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1.  Characterization of BRCA1 Ring Finger Variants of Uncertain Significance 
The majority of pathogenic mutations in BRCA1 result in a truncated protein. Although most missense changes in BRCA1 are of unknown functional significance, a handful of deleterious missense mutations have been identified. The majority of these occur in splice sites or highly conserved protein domains. Previously, we developed a predictive model, VUS Predict, to classify BRCA variants of uncertain significance as neutral or deleterious. It uses evolutionary prediction algorithms together with clinical information from cancer pathology reports and BRCA genetic testing results. Because of the higher probability that missense changes occurring in conserved BRCA1 domains are of pathogenic significance, we identified all individuals in our cohort who had been tested for BRCA1 and BRCA2 mutations who had missense changes in the BRCA1 ring finger domain and sought to classify those changes. We applied VUS Predict to three previously uncharacterized variants and four missense changes known to be deleterious. Two variants, L22S and T37K, were predicted to be deleterious and one variant, K45Q, was predicted to be neutral by VUS Predict. The mutations C39R, C44Y, C44S and C61G were confirmed as deleterious.
PMCID: PMC4283813  PMID: 19543972
BRCA1; variants of uncertain significance; ring finger domain; mutation characterization
2.  Chromosomal Aberrations in UVB-induced Tumors of Immunosuppressed Mice 
Genes, chromosomes & cancer  2009;48(6):490-501.
In immunocompromised individuals, such as organ transplant recipients, the risk of cutaneous squamous cell carcinoma (SCC) is increased 60-250 fold, and there is an increased likelihood to develop aggressive, metastatic SCC. An understanding of the genes involved in SCC tumorigenesis is critical to prevent SCC-associated morbidity and mortality. Mouse models show that different immunosuppressive drugs lead to SCCs varying in size, number, and malignant potential. In this study we utilized mouse models that mimic adult transplant recipients to study the effect of immunosuppressive drugs and UV light on SCC development. UV-induced tumors from six treatment groups, control, tacrolimus (Tac), rapamycin (Rap), cyclosporin (CsA), mycophenolate mofetil (MMF), and Rap plus CsA, were evaluated by array comparative genomic hybridication. Mouse SCCs appear to show similar genomic aberrations as those reported in human SCCs and offer the ability to identify genomic changes associated with specific and combinatorial effects of drugs. Fewer aberrations were seen in tumors of mice treated with MMF or Rap. Tumors from Tac treated animals showed the highest number of changes. Calcineurin inhibitors (Tac and CsA) did not cluster together by their genomic aberrations, indicating their contribution to UV mediated carcinogenesis may be through different pathways. The combination treatment (Rap plus CsA) did not cluster with either treatment individually, suggesting it may influence SCC tumorigenesis via a different mechanism. Future studies will identify specific genes mapping to regions of aberration that are different between treatment groups to identify target pathways that may be affected by these drugs.
PMCID: PMC2739622  PMID: 19296524
3.  Clinically Applicable Models to Characterize BRCA1 and BRCA2 Variants of Uncertain Significance 
Journal of Clinical Oncology  2008;26(33):5393-5400.
Twenty percent of individuals with a strong family and/or personal history of breast and ovarian cancer carry a deleterious mutation in BRCA1 or BRCA2. Identification of mutations in these genes is extremely beneficial for patients pursuing risk reduction strategies. Approximately 7% of individuals who have genetic testing of BRCA1 and BRCA2 carry a variant of uncertain significance (VUS), making clinical management less certain. The majority of identified VUS occur only in one to two individuals; these variants are not able to be classified using current classification models with segregation analysis components.
To develop a clinically applicable method that can predict the pathogenicity of VUS that does not require familial information or segregation analysis, we identified characteristics of breast or ovarian tumors that distinguished sporadic tumors from tumors with BRCA1 or BRCA2 mutations. Study participants included individuals with known deleterious mutations in BRCA1 or BRCA2 and individuals with classified or unclassified BRCA variants.
We applied the models to 57 tumors with 43 different deleterious BRCA mutations and 57 tumors with 54 unique classified and unclassified BRCA variants. Of the 33 previously unclassified VUS studied, we found evidence of neutrality for 21.
Our models showed 98% sensitivity and 76% specificity for predicting classified DNA changes. We classified 64% of unknown variants as neutral. Classification of VUS as neutral will have immediate benefit for those individuals and their family members. These models are adaptable for the clinic and will be useful for individuals with limited available family history.
PMCID: PMC2651073  PMID: 18824701
4.  Expression of cancer-testis antigens MAGEA1, MAGEA3, ACRBP, PRAME, SSX2, and CTAG2 in myxoid and round cell liposarcoma 
Myxoid and round-cell liposarcoma is a frequently encountered liposarcoma subtype. The mainstay of treatment remains surgical excision with or without chemoradiation. However, treatment options are limited in the setting of metastatic disease. Cancer-testis antigens are immunogenic antigens with the expression largely restricted to testicular germ cells and various malignancies, making them attractive targets for cancer immunotherapy. Gene expression studies have reported the expression of various cancer-testis antigens in liposarcoma, with mRNA expression of CTAG1B, CTAG2, MAGEA9, and PRAME described specifically in myxoid and round-cell liposarcoma. Herein, we further explore the expression of the cancer-testis antigens MAGEA1, ACRBP, PRAME, and SSX2 in myxoid and round-cell liposarcoma by immunohistochemistry in addition to determining mRNA levels of CTAG2 (LAGE-1), PRAME, and MAGEA3 by quantitative real-time PCR. Samples in formalin-fixed paraffin-embedded blocks (n=37) and frozen tissue (n=8) were obtained for immunohistochemistry and quantitative real-time PCR, respectively. Full sections were stained with antibodies to MAGEA1, ACRBP, PRAME, and SSX2 and staining was assessed for intensity (1–2+) and percent tumor positivity. The gene expression levels of CTAG2, PRAME, and MAGEA3 were measured by quantitative real-time PCR. In total, 37/37 (100%) of the samples showed predominantly strong, homogenous immunoreactivity for PRAME. There was a variable, focal expression of MAGEA1 (11%) and SSX2 (16%) and no expression of ACRBP. Quantitative real-time PCR demonstrated PRAME and CTAG2 transcripts in all eight samples: six tumors with high mRNA levels; two tumors with low mRNA levels. The gene expression of MAGEA3 was not detected in the majority of cases. In conclusion, myxoid and round-cell liposarcomas consistently express PRAME by immunohistochemistry as well as CTAG2 and PRAME by qualitative real-time PCR. This supports the use of cancer-testis antigen-targeted immunotherapy in the treatment of this malignancy.
PMCID: PMC4287229  PMID: 24457462
cancer-testis antigens; immunotherapeutics; myxoid and round-cell liposarcoma
5.  Design and Implementation of a Randomized Controlled Trial of Genomic Counseling for Patients with Chronic Disease 
We describe the development and implementation of a randomized controlled trial to investigate the impact of genomic counseling on a cohort of patients with heart failure (HF) or hypertension (HTN), managed at a large academic medical center, the Ohio State University Wexner Medical Center (OSUWMC). Our study is built upon the existing Coriell Personalized Medicine Collaborative (CPMC®). OSUWMC patient participants with chronic disease (CD) receive eight actionable complex disease and one pharmacogenomic test report through the CPMC® web portal. Participants are randomized to either the in-person post-test genomic counseling—active arm, versus web-based only return of results—control arm. Study-specific surveys measure: (1) change in risk perception; (2) knowledge retention; (3) perceived personal control; (4) health behavior change; and, for the active arm (5), overall satisfaction with genomic counseling. This ongoing partnership has spurred creation of both infrastructure and procedures necessary for the implementation of genomics and genomic counseling in clinical care and clinical research. This included creation of a comprehensive informed consent document and processes for prospective return of actionable results for multiple complex diseases and pharmacogenomics (PGx) through a web portal, and integration of genomic data files and clinical decision support into an EPIC-based electronic medical record. We present this partnership, the infrastructure, genomic counseling approach, and the challenges that arose in the design and conduct of this ongoing trial to inform subsequent collaborative efforts and best genomic counseling practices.
PMCID: PMC4051230  PMID: 24926413
implementation; genomics; medicine; randomized; patients; counseling; actionable; risk perception; pharmacogenomics
6.  DNA Glycosylases Involved in Base Excision Repair May Be Associated with Cancer Risk in BRCA1 and BRCA2 Mutation Carriers 
Osorio, Ana | Milne, Roger L. | Kuchenbaecker, Karoline | Vaclová, Tereza | Pita, Guillermo | Alonso, Rosario | Peterlongo, Paolo | Blanco, Ignacio | de la Hoya, Miguel | Duran, Mercedes | Díez, Orland | Ramón y Cajal, Teresa | Konstantopoulou, Irene | Martínez-Bouzas, Cristina | Andrés Conejero, Raquel | Soucy, Penny | McGuffog, Lesley | Barrowdale, Daniel | Lee, Andrew | SWE-BRCA,  | Arver, Brita | Rantala, Johanna | Loman, Niklas | Ehrencrona, Hans | Olopade, Olufunmilayo I. | Beattie, Mary S. | Domchek, Susan M. | Nathanson, Katherine | Rebbeck, Timothy R. | Arun, Banu K. | Karlan, Beth Y. | Walsh, Christine | Lester, Jenny | John, Esther M. | Whittemore, Alice S. | Daly, Mary B. | Southey, Melissa | Hopper, John | Terry, Mary B. | Buys, Saundra S. | Janavicius, Ramunas | Dorfling, Cecilia M. | van Rensburg, Elizabeth J. | Steele, Linda | Neuhausen, Susan L. | Ding, Yuan Chun | Hansen, Thomas v. O. | Jønson, Lars | Ejlertsen, Bent | Gerdes, Anne-Marie | Infante, Mar | Herráez, Belén | Moreno, Leticia Thais | Weitzel, Jeffrey N. | Herzog, Josef | Weeman, Kisa | Manoukian, Siranoush | Peissel, Bernard | Zaffaroni, Daniela | Scuvera, Giulietta | Bonanni, Bernardo | Mariette, Frederique | Volorio, Sara | Viel, Alessandra | Varesco, Liliana | Papi, Laura | Ottini, Laura | Tibiletti, Maria Grazia | Radice, Paolo | Yannoukakos, Drakoulis | Garber, Judy | Ellis, Steve | Frost, Debra | Platte, Radka | Fineberg, Elena | Evans, Gareth | Lalloo, Fiona | Izatt, Louise | Eeles, Ros | Adlard, Julian | Davidson, Rosemarie | Cole, Trevor | Eccles, Diana | Cook, Jackie | Hodgson, Shirley | Brewer, Carole | Tischkowitz, Marc | Douglas, Fiona | Porteous, Mary | Side, Lucy | Walker, Lisa | Morrison, Patrick | Donaldson, Alan | Kennedy, John | Foo, Claire | Godwin, Andrew K. | Schmutzler, Rita Katharina | Wappenschmidt, Barbara | Rhiem, Kerstin | Engel, Christoph | Meindl, Alfons | Ditsch, Nina | Arnold, Norbert | Plendl, Hans Jörg | Niederacher, Dieter | Sutter, Christian | Wang-Gohrke, Shan | Steinemann, Doris | Preisler-Adams, Sabine | Kast, Karin | Varon-Mateeva, Raymonda | Gehrig, Andrea | Stoppa-Lyonnet, Dominique | Sinilnikova, Olga M. | Mazoyer, Sylvie | Damiola, Francesca | Poppe, Bruce | Claes, Kathleen | Piedmonte, Marion | Tucker, Kathy | Backes, Floor | Rodríguez, Gustavo | Brewster, Wendy | Wakeley, Katie | Rutherford, Thomas | Caldés, Trinidad | Nevanlinna, Heli | Aittomäki, Kristiina | Rookus, Matti A. | van Os, Theo A. M. | van der Kolk, Lizet | de Lange, J. L. | Meijers-Heijboer, Hanne E. J. | van der Hout, A. H. | van Asperen, Christi J. | Gómez Garcia, Encarna B. | Hoogerbrugge, Nicoline | Collée, J. Margriet | van Deurzen, Carolien H. M. | van der Luijt, Rob B. | Devilee, Peter | HEBON,  | Olah, Edith | Lázaro, Conxi | Teulé, Alex | Menéndez, Mireia | Jakubowska, Anna | Cybulski, Cezary | Gronwald, Jacek | Lubinski, Jan | Durda, Katarzyna | Jaworska-Bieniek, Katarzyna | Johannsson, Oskar Th. | Maugard, Christine | Montagna, Marco | Tognazzo, Silvia | Teixeira, Manuel R. | Healey, Sue | Investigators, kConFab | Olswold, Curtis | Guidugli, Lucia | Lindor, Noralane | Slager, Susan | Szabo, Csilla I. | Vijai, Joseph | Robson, Mark | Kauff, Noah | Zhang, Liying | Rau-Murthy, Rohini | Fink-Retter, Anneliese | Singer, Christian F. | Rappaport, Christine | Geschwantler Kaulich, Daphne | Pfeiler, Georg | Tea, Muy-Kheng | Berger, Andreas | Phelan, Catherine M. | Greene, Mark H. | Mai, Phuong L. | Lejbkowicz, Flavio | Andrulis, Irene | Mulligan, Anna Marie | Glendon, Gord | Toland, Amanda Ewart | Bojesen, Anders | Pedersen, Inge Sokilde | Sunde, Lone | Thomassen, Mads | Kruse, Torben A. | Jensen, Uffe Birk | Friedman, Eitan | Laitman, Yael | Shimon, Shani Paluch | Simard, Jacques | Easton, Douglas F. | Offit, Kenneth | Couch, Fergus J. | Chenevix-Trench, Georgia | Antoniou, Antonis C. | Benitez, Javier
PLoS Genetics  2014;10(4):e1004256.
Single Nucleotide Polymorphisms (SNPs) in genes involved in the DNA Base Excision Repair (BER) pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of the components of the BER pathway, PARP1 (poly ADP ribose polymerase), and both BRCA1 and BRCA2. In the present study, we have performed a comprehensive analysis of 18 genes involved in BER using a tagging SNP approach in a large series of BRCA1 and BRCA2 mutation carriers. 144 SNPs were analyzed in a two stage study involving 23,463 carriers from the CIMBA consortium (the Consortium of Investigators of Modifiers of BRCA1 and BRCA2). Eleven SNPs showed evidence of association with breast and/or ovarian cancer at p<0.05 in the combined analysis. Four of the five genes for which strongest evidence of association was observed were DNA glycosylases. The strongest evidence was for rs1466785 in the NEIL2 (endonuclease VIII-like 2) gene (HR: 1.09, 95% CI (1.03–1.16), p = 2.7×10−3) for association with breast cancer risk in BRCA2 mutation carriers, and rs2304277 in the OGG1 (8-guanine DNA glycosylase) gene, with ovarian cancer risk in BRCA1 mutation carriers (HR: 1.12 95%CI: 1.03–1.21, p = 4.8×10−3). DNA glycosylases involved in the first steps of the BER pathway may be associated with cancer risk in BRCA1/2 mutation carriers and should be more comprehensively studied.
Author Summary
Women harboring a germ-line mutation in the BRCA1 or BRCA2 genes have a high lifetime risk to develop breast and/or ovarian cancer. However, not all carriers develop cancer and high variability exists regarding age of onset of the disease and type of tumor. One of the causes of this variability lies in other genetic factors that modulate the phenotype, the so-called modifier genes. Identification of these genes might have important implications for risk assessment and decision making regarding prevention of the disease. Given that BRCA1 and BRCA2 participate in the repair of DNA double strand breaks, here we have investigated whether variations, Single Nucleotide Polymorphisms (SNPs), in genes participating in other DNA repair pathway may be associated with cancer risk in BRCA carriers. We have selected the Base Excision Repair pathway because BRCA defective cells are extremely sensitive to the inhibition of one of its components, PARP1. Thanks to a large international collaborative effort, we have been able to identify at least two SNPs that are associated with increased cancer risk in BRCA1 and BRCA2 mutation carriers respectively. These findings could have implications not only for risk assessment, but also for treatment of BRCA1/2 mutation carriers with PARP inhibitors.
PMCID: PMC3974638  PMID: 24698998
7.  mrSNP: Software to detect SNP effects on microRNA binding 
BMC Bioinformatics  2014;15:73.
MicroRNAs (miRNAs) are short (19-23 nucleotides) non-coding RNAs that bind to sites in the 3’untranslated regions (3’UTR) of a targeted messenger RNA (mRNA). Binding leads to degradation of the transcript or blocked translation resulting in decreased expression of the targeted gene. Single nucleotide polymorphisms (SNPs) have been found in 3’UTRs that disrupt normal miRNA binding or introduce new binding sites and some of these have been associated with disease pathogenesis. This raises the importance of detecting miRNA targets and predicting the possible effects of SNPs on binding sites. In the last decade a number of studies have been conducted to predict the location of miRNA binding sites. However, there have been fewer algorithms published to analyze the effects of SNPs on miRNA binding. Moreover, the existing software has some shortcomings including the requirement for significant manual labor when working with huge lists of SNPs and that algorithms work only for SNPs present in databases such as dbSNP. These limitations become problematic as next-generation sequencing is leading to large numbers of novel variants in 3’UTRs.
In order to overcome these issues, we developed a web-server named mrSNP which predicts the impact of a SNP in a 3’UTR on miRNA binding. The proposed tool reduces the manual labor requirements and allows users to input any SNP that has been identified by any SNP-calling program. In testing the performance of mrSNP on SNPs experimentally validated to affect miRNA binding, mrSNP correctly identified 69% (11/16) of the SNPs disrupting binding.
mrSNP is a highly adaptable and performing tool for predicting the effect a 3’UTR SNP will have on miRNA binding. This tool has advantages over existing algorithms because it can assess the effect of novel SNPs on miRNA binding without requiring significant hands on time.
PMCID: PMC4067983  PMID: 24629096
miRNA; SNP; mRNA; microRNA binding
8.  Design and Implementation of a Randomized Controlled Trial of Genomic Counseling for Patients with Chronic Disease  
We describe the development and implementation of a randomized controlled trial to investigate the impact of genomic counseling on a cohort of patients with heart failure (HF) or hypertension (HTN), managed at a large academic medical center, the Ohio State University Wexner Medical Center (OSUWMC). Our study is built upon the existing Coriell Personalized Medicine Collaborative (CPMC®). OSUWMC patient participants with chronic disease (CD) receive eight actionable complex disease and one pharmacogenomic test report through the CPMC® web portal. Participants are randomized to either the in-person post-test genomic counseling—active arm, versus web-based only return of results—control arm. Study-specific surveys measure: (1) change in risk perception; (2) knowledge retention; (3) perceived personal control; (4) health behavior change; and, for the active arm (5), overall satisfaction with genomic counseling. This ongoing partnership has spurred creation of both infrastructure and procedures necessary for the implementation of genomics and genomic counseling in clinical care and clinical research. This included creation of a comprehensive informed consent document and processes for prospective return of actionable results for multiple complex diseases and pharmacogenomics (PGx) through a web portal, and integration of genomic data files and clinical decision support into an EPIC-based electronic medical record. We present this partnership, the infrastructure, genomic counseling approach, and the challenges that arose in the design and conduct of this ongoing trial to inform subsequent collaborative efforts and best genomic counseling practices.
PMCID: PMC4051230  PMID: 24926413
implementation; genomics; medicine; randomized; patients; counseling; actionable; risk perception; pharmacogenomics
9.  Allele-specific imbalance mapping identifies HDAC9 as a candidate gene for cutaneous squamous cell carcinoma 
More than 3.5 million non-melanoma skin cancers were treated in 2006; of these 700,000 were cutaneous squamous cell carcinomas (cSCC). Despite clear environmental causes for cSCC, studies also suggest genetic risk factors. A cSCC susceptibility locus, Skts5, was identified on mouse chromosome 12 by linkage analysis. The orthologous locus to Skts5 in humans maps to 7p21 and 7q31. These loci show copy number increases in approximately 10% of cSCC tumors. Here we show that an additional 15-22% of tumors exhibit copy-neutral loss of heterozygosity. Furthermore, our previous data identified microsatellite markers on 7p21 and 7q31 that demonstrate preferential allelic imbalance (PAI) in cSCC tumors. Based on these results, we hypothesized that the human orthologous locus to Skts5 would house a gene important in human cSCC development and that tumors would demonstrate allele-specific somatic alterations. To test this hypothesis, we performed quantitative genotyping of 108 single nucleotide polymorphisms (SNPs) mapping to candidate genes at human SKTS5 in paired normal and tumor DNAs. Nine SNPs in HDAC9 (rs801540, rs1178108, rs1178112, rs1726610, rs10243618, rs11764116, rs1178355, rs10269422, and rs12540872) showed PAI in tumors. These data suggest that HDAC9 variants may be selected for during cSCC tumorigenesis.
PMCID: PMC3831612  PMID: 23784969
HDAC9; cutaneous squamous cell carcinoma; allelic-specific imbalance; Skts5
10.  The Impact of 3′UTR Variants on Differential Expression of Candidate Cancer Susceptibility Genes 
PLoS ONE  2013;8(3):e58609.
Variants in regulatory regions are predicted to play an important role in disease susceptibility of common diseases. Polymorphisms mapping to microRNA (miRNA) binding sites have been shown to disrupt the ability of miRNAs to target genes resulting in differential mRNA and protein expression. Skin tumor susceptibility 5 (Skts5) was identified as a locus conferring susceptibility to chemically-induced skin cancer in NIH/Ola by SPRET/Outbred F1 backcrosses. To determine if polymorphisms between the strains which mapped to putative miRNA binding sites in the 3′ untranslated region (3′UTR) of genes at Skts5 influenced expression, we conducted a systematic evaluation of 3′UTRs of candidate genes across this locus. Nine genes had polymorphisms in their 3′UTRs which fit the linkage data and eight of these contained polymorphisms suspected to interfere with or introduce miRNA binding. 3′UTRs of six genes, Bcap29, Dgkb, Hbp1, Pik3cg, Twistnb, and Tspan13 differentially affected luciferase expression, but did not appear to be differentially regulated by the evaluated miRNAs predicted to bind to only one of the two isoforms. 3′UTRs from four additional genes chosen from the locus that fit less stringent criteria were evaluated. Ifrd1 and Etv1 showed differences and contained polymorphisms predicted to disrupt or create miRNA binding sites but showed no difference in regulation by the miRNAs tested. In summary, multiple 3′UTRs with putative functional variants between susceptible and resistant strains of mice influenced differential expression independent of predicted miRNA binding.
PMCID: PMC3589377  PMID: 23472213
11.  A non-synonymous polymorphism in IRS1 modifies risk of developing breast and ovarian cancers in BRCA1 and ovarian cancer in BRCA2 mutation carriers 
Ding, Yuan C. | McGuffog, Lesley | Healey, Sue | Friedman, Eitan | Laitman, Yael | Shani-Shimon–Paluch,  | Kaufman, Bella | Liljegren, Annelie | Lindblom, Annika | Olsson, Håkan | Kristoffersson, Ulf | Stenmark-Askmalm, Marie | Melin, Beatrice | Domchek, Susan M. | Nathanson, Katherine L. | Rebbeck, Timothy R. | Jakubowska, Anna | Lubinski, Jan | Jaworska, Katarzyna | Durda, Katarzyna | Gronwald, Jacek | Huzarski, Tomasz | Cybulski, Cezary | Byrski, Tomasz | Osorio, Ana | Cajal, Teresa Ramóny | Stavropoulou, Alexandra V | Benítez, Javier | Hamann, Ute | Rookus, Matti | Aalfs, Cora M. | de Lange, Judith L. | Meijers-Heijboer, Hanne E.J. | Oosterwijk, Jan C. | van Asperen, Christi J. | García, Encarna B. Gómez | Hoogerbrugge, Nicoline | Jager, Agnes | van der Luijt, Rob B. | Easton, Douglas F. | Peock, Susan | Frost, Debra | Ellis, Steve D. | Platte, Radka | Fineberg, Elena | Evans, D. Gareth | Lalloo, Fiona | Izatt, Louise | Eeles, Ros | Adlard, Julian | Davidson, Rosemarie | Eccles, Diana | Cole, Trevor | Cook, Jackie | Brewer, Carole | Tischkowitz, Marc | Godwin, Andrew K. | Pathak, Harsh | Stoppa-Lyonnet, Dominique | Sinilnikova, Olga M. | Mazoyer, Sylvie | Barjhoux, Laure | Léoné, Mélanie | Gauthier-Villars, Marion | Caux-Moncoutier, Virginie | de Pauw, Antoine | Hardouin, Agnès | Berthet, Pascaline | Dreyfus, Hélène | Ferrer, Sandra Fert | Collonge-Rame, Marie-Agnès | Sokolowska, Johanna | Buys, Saundra | Daly, Mary | Miron, Alex | Terry, Mary Beth | Chung, Wendy | John, Esther M | Southey, Melissa | Goldgar, David | Singer, Christian F | Maria, Muy-Kheng Tea | Gschwantler-Kaulich, Daphne | Fink-Retter, Anneliese | Hansen, Thomas v. O. | Ejlertsen, Bent | Johannsson, Oskar Th. | Offit, Kenneth | Sarrel, Kara | Gaudet, Mia M. | Vijai, Joseph | Robson, Mark | Piedmonte, Marion R | Andrews, Lesley | Cohn, David | DeMars, Leslie R. | DiSilvestro, Paul | Rodriguez, Gustavo | Toland, Amanda Ewart | Montagna, Marco | Agata, Simona | Imyanitov, Evgeny | Isaacs, Claudine | Janavicius, Ramunas | Lazaro, Conxi | Blanco, Ignacio | Ramus, Susan J | Sucheston, Lara | Karlan, Beth Y. | Gross, Jenny | Ganz, Patricia A. | Beattie, Mary S. | Schmutzler, Rita K. | Wappenschmidt, Barbara | Meindl, Alfons | Arnold, Norbert | Niederacher, Dieter | Preisler-Adams, Sabine | Gadzicki, Dorotehea | Varon-Mateeva, Raymonda | Deissler, Helmut | Gehrig, Andrea | Sutter, Christian | Kast, Karin | Nevanlinna, Heli | Aittomäki, Kristiina | Simard, Jacques | Spurdle, Amanda B. | Beesley, Jonathan | Chen, Xiaoqing | Tomlinson, Gail E. | Weitzel, Jeffrey | Garber, Judy E. | Olopade, Olufunmilayo I. | Rubinstein, Wendy S. | Tung, Nadine | Blum, Joanne L. | Narod, Steven A. | Brummel, Sean | Gillen, Daniel L. | Lindor, Noralane | Fredericksen, Zachary | Pankratz, Vernon S. | Couch, Fergus J. | Radice, Paolo | Peterlongo, Paolo | Greene, Mark H. | Loud, Jennifer T. | Mai, Phuong L. | Andrulis, Irene L. | Glendon, Gord | Ozcelik, Hilmi | Gerdes, Anne-Marie | Thomassen, Mads | Jensen, Uffe Birk | Skytte, Anne-Bine | Caligo, Maria A. | Lee, Andrew | Chenevix-Trench, Georgia | Antoniou, Antonis C | Neuhausen, Susan L.
We previously reported significant associations between genetic variants in insulin receptor substrate 1 (IRS1) and breast cancer risk in women carrying BRCA1 mutations. The objectives of this study were to investigate whether the IRS1 variants modified ovarian cancer risk and were associated with breast cancer risk in a larger cohort of BRCA1 and BRCA2 mutation carriers.
IRS1 rs1801123, rs1330645, and rs1801278 were genotyped in samples from 36 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Data were analyzed by a retrospective cohort approach modeling the associations with breast and ovarian cancer risks simultaneously. Analyses were stratified by BRCA1 and BRCA2 status and mutation class in BRCA1 carriers.
Rs1801278 (Gly972Arg) was associated with ovarian cancer risk for both BRCA1 [Hazard ratio (HR) = 1.43; 95% CI: 1.06–1.92; p = 0.019] and BRCA2 mutation carriers (HR=2.21; 95% CI: 1.39–3.52, p=0.0008). For BRCA1 mutation carriers, the breast cancer risk was higher in carriers with class 2 mutations than class 1 (mutations (class 2 HR=1.86, 95% CI: 1.28–2.70; class 1 HR=0.86, 95%CI:0.69–1.09; p-for difference=0.0006). Rs13306465 was associated with ovarian cancer risk in BRCA1 class 2 mutation carriers (HR = 2.42; p = 0.03).
The IRS1 Gly972Arg SNP, which affects insulin-like growth factor and insulin signaling, modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers and breast cancer risk in BRCA1 class 2 mutation carriers.
These findings may prove useful for risk prediction for breast and ovarian cancers in BRCA1 and BRCA2 mutation carriers.
PMCID: PMC3415567  PMID: 22729394
Breast cancer; Ovarian cancer; BRCA1 and BRCA2 mutation carriers; insulin receptor substrate 1; Insulin-like growth factor /insulin (IGF/INS) signaling
12.  Haplotype structure in Ashkenazi Jewish BRCA1 and BRCA2 mutation carriers 
Im, Kate M. | Kirchhoff, Tomas | Wang, Xianshu | Green, Todd | Chow, Clement Y. | Vijai, Joseph | Korn, Joshua | Gaudet, Mia M. | Fredericksen, Zachary | Pankratz, V. Shane | Guiducci, Candace | Crenshaw, Andrew | McGuffog, Lesley | Kartsonaki, Christiana | Morrison, Jonathan | Healey, Sue | Sinilnikova, Olga M. | Mai, Phuong L. | Greene, Mark H. | Piedmonte, Marion | Rubinstein, Wendy S. | Hogervorst, Frans B. | Rookus, Matti A. | Collée, J. Margriet | Hoogerbrugge, Nicoline | van Asperen, Christi J. | Meijers-Heijboer, Hanne E. J. | Van Roozendaal, Cees E. | Caldes, Trinidad | Perez-Segura, Pedro | Jakubowska, Anna | Lubinski, Jan | Huzarski, Tomasz | Blecharz, Paweł | Nevanlinna, Heli | Aittomäki, Kristiina | Lazaro, Conxi | Blanco, Ignacio | Barkardottir, Rosa B. | Montagna, Marco | D'Andrea, Emma | Devilee, Peter | Olopade, Olufunmilayo I. | Neuhausen, Susan L. | Peissel, Bernard | Bonanni, Bernardo | Peterlongo, Paolo | Singer, Christian F. | Rennert, Gad | Lejbkowicz, Flavio | Andrulis, Irene L. | Glendon, Gord | Ozcelik, Hilmi | Toland, Amanda Ewart | Caligo, Maria Adelaide | Beattie, Mary S. | Chan, Salina | Domchek, Susan M. | Nathanson, Katherine L. | Rebbeck, Timothy R. | Phelan, Catherine | Narod, Steven | John, Esther M. | Hopper, John L. | Buys, Saundra S. | Daly, Mary B. | Southey, Melissa C. | Terry, Mary-Beth | Tung, Nadine | Hansen, Thomas v. O. | Osorio, Ana | Benitez, Javier | Durán, Mercedes | Weitzel, Jeffrey N. | Garber, Judy | Hamann, Ute | Peock, Susan | Cook, Margaret | Oliver, Clare T. | Frost, Debra | Platte, Radka | Evans, D. Gareth | Eeles, Ros | Izatt, Louise | Paterson, Joan | Brewer, Carole | Hodgson, Shirley | Morrison, Patrick J. | Porteous, Mary | Walker, Lisa | Rogers, Mark T. | Side, Lucy E. | Godwin, Andrew K. | Schmutzler, Rita K. | Wappenschmidt, Barbara | Laitman, Yael | Meindl, Alfons | Deissler, Helmut | Varon-Mateeva, Raymonda | Preisler-Adams, Sabine | Kast, Karin | Venat-Bouvet, Laurence | Stoppa-Lyonnet, Dominique | Chenevix-Trench, Georgia | Easton, Douglas F. | Klein, Robert J. | Daly, Mark J. | Friedman, Eitan | Dean, Michael | Clark, Andrew G. | Altshuler, David M. | Antoniou, Antonis C. | Couch, Fergus J. | Offit, Kenneth | Gold, Bert
Human genetics  2011;130(5):685-699.
Abstract Three founder mutations in BRCA1 and BRCA2 contribute to the risk of hereditary breast and ovarian cancer in Ashkenazi Jews (AJ). They are observed at increased frequency in the AJ compared to other BRCA mutations in Caucasian non-Jews (CNJ). Several authors have proposed that elevated allele frequencies in the surrounding genomic regions reflect adaptive or balancing selection. Such proposals predict long-range linkage dis-equilibrium (LD) resulting from a selective sweep, although genetic drift in a founder population may also act to create long-distance LD. To date, few studies have used the tools of statistical genomics to examine the likelihood of long-range LD at a deleterious locus in a population that faced a genetic bottleneck. We studied the genotypes of hundreds of women from a large international consortium of BRCA1 and BRCA2 mutation carriers and found that AJ women exhibited long-range haplotypes compared to CNJ women. More than 50% of the AJ chromosomes with the BRCA1 185delAG mutation share an identical 2.1 Mb haplotype and nearly 16% of AJ chromosomes carrying the BRCA2 6174delT mutation share a 1.4 Mb haplotype. Simulations based on the best inference of Ashkenazi population demography indicate that long-range haplotypes are expected in the context of a genome-wide survey. Our results are consistent with the hypothesis that a local bottleneck effect from population size constriction events could by chance have resulted in the large haplotype blocks observed at high frequency in the BRCA1 and BRCA2 regions of Ashkenazi Jews.
PMCID: PMC3196382  PMID: 21597964
13.  Ovarian Cancer Susceptibility Alleles and Risk of Ovarian Cancer in BRCA1 and BRCA2 Mutation Carriers 
Ramus, Susan J. | Antoniou, Antonis C | Kuchenbaecker, Karoline B. | Soucy, Penny | Beesley, Jonathan | Chen, Xiaoqing | McGuffog, Lesley | Sinilnikova, Olga M. | Healey, Sue | Barrowdale, Daniel | Lee, Andrew | Thomassen, Mads | Gerdes, Anne-Marie | Kruse, Torben A. | Jensen, Uffe Birk | Skytte, Anne-Bine | Caligo, Maria A. | Liljegren, Annelie | Lindblom, Annika | Olsson, Håkan | Kristoffersson, Ulf | Stenmark-Askmalm, Marie | Melin, Beatrice | Domchek, Susan M. | Nathanson, Katherine L. | Rebbeck, Timothy R. | Jakubowska, Anna | Lubinski, Jan | Jaworska, Katarzyna | Durda, Katarzyna | Złowocka, Elżbieta | Gronwald, Jacek | Huzarski, Tomasz | Byrski, Tomasz | Cybulski, Cezary | Toloczko-Grabarek, Aleksandra | Osorio, Ana | Benitez, Javier | Duran, Mercedes | Tejada, Maria-Isabel | Hamann, Ute | Rookus, Matti | van Leeuwen, Flora E. | Aalfs, Cora M. | Meijers-Heijboer, Hanne E.J. | van Asperen, Christi J. | van Roozendaal, K.E.P. | Hoogerbrugge, Nicoline | Collée, J. Margriet | Kriege, Mieke | van der Luijt, Rob B. | Peock, Susan | Frost, Debra | Ellis, Steve D. | Platte, Radka | Fineberg, Elena | Evans, D. Gareth | Lalloo, Fiona | Jacobs, Chris | Eeles, Ros | Adlard, Julian | Davidson, Rosemarie | Eccles, Diana | Cole, Trevor | Cook, Jackie | Paterson, Joan | Douglas, Fiona | Brewer, Carole | Hodgson, Shirley | Morrison, Patrick J. | Walker, Lisa | Porteous, Mary E. | Kennedy, M. John | Pathak, Harsh | Godwin, Andrew K. | Stoppa-Lyonnet, Dominique | Caux-Moncoutier, Virginie | de Pauw, Antoine | Gauthier-Villars, Marion | Mazoyer, Sylvie | Léoné, Mélanie | Calender, Alain | Lasset, Christine | Bonadona, Valérie | Hardouin, Agnès | Berthet, Pascaline | Bignon, Yves-Jean | Uhrhammer, Nancy | Faivre, Laurence | Loustalot, Catherine | Buys, Saundra | Daly, Mary | Miron, Alex | Terry, Mary Beth | Chung, Wendy K. | John, Esther M | Southey, Melissa | Goldgar, David | Singer, Christian F | Tea, Muy-Kheng | Pfeiler, Georg | Fink-Retter, Anneliese | Hansen, Thomas v. O. | Ejlertsen, Bent | Johannsson, Oskar Th. | Offit, Kenneth | Kirchhoff, Tomas | Gaudet, Mia M. | Vijai, Joseph | Robson, Mark | Piedmonte, Marion | Phillips, Kelly-Anne | Van Le, Linda | Hoffman, James S | Toland, Amanda Ewart | Montagna, Marco | Tognazzo, Silvia | Imyanitov, Evgeny | Isaacs, Claudine | Janavicius, Ramunas | Lazaro, Conxi | Blanco, Ignacio | Tornero, Eva | Navarro, Matilde | Moysich, Kirsten B. | Karlan, Beth Y. | Gross, Jenny | Olah, Edith | Vaszko, Tibor | Teo, Soo-Hwang | Ganz, Patricia A. | Beattie, Mary S. | Dorfling, Cecelia M | van Rensburg, Elizabeth J | Diez, Orland | Kwong, Ava | Schmutzler, Rita K. | Wappenschmidt, Barbara | Engel, Christoph | Meindl, Alfons | Ditsch, Nina | Arnold, Norbert | Heidemann, Simone | Niederacher, Dieter | Preisler-Adams, Sabine | Gadzicki, Dorotehea | Varon-Mateeva, Raymonda | Deissler, Helmut | Gehrig, Andrea | Sutter, Christian | Kast, Karin | Fiebig, Britta | Schäfer, Dieter | Caldes, Trinidad | de la Hoya, Miguel | Nevanlinna, Heli | Aittomäki, Kristiina | Plante, Marie | Spurdle, Amanda B. | Neuhausen, Susan L. | Ding, Yuan Chun | Wang, Xianshu | Lindor, Noralane | Fredericksen, Zachary | Pankratz, V. Shane | Peterlongo, Paolo | Manoukian, Siranoush | Peissel, Bernard | Zaffaroni, Daniela | Bonanni, Bernardo | Bernard, Loris | Dolcetti, Riccardo | Papi, Laura | Ottini, Laura | Radice, Paolo | Greene, Mark H. | Mai, Phuong L. | Andrulis, Irene L. | Glendon, Gord | Ozcelik, Hilmi | Pharoah, Paul D.P. | Gayther, Simon A. | Simard, Jacques | Easton, Douglas F. | Couch, Fergus J. | Chenevix-Trench, Georgia
Human mutation  2012;33(4):690-702.
Germline mutations in BRCA1 and BRCA2 are associated with increased risks of breast and ovarian cancer. A genome-wide association study (GWAS) identified six alleles associated with risk of ovarian cancer for women in the general population. We evaluated four of these loci as potential modifiers of ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Four single-nucleotide polymorphisms (SNPs), rs10088218 (at 8q24), rs2665390 (at 3q25), rs717852 (at 2q31), and rs9303542 (at 17q21), were genotyped in 12,599 BRCA1 and 7,132 BRCA2 carriers, including 2,678 ovarian cancer cases. Associations were evaluated within a retrospective cohort approach. All four loci were associated with ovarian cancer risk in BRCA2 carriers; rs10088218 per-allele hazard ratio (HR) = 0.81 (95% CI: 0.67–0.98) P-trend = 0.033, rs2665390 HR = 1.48 (95% CI: 1.21–1.83) P-trend = 1.8 × 10−4, rs717852 HR = 1.25 (95% CI: 1.10–1.42) P-trend = 6.6 × 10−4, rs9303542 HR = 1.16 (95% CI: 1.02–1.33) P-trend = 0.026. Two loci were associated with ovarian cancer risk in BRCA1 carriers; rs10088218 per-allele HR = 0.89 (95% CI: 0.81–0.99) P-trend = 0.029, rs2665390 HR = 1.25 (95% CI: 1.10–1.42) P-trend = 6.1 × 10−4. The HR estimates for the remaining loci were consistent with odds ratio estimates for the general population. The identification of multiple loci modifying ovarian cancer risk may be useful for counseling women with BRCA1 and BRCA2 mutations regarding their risk of ovarian cancer.
PMCID: PMC3458423  PMID: 22253144
ovarian cancer; BRCA1; BRCA2; association; SNP
14.  Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) 
Mavaddat, Nasim | Barrowdale, Daniel | Andrulis, Irene L. | Domchek, Susan M. | Eccles, Diana | Nevanlinna, Heli | Ramus, Susan J. | Spurdle, Amanda | Robson, Mark | Sherman, Mark | Mulligan, Anna Marie | Couch, Fergus J. | Engel, Christoph | McGuffog, Lesley | Healey, Sue | Sinilnikova, Olga M. | Southey, Melissa C. | Terry, Mary Beth | Goldgar, David | O’Malley, Frances | John, Esther M. | Janavicius, Ramunas | Tihomirova, Laima | Hansen, Thomas v O | Nielsen, Finn C. | Osorio, Ana | Stavropoulou, Alexandra | Benítez, Javier | Manoukian, Siranoush | Peissel, Bernard | Barile, Monica | Volorio, Sara | Pasini, Barbara | Dolcetti, Riccardo | Putignano, Anna Laura | Ottini, Laura | Radice, Paolo | Hamann, Ute | Rashid, Muhammad U. | Hogervorst, Frans B. | Kriege, Mieke | van der Luijt, Rob B. | Peock, Susan | Frost, Debra | Evans, D. Gareth | Brewer, Carole | Walker, Lisa | Rogers, Mark T. | Side, Lucy E. | Houghton, Catherine | Weaver, JoEllen | Godwin, Andrew K. | Schmutzler, Rita K. | Wappenschmidt, Barbara | Meindl, Alfons | Kast, Karin | Arnold, Norbert | Niederacher, Dieter | Sutter, Christian | Deissler, Helmut | Gadzicki, Doroteha | Preisler-Adams, Sabine | Varon-Mateeva, Raymonda | Schönbuchner, Ines | Gevensleben, Heidrun | Stoppa-Lyonnet, Dominique | Belotti, Muriel | Barjhoux, Laure | Isaacs, Claudine | Peshkin, Beth N. | Caldes, Trinidad | de al Hoya, Miguel | Cañadas, Carmen | Heikkinen, Tuomas | Heikkilä, Päivi | Aittomäki, Kristiina | Blanco, Ignacio | Lazaro, Conxi | Brunet, Joan | Agnarsson, Bjarni A. | Arason, Adalgeir | Barkardottir, Rosa B. | Dumont, Martine | Simard, Jacques | Montagna, Marco | Agata, Simona | D’Andrea, Emma | Yan, Max | Fox, Stephen | Rebbeck, Timothy R. | Rubinstein, Wendy | Tung, Nadine | Garber, Judy E. | Wang, Xianshu | Fredericksen, Zachary | Pankratz, Vernon S. | Lindor, Noralane M. | Szabo, Csilla | Offit, Kenneth | Sakr, Rita | Gaudet, Mia M. | Singer, Christian F. | Tea, Muy-Kheng | Rappaport, Christine | Mai, Phuong L. | Greene, Mark H. | Sokolenko, Anna | Imyanitov, Evgeny | Toland, Amanda Ewart | Senter, Leigha | Sweet, Kevin | Thomassen, Mads | Gerdes, Anne-Marie | Kruse, Torben | Caligo, Maria | Aretini, Paolo | Rantala, Johanna | von Wachenfeld, Anna | Henriksson, Karin | Steele, Linda | Neuhausen, Susan L. | Nussbaum, Bob | Beattie, Mary | Odunsi, Kunle | Sucheston, Lara | Gayther, Simon A | Nathanson, Kate | Gross, Jenny | Walsh, Christine | Karlan, Beth | Chenevix-Trench, Georgia | Easton, Douglas F. | Antoniou, Antonis C.
Previous small studies found that BRCA1 and BRCA2 breast tumors differ in their pathology. Analysis of larger datasets of mutation carriers should allow further tumor characterization.
We used data from 4,325 BRCA1 and 2,568 BRCA2 mutation carriers to analyze the pathology of invasive breast, ovarian and contralateral breast cancers.
There was strong evidence that the proportion of estrogen receptor (ER)-negative breast tumors decreased with age at diagnosis among BRCA1 (p-trend=1.2×10−5) but increased with age at diagnosis among BRCA2 carriers (p-trend=6.8×10−6). The proportion of triple negative tumors decreased with age at diagnosis in BRCA1 carriers but increased with age at diagnosis of BRCA2 carriers. In both BRCA1 and BRCA2 carriers, ER-negative tumors were of higher histological grade than ER-positive tumors (Grade 3 vs. Grade 1, p=1.2×10−13 for BRCA1 and p=0.001 for BRCA2). ER and progesterone receptor (PR) expression were independently associated with mutation carrier status (ER-positive odds ratio (OR) for BRCA2=9.4, 95%CI:7.0-12.6 and PR-positive OR=1.7, 95%CI:1.3-2.3, under joint analysis). Lobular tumors were more likely to be BRCA2-related (OR for BRCA2=3.3, 95%CI:2.4-4.4, p=4.4×10−14), and medullary tumors BRCA1-related (OR for BRCA2=0.25, 95%CI:0.18-0.35, p=2.3×10−15). ER-status of the first breast cancer was predictive of ER-status of asynchronous contralateral breast cancer (p=0.0004 for BRCA1; p=0.002 for BRCA2). There were no significant differences in ovarian cancer morphology between BRCA1 and BRCA2 carriers (serous:67%; mucinous:1%; endometriod:12%; clear-cell:2%).
Pathology characteristics of BRCA1 and BRCA2 tumors may be useful for improving risk prediction algorithms and informing clinical strategies for screening and prophylaxis.
PMCID: PMC3272407  PMID: 22144499
pathology; breast; BRCA1; BRCA2; contralateral
15.  Evaluation of Allele-Specific Somatic Changes of Genome-Wide Association Study Susceptibility Alleles in Human Colorectal Cancers 
PLoS ONE  2012;7(5):e37672.
Tumors frequently exhibit loss of tumor suppressor genes or allelic gains of activated oncogenes. A significant proportion of cancer susceptibility loci in the mouse show somatic losses or gains consistent with the presence of a tumor susceptibility or resistance allele. Thus, allele-specific somatic gains or losses at loci may demarcate the presence of resistance or susceptibility alleles. The goal of this study was to determine if previously mapped susceptibility loci for colorectal cancer show evidence of allele-specific somatic events in colon tumors.
We performed quantitative genotyping of 16 single nucleotide polymorphisms (SNPs) showing statistically significant association with colorectal cancer in published genome-wide association studies (GWAS). We genotyped 194 paired normal and colorectal tumor DNA samples and 296 paired validation samples to investigate these SNPs for allele-specific somatic gains and losses. We combined analysis of our data with published data for seven of these SNPs.
No statistically significant evidence for allele-specific somatic selection was observed for the tested polymorphisms in the discovery set. The rs6983267 variant, which has shown preferential loss of the non-risk T allele and relative gain of the risk G allele in previous studies, favored relative gain of the G allele in the combined discovery and validation samples (corrected p-value = 0.03). When we combined our data with published allele-specific imbalance data for this SNP, the G allele of rs6983267 showed statistically significant evidence of relative retention (p-value = 2.06×10−4).
Our results suggest that the majority of variants identified as colon cancer susceptibility alleles through GWAS do not exhibit somatic allele-specific imbalance in colon tumors. Our data confirm previously published results showing allele-specific imbalance for rs6983267. These results indicate that allele-specific imbalance of cancer susceptibility alleles may not be a common phenomenon in colon cancer.
PMCID: PMC3357346  PMID: 22629442
16.  Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers: implications for risk prediction 
Antoniou, Antonis C | Beesley, Jonathan | McGuffog, Lesley | Sinilnikova, Olga M. | Healey, Sue | Neuhausen, Susan L. | Ding, Yuan Chun | Rebbeck, Timothy R. | Weitzel, Jeffrey N. | Lynch, Henry T. | Isaacs, Claudine | Ganz, Patricia A. | Tomlinson, Gail | Olopade, Olufunmilayo I. | Couch, Fergus J. | Wang, Xianshu | Lindor, Noralane M. | Pankratz, Vernon S. | Radice, Paolo | Manoukian, Siranoush | Peissel, Bernard | Zaffaroni, Daniela | Barile, Monica | Viel, Alessandra | Allavena, Anna | Dall’Olio, Valentina | Peterlongo, Paolo | Szabo, Csilla I. | Zikan, Michal | Claes, Kathleen | Poppe, Bruce | Foretova, Lenka | Mai, Phuong L. | Greene, Mark H. | Rennert, Gad | Lejbkowicz, Flavio | Glendon, Gord | Ozcelik, Hilmi | Andrulis, Irene L. | Thomassen, Mads | Gerdes, Anne-Marie | Sunde, Lone | Cruger, Dorthe | Jensen, Uffe Birk | Caligo, Maria | Friedman, Eitan | Kaufman, Bella | Laitman, Yael | Milgrom, Roni | Dubrovsky, Maya | Cohen, Shimrit | Borg, Ake | Jernström, Helena | Lindblom, Annika | Rantala, Johanna | Stenmark-Askmalm, Marie | Melin, Beatrice | Nathanson, Kate | Domchek, Susan | Jakubowska, Ania | Lubinski, Jan | Huzarski, Tomasz | Osorio, Ana | Lasa, Adriana | Durán, Mercedes | Tejada, Maria-Isabel | Godino, Javier | Benitez, Javier | Hamann, Ute | Kriege, Mieke | Hoogerbrugge, Nicoline | van der Luijt, Rob B | van Asperen, Christi J | Devilee, Peter | Meijers-Heijboer, E.J. | Blok, Marinus J | Aalfs, Cora M. | Hogervorst, Frans | Rookus, Matti | Cook, Margaret | Oliver, Clare | Frost, Debra | Conroy, Don | Evans, D. Gareth | Lalloo, Fiona | Pichert, Gabriella | Davidson, Rosemarie | Cole, Trevor | Cook, Jackie | Paterson, Joan | Hodgson, Shirley | Morrison, Patrick J. | Porteous, Mary E. | Walker, Lisa | Kennedy, M. John | Dorkins, Huw | Peock, Susan | Godwin, Andrew K. | Stoppa-Lyonnet, Dominique | de Pauw, Antoine | Mazoyer, Sylvie | Bonadona, Valérie | Lasset, Christine | Dreyfus, Hélène | Leroux, Dominique | Hardouin, Agnès | Berthet, Pascaline | Faivre, Laurence | Loustalot, Catherine | Noguchi, Tetsuro | Sobol, Hagay | Rouleau, Etienne | Nogues, Catherine | Frénay, Marc | Vénat-Bouvet, Laurence | Hopper, John L. | Daly, Mary B. | Terry, Mary B. | John, Esther M. | Buys, Saundra S. | Yassin, Yosuf | Miron, Alex | Goldgar, David | Singer, Christian F. | Dressler, Anne Catharina | Gschwantler-Kaulich, Daphne | Pfeiler, Georg | Hansen, Thomas V. O. | Jønson, Lars | Agnarsson, Bjarni A. | Kirchhoff, Tomas | Offit, Kenneth | Devlin, Vincent | Dutra-Clarke, Ana | Piedmonte, Marion | Rodriguez, Gustavo C. | Wakeley, Katie | Boggess, John F. | Basil, Jack | Schwartz, Peter E. | Blank, Stephanie V. | Toland, Amanda Ewart | Montagna, Marco | Casella, Cinzia | Imyanitov, Evgeny | Tihomirova, Laima | Blanco, Ignacio | Lazaro, Conxi | Ramus, Susan J. | Sucheston, Lara | Karlan, Beth Y. | Gross, Jenny | Schmutzler, Rita | Wappenschmidt, Barbara | Engel, Christoph | Meindl, Alfons | Lochmann, Magdalena | Arnold, Norbert | Heidemann, Simone | Varon-Mateeva, Raymonda | Niederacher, Dieter | Sutter, Christian | Deissler, Helmut | Gadzicki, Dorothea | Preisler-Adams, Sabine | Kast, Karin | Schönbuchner, Ines | Caldes, Trinidad | de la Hoya, Miguel | Aittomäki, Kristiina | Nevanlinna, Heli | Simard, Jacques | Spurdle, Amanda B. | Holland, Helene | Chen, Xiaoqing | Platte, Radka | Chenevix-Trench, Georgia | Easton, Douglas F.
Cancer research  2010;70(23):9742-9754.
The known breast cancer (BC) susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1,LSP1 and 2q35 confer increased risks of BC for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of three additional SNPs, rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11 and rs10941679 at 5p12 and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased BC risk for BRCA2 carriers (per-allele Hazard Ratio (HR)=1.10, 95%CI:1.03-1.18, p=0.006 and HR=1.09, 95%CI:1.01-1.19, p=0.03, respectively). Neither SNP was associated with BC risk for BRCA1 carriers and rs6504950 was not associated with BC for either BRCA1 or BRCA2 carriers. Of the nine polymorphisms investigated, seven were associated with BC for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, p-values:7×10−11-0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (p=0.0049, 0.03 respectively). All risk associated polymorphisms appear to interact multiplicatively on BC risk for mutation carriers. Based on the joint genotype distribution of the seven risk associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e. between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing BC by age 80, compared with 42-50% for the 5% of carriers at lowest risk. Our findings indicated that these risk differences may be sufficient to influence the clinical management of mutation carriers.
PMCID: PMC2999830  PMID: 21118973
BRCA1; BRCA2; genetic modifier; common variant; genome-wide association study; penetrance; genetic counseling
17.  The effect of BRCA1 missense mutations on homology directed recombination 
Cancer research  2010;70(3):988-995.
There have been few published analyses of the effects of missense mutations of the BRCA1 gene on BRCA1 protein function. In this study, we adapted a previously described homology directed recombination (HDR) assay to the analysis of the effects of BRCA1 point substitutions on its function in recombination. We established a HeLa-derived cell line, which has integrated in its genome a recombination substrate. Following transfection of a plasmid that expresses the endonuclease that creates a double-stranded break in the recombination substrate, HDR is readily scored by the percentage of GFP-positive cells. By combining RNAi specific for the cellular BRCA1 mRNA with expression of BRCA1 mutants resistant to the RNAi, we could effectively replace the endogenous BRCA1 protein with selected point mutants of BRCA1 and test these in the recombination assay. We found that both, the amino- and carboxy-terminal ~300 residues of BRCA1 were essential for directing HDR. Sixteen missense mutants from the amino terminus of BRCA1 were analyzed for function in HDR, and we found that several point mutants fully replaced the wild-type BRCA1 and are neutral in this process. Mutation of any single zinc-coordinating residue was fully defective in this assay. Several protein variants due to missense mutations, including methionine-18 to threonine and threonine-37 to arginine were also found to be defective for recombination. We have thus established a robust assay system for the analysis of the effects of specific missense mutations of BRCA1 in regulating the homologous recombination process.
PMCID: PMC2943742  PMID: 20103620
18.  Germline Variation Controls the Architecture of Somatic Alterations in Tumors 
PLoS Genetics  2010;6(9):e1001136.
Studies have suggested that somatic events in tumors can depend on an individual's constitutional genotype. We used squamous cell carcinomas (SCC) of the skin, which arise in high multiplicity in organ transplant recipients, as a model to compare the pattern of somatic alterations within and across individuals. Specifically, we performed array comparative genomic hybridization on 104 tumors from 25 unrelated individuals who each had three or more independently arisen SCCs and compared the profiles occurring within patients to profiles of tumors across a larger set of 135 patients. In general, chromosomal aberrations in SCCs were more similar within than across individuals (two-sided exact-test p-value ), consistent with the notion that the genetic background was affecting the pattern of somatic changes. To further test this possibility, we performed allele-specific imbalance studies using microsatellite markers mapping to 14 frequently aberrant regions of multiple independent tumors from 65 patients. We identified nine loci which show evidence of preferential allelic imbalance. One of these loci, 8q24, corresponded to a region in which multiple single nucleotide polymorphisms have been associated with increased cancer risk in genome-wide association studies (GWAS). We tested three implicated variants and identified one, rs13281615, with evidence of allele-specific imbalance (p-value = 0.012). The finding of an independently identified cancer susceptibility allele with allele-specific imbalance in a genomic region affected by recurrent DNA copy number changes suggest that it may also harbor risk alleles for SCC. Together these data provide strong evidence that the genetic background is a key driver of somatic events in cancer, opening an opportunity to expand this approach to identify cancer risk alleles.
Author Summary
Tumors exhibit DNA copy number gains and losses, many of which alter the dosage of genes that promote or suppress tumorigenesis. Evidence from familial cancer syndromes and animal models have shown that DNA copy number changes acquired somatically during tumor progression can be controlled by the constitutional genotype. The genetic heterogeneity among humans makes it difficult to systematically assess the extent of this effect. We used a unique clinical scenario of squamous cell carcinoma (SCC), which can arise in high multiplicity within patients, to compare the pattern of somatic alterations on a homogeneous genetic background. We examined the genome-wide pattern of DNA copy number changes of tumors from individuals who had three or more independent SCCs. We identified multiple chromosomal regions that showed higher frequency of change in SCCs within patients than across patients, suggesting that the genetic background of the individual is important in driving these changes. We further confirmed this by identifying eight regions with strong evidence for a selection of loss or gain of a particular allele within patients. Together these data demonstrate that the genetic background of an individual influences the pattern of somatic alterations in tumors, offering a novel approach to map susceptibility alleles.
PMCID: PMC2944791  PMID: 20885788
19.  Epigenetic alterations in the breast: Implications for breast cancer detection, prognosis and treatment 
Seminars in cancer biology  2009;19(3):165-171.
Epigenetic alterations of the genome such as DNA promoter methylation and chromatin remodeling play an important role in tumorigenesis. Recent findings indicate epigenetic modifications as key factors in breast carcinogenesis. These modifications are quite appealing as targets for preventative care and therapeutics because of their potential for reversal. Future medical care for breast cancer patients will likely depend upon a better understanding of the roles epigenetic modifications play in carcinogenesis. Here, we discuss the importance of epigenetics in breast cancer detection, prognosis, and therapy with an emphasis on mechanisms and epigenetic contributions to field cancerization effects.
PMCID: PMC2734184  PMID: 19429480
epigenetics; breast cancer; field cancerization BRCA; ER
20.  Sequence divergence of Mus spretus and Mus musculus across a skin cancer susceptibility locus 
BMC Genomics  2008;9:626.
Mus spretus diverged from Mus musculus over one million years ago. These mice are genetically and phenotypically divergent. Despite the value of utilizing M. musculus and M. spretus for quantitative trait locus (QTL) mapping, relatively little genomic information on M. spretus exists, and most of the available sequence and polymorphic data is for one strain of M. spretus, Spret/Ei. In previous work, we mapped fifteen loci for skin cancer susceptibility using four different M. spretus by M. musculus F1 backcrosses. One locus, skin tumor susceptibility 5 (Skts5) on chromosome 12, shows strong linkage in one cross.
To identify potential candidate genes for Skts5, we sequenced 65 named and unnamed genes and coding elements mapping to the peak linkage area in outbred spretus, Spret/EiJ, FVB/NJ, and NIH/Ola. We identified polymorphisms in 62 of 65 genes including 122 amino acid substitutions. To look for polymorphisms consistent with the linkage data, we sequenced exons with amino acid polymorphisms in two additional M. spretus strains and one additional M. musculus strain generating 40.1 kb of sequence data. Eight candidate variants were identified that fit with the linkage data. To determine the degree of variation across M. spretus, we conducted phylogenetic analyses. The relatedness of the M. spretus strains at this locus is consistent with the proximity of region of ascertainment of the ancestral mice.
Our analyses suggest that, if Skts5 on chromosome 12 is representative of other regions in the genome, then published genomic data for Spret/EiJ are likely to be of high utility for genomic studies in other M. spretus strains.
PMCID: PMC2628916  PMID: 19105829

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