risk due to the CHEK2?1100delC mutation within a familial non-BRCA1/2 breast cancer setting.
Related JoVE Video
Reflecting on earlier experiences with unsolicited findings: points to consider for next-generation sequencing and informed consent in diagnostics.
Hum. Mutat.
PUBLISHED: 01-07-2013
Show Abstract
Hide Abstract
High-throughput nucleotide sequencing (often referred to as next-generation sequencing; NGS) is increasingly being chosen as a diagnostic tool for cases of expected but unresolved genetic origin. When exploring a higher number of genetic variants, there is a higher chance of detecting unsolicited findings. The consequential increased need for decisions on disclosure of these unsolicited findings poses a challenge for the informed consent procedure. This article discusses the ethical and practical dilemmas encountered when contemplating informed consent for NGS in diagnostics from a multidisciplinary point of view. By exploring recent similar experiences with unsolicited findings in other settings, an attempt is made to describe what can be learned so far for implementing NGS in standard genetic diagnostics. The article concludes with a set of points to consider in order to guide decision-making on the extent of return of results in relation to the mode of informed consent. We hereby aim to provide a sound basis for developing guidelines for optimizing the informed consent procedure.
Related JoVE Video
Routine testing for PALB2 mutations in familial pancreatic cancer families and breast cancer families with pancreatic cancer is not indicated.
Eur. J. Hum. Genet.
PUBLISHED: 12-14-2011
Show Abstract
Hide Abstract
PALB2-mutation carriers not only have an increased risk for breast cancer (BC) but also for pancreatic cancer (PC). Thus far, PALB2 mutations have been mainly found in PC patients from families affected by both PC and BC. As it is well known that the prevalence of gene mutations varies between different populations, we studied the prevalence of PALB2 mutations in a Dutch cohort of non-BRCA1/2 familial PC (FPC) families and in non-BRCA1/2 familial BC (FBC) families with at least one PC case. Mutation analysis included direct sequencing and multiplex ligation-dependent probe amplification (MLPA) and was performed in a total of 64 patients from 56 distinct families (28 FPC families, 28 FBC families). In total, 31 patients (48%) originated from FPC families; 24 were FPC patients (77%), 6 had a personal history of BC (19%) and 1 was a suspected carrier (3.2%). The remaining 33 patients (52%) were all female BC patients of whom 31 (94%) had a family history of PC and 2 (6.1%) had a personal history of PC. In none of these 64 patients a PALB2 mutation was found. Therefore, PALB2 does not have a major causal role in familial clustering of PC and BC in non-BRCA1/2 families in the Dutch population.
Related JoVE Video
CHEK2*1100delC homozygosity is associated with a high breast cancer risk in women.
J. Med. Genet.
PUBLISHED: 11-05-2011
Show Abstract
Hide Abstract
Mutations in the CHEK2 gene confer a moderately increased breast cancer risk. The risk for female carriers of the CHEK2*1100delC mutation is twofold increased. Breast cancer risk for carrier women is higher in a familial breast cancer setting which is due to coinheritance of additional genetic risk factors. This study investigated the occurrence of homozygosity for the CHEK2*1100delC allele among familial breast cancer cases and the associated breast cancer risk.
Related JoVE Video
Familial multiple discoid fibromas: a look-alike of Birt-Hogg-Dubé syndrome not linked to the FLCN locus.
J. Am. Acad. Dermatol.
PUBLISHED: 07-26-2011
Show Abstract
Hide Abstract
Previously, we proposed that familial multiple trichodiscomas (OMIM 190340) is distinct from Birt-Hogg-Dubé syndrome (BHD) (OMIM #135150). BHD is characterized by multiple fibrofolliculomas/trichodiscomas, lung cysts, pneumothorax, and renal cell cancer. Germline FLCN mutations can be detected in most but not all BHD families.
Related JoVE Video
Interplay between BRCA1 and RHAMM regulates epithelial apicobasal polarization and may influence risk of breast cancer.
Christopher A Maxwell, Javier Benitez, Laia Gómez-Baldó, Ana Osorio, Núria Bonifaci, Ricardo Fernandez-Ramires, Sylvain V Costes, Elisabet Guinó, Helen Chen, Gareth J R Evans, Pooja Mohan, Isabel Català, Anna Petit, Helena Aguilar, Alberto Villanueva, Alvaro Aytes, Jordi Serra-Musach, Gad Rennert, Flavio Lejbkowicz, Paolo Peterlongo, Siranoush Manoukian, Bernard Peissel, Carla B Ripamonti, Bernardo Bonanni, Alessandra Viel, Anna Allavena, Loris Bernard, Paolo Radice, Eitan Friedman, Bella Kaufman, Yael Laitman, Maya Dubrovsky, Roni Milgrom, Anna Jakubowska, Cezary Cybulski, Bohdan Górski, Katarzyna Jaworska, Katarzyna Durda, Grzegorz Sukiennicki, Jan Lubiński, Yin Yao Shugart, Susan M Domchek, Richard Letrero, Barbara L Weber, Frans B L Hogervorst, Matti A Rookus, J Margriet Collée, Peter Devilee, Marjolijn J Ligtenberg, Rob B van der Luijt, Cora M Aalfs, Quinten Waisfisz, Juul Wijnen, Cornelis E P van Roozendaal, , Douglas F Easton, Susan Peock, Margaret Cook, Clare Oliver, Debra Frost, Patricia Harrington, D Gareth Evans, Fiona Lalloo, Rosalind Eeles, Louise Izatt, Carol Chu, Diana Eccles, Fiona Douglas, Carole Brewer, Heli Nevanlinna, Tuomas Heikkinen, Fergus J Couch, Noralane M Lindor, Xianshu Wang, Andrew K Godwin, Maria A Caligo, Grazia Lombardi, Niklas Loman, Per Karlsson, Hans Ehrencrona, Anna von Wachenfeldt, Rosa Bjork Barkardottir, Ute Hamann, Muhammad U Rashid, Adriana Lasa, Trinidad Caldés, Raquel Andrés, Michael Schmitt, Volker Assmann, Kristen Stevens, Kenneth Offit, João Curado, Hagen Tilgner, Roderic Guigo, Gemma Aiza, Joan Brunet, Joan Castellsagué, Griselda Martrat, Ander Urruticoechea, Ignacio Blanco, Laima Tihomirova, David E Goldgar, Saundra Buys, Esther M John, Alexander Miron, Melissa Southey, Mary B Daly, Rita K Schmutzler, Barbara Wappenschmidt, Alfons Meindl, Norbert Arnold, Helmut Deissler, Raymonda Varon-Mateeva, Christian Sutter, Dieter Niederacher, Evgeny Imyamitov, Olga M Sinilnikova, Dominique Stoppa-Lyonne, Sylvie Mazoyer, Carole Verny-Pierre, Laurent Castera, Antoine de Pauw, Yves-Jean Bignon, Nancy Uhrhammer, Jean-Philippe Peyrat, Philippe Vennin, Sandra Fert Ferrer, Marie-Agnès Collonge-Rame, Isabelle Mortemousque, Amanda B Spurdle, Jonathan Beesley, Xiaoqing Chen, Sue Healey, Mary Helen Barcellos-Hoff, Marc Vidal, Stephen B Gruber, Conxi Lazaro, Gabriel Capellà, Lesley McGuffog, Katherine L Nathanson, Antonis C Antoniou, Georgia Chenevix-Trench, Markus C Fleisch, Victor Moreno, Miguel Angel Pujana.
PLoS Biol.
PUBLISHED: 06-08-2011
Show Abstract
Hide Abstract
Differentiated mammary epithelium shows apicobasal polarity, and loss of tissue organization is an early hallmark of breast carcinogenesis. In BRCA1 mutation carriers, accumulation of stem and progenitor cells in normal breast tissue and increased risk of developing tumors of basal-like type suggest that BRCA1 regulates stem/progenitor cell proliferation and differentiation. However, the function of BRCA1 in this process and its link to carcinogenesis remain unknown. Here we depict a molecular mechanism involving BRCA1 and RHAMM that regulates apicobasal polarity and, when perturbed, may increase risk of breast cancer. Starting from complementary genetic analyses across families and populations, we identified common genetic variation at the low-penetrance susceptibility HMMR locus (encoding for RHAMM) that modifies breast cancer risk among BRCA1, but probably not BRCA2, mutation carriers: n?=?7,584, weighted hazard ratio ((w)HR)?=?1.09 (95% CI 1.02-1.16), p(trend)?=?0.017; and n?=?3,965, (w)HR?=?1.04 (95% CI 0.94-1.16), p(trend)?=?0.43; respectively. Subsequently, studies of MCF10A apicobasal polarization revealed a central role for BRCA1 and RHAMM, together with AURKA and TPX2, in essential reorganization of microtubules. Mechanistically, reorganization is facilitated by BRCA1 and impaired by AURKA, which is regulated by negative feedback involving RHAMM and TPX2. Taken together, our data provide fundamental insight into apicobasal polarization through BRCA1 function, which may explain the expanded cell subsets and characteristic tumor type accompanying BRCA1 mutation, while also linking this process to sporadic breast cancer through perturbation of HMMR/RHAMM.
Related JoVE Video
Evidence for SMAD3 as a modifier of breast cancer risk in BRCA2 mutation carriers.
Breast Cancer Res.
PUBLISHED: 08-27-2010
Show Abstract
Hide Abstract
Current attempts to identify genetic modifiers of BRCA1 and BRCA2 associated risk have focused on a candidate gene approach, based on knowledge of gene functions, or the development of large genome-wide association studies. In this study, we evaluated 24 SNPs tagged to 14 candidate genes derived through a novel approach that analysed gene expression differences to prioritise candidate modifier genes for association studies.
Related JoVE Video
Fanconi anemia gene mutations are not involved in sporadic Wilms tumor.
Pediatr Blood Cancer
PUBLISHED: 07-01-2010
Show Abstract
Hide Abstract
Bi-allelic germline mutations of the Fanconi anemia (FA) genes, PALB2/FANCN and BRCA2/FANCD1, have been reported in a few Wilms tumor (WT) patients with an atypical FA phenotype. Therefore, we screened a random cohort of 47 Dutch WT cases for germline mutations in these two FA-genes by DNA sequencing and Multiplex Ligation-dependent Probe Amplification (MLPA). Although several cases appeared to carry missense variants, no bi-allelic pathogenic mutations were identified, indicating that bi-allelic mutations in these FA-genes do not contribute significantly to the occurrence of WT.
Related JoVE Video
Spontaneous abrogation of the G?DNA damage checkpoint has clinical benefits but promotes leukemogenesis in Fanconi anemia patients.
J. Clin. Invest.
PUBLISHED: 05-27-2010
Show Abstract
Hide Abstract
DNA damage checkpoints in the cell cycle may be important barriers against cancer progression in human cells. Fanconi anemia (FA) is an inherited DNA instability disorder that is associated with bone marrow failure and a strong predisposition to cancer. Although FA cells experience constitutive chromosomal breaks, cell cycle arrest at the G2 DNA damage checkpoint, and an excess of cell death, some patients do become clinically stable, and the mechanisms underlying this, other than spontaneous reversion of the disease-causing mutation, are not well understood. Here we have defined a clonal phenotype, termed attenuation, in which FA patients acquire an abrogation of the G2 checkpoint arrest. Attenuated cells expressed lower levels of CHK1 (also known as CHEK1) and p53. The attenuation could be recapitulated by modulating the ATR/CHK1 pathway, and CHK1 inhibition protected FA cells from cell death. FA patients who expressed the attenuated phenotype had mild bone marrow deficiency and reached adulthood, but several of them eventually developed myelodysplasia or leukemia. Better understanding of attenuation might help predict a patients clinical course and guide choice of treatment. Our results also highlight the importance of evaluating the cellular DNA damage checkpoint and repair pathways in cancer therapies in general.
Related JoVE Video
Common variants in LSP1, 2q35 and 8q24 and breast cancer risk for BRCA1 and BRCA2 mutation carriers.
Antonis C Antoniou, Olga M Sinilnikova, Lesley McGuffog, Sue Healey, Heli Nevanlinna, Tuomas Heikkinen, Jacques Simard, Amanda B Spurdle, Jonathan Beesley, Xiaoqing Chen, , Susan L Neuhausen, Yuan C Ding, Fergus J Couch, Xianshu Wang, Zachary Fredericksen, Paolo Peterlongo, Bernard Peissel, Bernardo Bonanni, Alessandra Viel, Loris Bernard, Paolo Radice, Csilla I Szabo, Lenka Foretova, Michal Zikán, Kathleen Claes, Mark H Greene, Phuong L Mai, Gad Rennert, Flavio Lejbkowicz, Irene L Andrulis, Hilmi Ozcelik, Gord Glendon, Anne-Marie Gerdes, Mads Thomassen, Lone Sunde, Maria A Caligo, Yael Laitman, Tair Kontorovich, Shimrit Cohen, Bella Kaufman, Efrat Dagan, Ruth Gershoni Baruch, Eitan Friedman, Katja Harbst, Gisela Barbany-Bustinza, Johanna Rantala, Hans Ehrencrona, Per Karlsson, Susan M Domchek, Katherine L Nathanson, Ana Osorio, Ignacio Blanco, Adriana Lasa, Javier Benitez, Ute Hamann, Frans B L Hogervorst, Matti A Rookus, J Margriet Collée, Peter Devilee, Marjolijn J Ligtenberg, Rob B van der Luijt, Cora M Aalfs, Quinten Waisfisz, Juul Wijnen, Cornelis E P van Roozendaal, Susan Peock, Margaret Cook, Debra Frost, Clare Oliver, Radka Platte, D Gareth Evans, Fiona Lalloo, Rosalind Eeles, Louise Izatt, Rosemarie Davidson, Carol Chu, Diana Eccles, Trevor Cole, Shirley Hodgson, Andrew K Godwin, Dominique Stoppa-Lyonnet, Bruno Buecher, Mélanie Léoné, Brigitte Bressac-de Paillerets, Audrey Remenieras, Olivier Caron, Gilbert M Lenoir, Nicolas Sévenet, Michel Longy, Sandra Fert Ferrer, Fabienne Prieur, David Goldgar, Alexander Miron, Esther M John, Saundra S Buys, Mary B Daly, John L Hopper, Mary Beth Terry, Yosuf Yassin, Christian Singer, Daphne Gschwantler-Kaulich, Christine Staudigl, Thomas V O Hansen, Rosa Bjork Barkardottir, Tomas Kirchhoff, Prodipto Pal, Kristi Kosarin, Kenneth Offit, Marion Piedmonte, Gustavo C Rodriguez, Katie Wakeley, John F Boggess, Jack Basil, Peter E Schwartz, Stephanie V Blank, Amanda E Toland, Marco Montagna, Cinzia Casella, Evgeny N Imyanitov, Anna Allavena, Rita K Schmutzler, Beatrix Versmold, Christoph Engel, Alfons Meindl, Nina Ditsch, Norbert Arnold, Dieter Niederacher, Helmut Deissler, Britta Fiebig, Christian Suttner, Ines Schönbuchner, Dorothea Gadzicki, Trinidad Caldés, Miguel de la Hoya, Karen A Pooley, Douglas F Easton, Georgia Chenevix-Trench.
Hum. Mol. Genet.
PUBLISHED: 08-05-2009
Show Abstract
Hide Abstract
Genome-wide association studies of breast cancer have identified multiple single nucleotide polymorphisms (SNPs) that are associated with increased breast cancer risks in the general population. In a previous study, we demonstrated that the minor alleles at three of these SNPs, in FGFR2, TNRC9 and MAP3K1, also confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. Three additional SNPs rs3817198 at LSP1, rs13387042 at 2q35 and rs13281615 at 8q24 have since been reported to be associated with breast cancer in the general population, and in this study we evaluated their association with breast cancer risk in 9442 BRCA1 and 5665 BRCA2 mutation carriers from 33 study centres. The minor allele of rs3817198 was associated with increased breast cancer risk only for BRCA2 mutation carriers [hazard ratio (HR) = 1.16, 95% CI: 1.07-1.25, P-trend = 2.8 x 10(-4)]. The best fit for the association of SNP rs13387042 at 2q35 with breast cancer risk was a dominant model for both BRCA1 and BRCA2 mutation carriers (BRCA1: HR = 1.14, 95% CI: 1.04-1.25, P = 0.0047; BRCA2: HR = 1.18 95% CI: 1.04-1.33, P = 0.0079). SNP rs13281615 at 8q24 was not associated with breast cancer for either BRCA1 or BRCA2 mutation carriers, but the estimated association for BRCA2 mutation carriers (per-allele HR = 1.06, 95% CI: 0.98-1.14) was consistent with odds ratio estimates derived from population-based case-control studies. The LSP1 and 2q35 SNPs appear to interact multiplicatively on breast cancer risk for BRCA2 mutation carriers. There was no evidence that the associations vary by mutation type depending on whether the mutated protein is predicted to be stable or not.
Related JoVE Video
The cellular phenotype of Roberts syndrome fibroblasts as revealed by ectopic expression of ESCO2.
PLoS ONE
PUBLISHED: 04-15-2009
Show Abstract
Hide Abstract
Cohesion between sister chromatids is essential for faithful chromosome segregation. In budding yeast, the acetyltransferase Eco1/Ctf7 establishes cohesion during DNA replication in S phase and in response to DNA double strand breaks in G2/M phase. In humans two Eco1 orthologs exist: ESCO1 and ESCO2. Both proteins are required for proper sister chromatid cohesion, but their exact function is unclear at present. Since ESCO2 has been identified as the gene defective in the rare autosomal recessive cohesinopathy Roberts syndrome (RBS), cells from RBS patients can be used to elucidate the role of ESCO2. We investigated for the first time RBS cells in comparison to isogenic controls that stably express V5- or GFP-tagged ESCO2. We show that the sister chromatid cohesion defect in the transfected cell lines is rescued and suggest that ESCO2 is regulated by proteasomal degradation in a cell cycle-dependent manner. In comparison to the corrected cells RBS cells were hypersensitive to the DNA-damaging agents mitomycin C, camptothecin and etoposide, while no particular sensitivity to UV, ionizing radiation, hydroxyurea or aphidicolin was found. The cohesion defect of RBS cells and their hypersensitivity to DNA-damaging agents were not corrected by a patient-derived ESCO2 acetyltransferase mutant (W539G), indicating that the acetyltransferase activity of ESCO2 is essential for its function. In contrast to a previous study on cells from patients with Cornelia de Lange syndrome, another cohesinopathy, RBS cells failed to exhibit excessive chromosome aberrations after irradiation in G2 phase of the cell cycle. Our results point at an S phase-specific role for ESCO2 in the maintenance of genome stability.
Related JoVE Video
Correlation of minimal residual disease cell frequency with molecular genotype in patients with acute myeloid leukemia.
Haematologica
PUBLISHED: 02-13-2009
Show Abstract
Hide Abstract
About 70-80 percent of patients with acute myeloid leukemia enter complete remission, but at least half of these patients who achieve remission go on to relapse. Improved treatment is likely to come from increasing the time to relapse, especially for younger patients. With the vastly increasing number of targeted therapies there is a strong need for short-term end-points to efficiently test such therapies for further pursuance. Minimal residual disease assessment may offer such an end-point since it is a strong independent prognostic factor. As proof of principle we examined this concept for FLT3-ITD status at diagnosis.
Related JoVE Video
A meta-analysis of genome-wide association studies of breast cancer identifies two novel susceptibility loci at 6q14 and 20q11.
Afshan Siddiq, Fergus J Couch, Gary K Chen, Sara Lindstrom, Diana Eccles, Robert C Millikan, Kyriaki Michailidou, Daniel O Stram, Lars Beckmann, Suhn Kyong Rhie, Christine B Ambrosone, Kristiina Aittomäki, Pilar Amiano, Carmel Apicella, , Laura Baglietto, Elisa V Bandera, Matthias W Beckmann, Christine D Berg, Leslie Bernstein, Carl Blomqvist, Hiltrud Brauch, Louise Brinton, Quang M Bui, Julie E Buring, Saundra S Buys, Daniele Campa, Jane E Carpenter, Daniel I Chasman, Jenny Chang-Claude, Constance Chen, Francoise Clavel-Chapelon, Angela Cox, Simon S Cross, Kamila Czene, Sandra L Deming, Robert B Diasio, W Ryan Diver, Alison M Dunning, Lorraine Durcan, Arif B Ekici, Peter A Fasching, Heather Spencer Feigelson, Laura Fejerman, Jonine D Figueroa, Olivia Fletcher, Dieter Flesch-Janys, Mia M Gaudet, Susan M Gerty, Jorge L Rodriguez-Gil, Graham G Giles, Carla H van Gils, Andrew K Godwin, Nikki Graham, Dario Greco, Per Hall, Susan E Hankinson, Arndt Hartmann, Rebecca Hein, Judith Heinz, Robert N Hoover, John L Hopper, Jennifer J Hu, Scott Huntsman, Sue A Ingles, Astrid Irwanto, Claudine Isaacs, Kevin B Jacobs, Esther M John, Christina Justenhoven, Rudolf Kaaks, Laurence N Kolonel, Gerhard A Coetzee, Mark Lathrop, Loic Le Marchand, Adam M Lee, I-Min Lee, Timothy Lesnick, Peter Lichtner, Jianjun Liu, Eiliv Lund, Enes Makalic, Nicholas G Martin, Catriona A McLean, Hanne Meijers-Heijboer, Alfons Meindl, Penelope Miron, Kristine R Monroe, Grant W Montgomery, Bertram Müller-Myhsok, Stefan Nickels, Sarah J Nyante, Curtis Olswold, Kim Overvad, Domenico Palli, Daniel J Park, Julie R Palmer, Harsh Pathak, Julian Peto, Paul Pharoah, Nazneen Rahman, Fernando Rivadeneira, Daniel F Schmidt, Rita K Schmutzler, Susan Slager, Melissa C Southey, Kristen N Stevens, Hans-Peter Sinn, Michael F Press, Eric Ross, Elio Riboli, Paul M Ridker, Fredrick R Schumacher, Gianluca Severi, Isabel Dos Santos Silva, Jennifer Stone, Malin Sund, William J Tapper, Michael J Thun, Ruth C Travis, Clare Turnbull, André G Uitterlinden, Quinten Waisfisz, Xianshu Wang, Zhaoming Wang, Joellen Weaver, Rüdiger Schulz-Wendtland, Lynne R Wilkens, David Van Den Berg, Wei Zheng, Regina G Ziegler, Elad Ziv, Heli Nevanlinna, Douglas F Easton, David J Hunter, Brian E Henderson, Stephen J Chanock, Montserrat Garcia-Closas, Peter Kraft, Christopher A Haiman, Celine M Vachon.
Hum. Mol. Genet.
Show Abstract
Hide Abstract
Genome-wide association studies (GWAS) of breast cancer defined by hormone receptor status have revealed loci contributing to susceptibility of estrogen receptor (ER)-negative subtypes. To identify additional genetic variants for ER-negative breast cancer, we conducted the largest meta-analysis of ER-negative disease to date, comprising 4754 ER-negative cases and 31 663 controls from three GWAS: NCI Breast and Prostate Cancer Cohort Consortium (BPC3) (2188 ER-negative cases; 25 519 controls of European ancestry), Triple Negative Breast Cancer Consortium (TNBCC) (1562 triple negative cases; 3399 controls of European ancestry) and African American Breast Cancer Consortium (AABC) (1004 ER-negative cases; 2745 controls). We performed in silico replication of 86 SNPs at P ? 1 × 10(-5) in an additional 11 209 breast cancer cases (946 with ER-negative disease) and 16 057 controls of Japanese, Latino and European ancestry. We identified two novel loci for breast cancer at 20q11 and 6q14. SNP rs2284378 at 20q11 was associated with ER-negative breast cancer (combined two-stage OR = 1.16; P = 1.1 × 10(-8)) but showed a weaker association with overall breast cancer (OR = 1.08, P = 1.3 × 10(-6)) based on 17 869 cases and 43 745 controls and no association with ER-positive disease (OR = 1.01, P = 0.67) based on 9965 cases and 22 902 controls. Similarly, rs17530068 at 6q14 was associated with breast cancer (OR = 1.12; P = 1.1 × 10(-9)), and with both ER-positive (OR = 1.09; P = 1.5 × 10(-5)) and ER-negative (OR = 1.16, P = 2.5 × 10(-7)) disease. We also confirmed three known loci associated with ER-negative (19p13) and both ER-negative and ER-positive breast cancer (6q25 and 12p11). Our results highlight the value of large-scale collaborative studies to identify novel breast cancer risk loci.
Related JoVE Video
Analysis of the novel fanconi anemia gene SLX4/FANCP in familial breast cancer cases.
Hum. Mutat.
Show Abstract
Hide Abstract
SLX4/FANCP is a recently discovered novel disease gene for Fanconi anemia (FA), a rare recessive disorder characterized by chromosomal instability and increased cancer susceptibility. Three of the 15 FA genes are breast cancer susceptibility genes in heterozygous mutation carriers--BRCA2, PALB2, and BRIP1. To investigate if defects in SLX4 also predispose to breast cancer, the gene was sequenced in a cohort of 729 BRCA1/BRCA2-negative familial breast cancer cases. We identified a single splice site mutation (c.2013+2T>A), which causes a frameshift by skipping of exon 8. We also identified 39 missense variants, four of which were selected for functional testing in a Mitomycin C-induced growth inhibition assay, and appeared indistinguishable from wild type. Although this is the first study that describes a truncating SLX4 mutation in breast cancer patients, our data indicate that germline mutations in SLX4 are very rare and are unlikely to make a significant contribution to familial breast cancer.
Related JoVE Video
Proteomics of mouse BRCA1-deficient mammary tumors identifies DNA repair proteins with potential diagnostic and prognostic value in human breast cancer.
Mol. Cell Proteomics
Show Abstract
Hide Abstract
Breast cancer 1, early onset (BRCA1) hereditary breast cancer, a type of cancer with defects in the homology-directed DNA repair pathway, would benefit from the identification of proteins for diagnosis, which might also be of potential use as screening, prognostic, or predictive markers. Sporadic breast cancers with defects in the BRCA1 pathway might also be diagnosed. We employed proteomics based on one-dimensional gel electrophoresis in combination with nano-LC-MS/MS and spectral counting to compare the protein profiles of mammary tumor tissues of genetic mouse models either deficient or proficient in BRCA1. We identified a total of 3,545 proteins, of which 801 were significantly differentially regulated between the BRCA1-deficient and -proficient breast tumors. Pathway and protein complex analysis identified DNA repair and related functions as the major processes associated with the up-regulated proteins in the BRCA1-deficient tumors. In addition, by selecting highly connected nodes, we identified a BRCA1 deficiency signature of 45 proteins that enriches for homology-directed DNA repair deficiency in human gene expression breast cancer data sets. This signature also exhibits prognostic power across multiple data sets, with optimal performance in a data set enriched in tumors deficient in homology-directed DNA repair. In conclusion, by comparing mouse proteomes from BRCA1-proficient and -deficient mammary tumors, we were able to identify several markers associated with BRCA1 deficiency and a prognostic signature for human breast cancer deficient in homology-directed DNA repair.
Related JoVE Video
Genome-wide association analysis identifies three new breast cancer susceptibility loci.
Maya Ghoussaini, Olivia Fletcher, Kyriaki Michailidou, Clare Turnbull, Marjanka K Schmidt, Ed Dicks, Joe Dennis, Qin Wang, Manjeet K Humphreys, Craig Luccarini, Caroline Baynes, Don Conroy, Melanie Maranian, Shahana Ahmed, Kristy Driver, Nichola Johnson, Nicholas Orr, Isabel Dos Santos Silva, Quinten Waisfisz, Hanne Meijers-Heijboer, André G Uitterlinden, Fernando Rivadeneira, , Per Hall, Kamila Czene, Astrid Irwanto, Jianjun Liu, Heli Nevanlinna, Kristiina Aittomäki, Carl Blomqvist, Alfons Meindl, Rita K Schmutzler, Bertram Müller-Myhsok, Peter Lichtner, Jenny Chang-Claude, Rebecca Hein, Stefan Nickels, Dieter Flesch-Janys, Helen Tsimiklis, Enes Makalic, Daniel Schmidt, Minh Bui, John L Hopper, Carmel Apicella, Daniel J Park, Melissa Southey, David J Hunter, Stephen J Chanock, Annegien Broeks, Senno Verhoef, Frans B L Hogervorst, Peter A Fasching, Michael P Lux, Matthias W Beckmann, Arif B Ekici, Elinor Sawyer, Ian Tomlinson, Michael Kerin, Frederik Marme, Andreas Schneeweiss, Christof Sohn, Barbara Burwinkel, Pascal Guénel, Thérèse Truong, Emilie Cordina-Duverger, Florence Menegaux, Stig E Bojesen, Børge G Nordestgaard, Sune F Nielsen, Henrik Flyger, Roger L Milne, M Rosario Alonso, Anna González-Neira, Javier Benitez, Hoda Anton-Culver, Argyrios Ziogas, Leslie Bernstein, Christina Clarke Dur, Hermann Brenner, Heiko Muller, Volker Arndt, Christa Stegmaier, Christina Justenhoven, Hiltrud Brauch, Thomas Brüning, Shan Wang-Gohrke, Ursula Eilber, Thilo Dörk, Peter Schürmann, Michael Bremer, Peter Hillemanns, Natalia V Bogdanova, Natalia N Antonenkova, Yuri I Rogov, Johann H Karstens, Marina Bermisheva, Darya Prokofieva, Elza Khusnutdinova, Annika Lindblom, Sara Margolin, Arto Mannermaa, Vesa Kataja, Veli-Matti Kosma, Jaana M Hartikainen, Diether Lambrechts, Betul T Yesilyurt, Giuseppe Floris, Karin Leunen, Siranoush Manoukian, Bernardo Bonanni, Stefano Fortuzzi, Paolo Peterlongo, Fergus J Couch, Xianshu Wang, Kristen Stevens, Adam Lee, Graham G Giles, Laura Baglietto, Gianluca Severi, Catriona McLean, Grethe Grenaker Alnaes, Vessela Kristensen, Anne-Lise Børrensen-Dale, Esther M John, Alexander Miron, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Saila Kauppila, Irene L Andrulis, Gord Glendon, Anna Marie Mulligan, Peter Devilee, Christie J van Asperen, Rob A E M Tollenaar, Caroline Seynaeve, Jonine D Figueroa, Montserrat Garcia-Closas, Louise Brinton, Jolanta Lissowska, Maartje J Hooning, Antoinette Hollestelle, Rogier A Oldenburg, Ans M W van den Ouweland, Angela Cox, Malcolm W R Reed, Mitul Shah, Ania Jakubowska, Jan Lubiński, Katarzyna Jaworska, Katarzyna Durda, Michael Jones, Minouk Schoemaker, Alan Ashworth, Anthony Swerdlow, Jonathan Beesley, Xiaoqing Chen, Kenneth R Muir, Artitaya Lophatananon, Suthee Rattanamongkongul, Arkom Chaiwerawattana, Daehee Kang, Keun-Young Yoo, Dong-Young Noh, Chen-Yang Shen, Jyh-Cherng Yu, Pei-Ei Wu, Chia-Ni Hsiung, Annie Perkins, Ruth Swann, Louiza Velentzis, Diana M Eccles, Will J Tapper, Susan M Gerty, Nikki J Graham, Bruce A J Ponder, Georgia Chenevix-Trench, Paul D P Pharoah, Mark Lathrop, Alison M Dunning, Nazneen Rahman, Julian Peto, Douglas F Easton.
Nat. Genet.
Show Abstract
Hide Abstract
Breast cancer is the most common cancer among women. To date, 22 common breast cancer susceptibility loci have been identified accounting for ?8% of the heritability of the disease. We attempted to replicate 72 promising associations from two independent genome-wide association studies (GWAS) in ?70,000 cases and ?68,000 controls from 41 case-control studies and 9 breast cancer GWAS. We identified three new breast cancer risk loci at 12p11 (rs10771399; P = 2.7 × 10(-35)), 12q24 (rs1292011; P = 4.3 × 10(-19)) and 21q21 (rs2823093; P = 1.1 × 10(-12)). rs10771399 was associated with similar relative risks for both estrogen receptor (ER)-negative and ER-positive breast cancer, whereas the other two loci were associated only with ER-positive disease. Two of the loci lie in regions that contain strong plausible candidate genes: PTHLH (12p11) has a crucial role in mammary gland development and the establishment of bone metastasis in breast cancer, and NRIP1 (21q21) encodes an ER cofactor and has a role in the regulation of breast cancer cell growth.
Related JoVE Video

What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

How does it work?

We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

Video X seems to be unrelated to Abstract Y...

In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.