Susan M Domchek

Publications (104)811.25 Total impact

• Source

  Available from: Robert A Vierkant

  Article: Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer.

  Stig E Bojesen, Karen A Pooley, Sharon E Johnatty, Jonathan Beesley, Kyriaki Michailidou, Jonathan P Tyrer, Stacey L Edwards, Hilda A Pickett, Howard C Shen, Chanel E Smart, [......], Simon A Gayther, Paul D P Pharoah, Roger R Reddel, Ellen L Goode, Mark H Greene, Douglas F Easton, Andrew Berchuck, Antonis C Antoniou, Georgia Chenevix-Trench, Alison M Dunning
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  ABSTRACT: TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOGs, we analyzed ∼480 SNPs at the TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also available for 53,724 participants. Most associations cluster into three independent peaks. The minor allele at the peak 1 SNP rs2736108 associates with longer telomeres (P = 5.8 × 10(-7)), lower risks for estrogen receptor (ER)-negative (P = 1.0 × 10(-8)) and BRCA1 mutation carrier (P = 1.1 × 10(-5)) breast cancers and altered promoter assay signal. The minor allele at the peak 2 SNP rs7705526 associates with longer telomeres (P = 2.3 × 10(-14)), higher risk of low-malignant-potential ovarian cancer (P = 1.3 × 10(-15)) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (P = 1.2 × 10(-12)) and BRCA1 mutation carrier (P = 1.6 × 10(-14)) breast and invasive ovarian (P = 1.3 × 10(-11)) cancer risks but not via altered telomere length. The cancer risk alleles of rs2242652 and rs10069690, respectively, increase silencing and generate a truncated TERT splice variant.
  Nature Genetics 03/2013; 45(4):371-384. · 35.53 Impact Factor
• Article: Incremental impact of breast cancer SNP panel on risk classification in a screening population of white and African American women.

  Anne Marie McCarthy, Katrina Armstrong, Elizabeth Handorf, Leigh Boghossian, Marisa Jones, Jinbo Chen, Mirar Bristol Demeter, Erin McGuire, Emily F Conant, Susan M Domchek
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  ABSTRACT: Breast cancer risk prediction remains imperfect, particularly among non-white populations. This study examines the impact of including single-nucleotide polymorphism (SNP) alleles in risk prediction for white and African American women undergoing screening mammogram. Using a prospective cohort study, standard risk information and buccal swabs were collected at the time of screening mammography. A 12 SNP panel was performed by deCODE genetics. Five-year and lifetime risks incorporating SNPs were calculated by multiplying estimated Breast Cancer Risk Assessment Tool (BCRAT) risk by the total genetic risk ratio. Concordance between the BCRAT and the combined model (BCRAT + SNPs) in identifying high-risk women was measured using the kappa statistic. SNP data were available for 810 women (39 % African American, 55 % white). The mean BCRAT 5-year risk was 1.71 % for whites and 1.18 % for African Americans. Mean genetic risk ratios were 1.09 in whites and 1.29 in African Americans. Among whites, three SNPs had higher frequencies, and among African Americans, seven SNPs had higher and four had lower high-risk allele frequencies than previously reported. Agreement between the BCRAT and the combined model was relatively low for identifying high-risk women (5-year κ = 0.54, lifetime κ = 0.36). Addition of SNPs had the greatest effect among African Americans, with 12.4 % identified as having high-5-year risk by BCRAT, but 33 % by the combined model. A greater proportion of African Americans were reclassified as having high-5-year risk than whites using the combined model (21 vs. 10 %). The addition of SNPs to the BCRAT reclassifies the high-risk status of some women undergoing screening mammography, particularly African Americans. Further research is needed to determine the clinical validity and utility of the SNP panel for use in breast cancer risk prediction, particularly among African Americans for whom these risk alleles have generally not been validated.
  Breast Cancer Research and Treatment 03/2013; · 4.43 Impact Factor
• Article: Fine-mapping of Breast Cancer Genome-wide Association Studies Loci in Women of African Ancestry Identifies Novel Susceptibility Markers.

  Yonglan Zheng, Temidayo O Ogundiran, Adeyinka G Falusi, Katherine L Nathanson, Esther M John, Anselm J M Hennis, Stefan Ambs, Susan M Domchek, Timothy R Rebbeck, Michael S Simon, [......], Maria Cristina Leske, Abayomi Odetunde, Qun Niu, Jing Zhang, Chibuzor Afolabi, Eric R Gamazon, Nancy J Cox, Christopher O Olopade, Olopade I Olufunmilayo, Dezheng Huo
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  ABSTRACT: Numerous single nucleotide polymorphisms (SNPs) associated with breast cancer susceptibility have been identified by genome-wide association studies (GWAS). However, these SNPs were primarily discovered and validated in women of European and Asian ancestry. Because linkage disequilibrium (LD) is ancestry-dependent and heterogeneous among racial/ethnic populations, we evaluated common genetic variants at 22 GWAS-identified breast cancer susceptibility loci in a pooled sample of 1502 breast cancer cases and 1378 controls of African ancestry. None of the 22 GWAS index SNPs could be validated, challenging the direct generalizability of breast cancer risk variants identified in Caucasians or Asians to other populations. Novel breast cancer risk variants for women of African ancestry were identified in regions including 5p12 (odds ratio [OR] = 1.40, 95% confidence interval [CI]: 1.11-1.76; P = 0.004), 5q11.2 (OR = 1.22, 95% CI: 1.09-1.36; P = 0.00053), and 10p15.1 (OR = 1.22, 95% CI: 1.08-1.38; P = 0.0015). We also found positive association signals in three regions (6q25.1, 10q26.13, and 16q12.1-q12.2) previously confirmed by fine-mapping in women of African ancestry. In addition, polygenic model indicated that 8 best markers in this study, compared to 22 GWAS-identified SNPs, could better predict breast cancer risk in Black women (per allele OR = 1.21, 95% CI: 1.16-1.27; P = 9.7×10-16). Our results demonstrate that fine-mapping is a powerful approach to better characterizing breast cancer risk alleles in diverse populations. Future studies in women of African ancestry hold promise to discover additional variants for breast cancer susceptibility with clinical implications throughout the African Diaspora.
  Carcinogenesis 03/2013; · 5.70 Impact Factor
• Article: Multiplex Genetic Testing for Cancer Susceptibility: Out on the High Wire Without a Net?

  Susan M Domchek, Angela Bradbury, Judy E Garber, Kenneth Offit, Mark E Robson
  Journal of Clinical Oncology 03/2013; · 18.37 Impact Factor
• Article: Identification of a BRCA2-Specific Modifier Locus at 6p24 Related to Breast Cancer Risk.

  Mia M Gaudet, Karoline B Kuchenbaecker, Joseph Vijai, Robert J Klein, Tomas Kirchhoff, Lesley McGuffog, Daniel Barrowdale, Alison M Dunning, Andrew Lee, Joe Dennis, [......], Guillermo Pita, M Rosario Alonso, Per Hall, Fergus J Couch, Jacques Simard, David Altshuler, Douglas F Easton, Georgia Chenevix-Trench, Antonis C Antoniou, Kenneth Offit
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  ABSTRACT: Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9×10(-8)). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer.
  PLoS Genetics 03/2013; 9(3):e1003173. · 8.69 Impact Factor
• Article: Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk.

  Fergus J Couch, Xianshu Wang, Lesley McGuffog, Andrew Lee, Curtis Olswold, Karoline B Kuchenbaecker, Penny Soucy, Zachary Fredericksen, Daniel Barrowdale, Joe Dennis, [......], Chen Wang, Steven Hart, Kristen Stevens, Jacques Simard, Tomi Pastinen, Vernon S Pankratz, Kenneth Offit, Douglas F Easton, Georgia Chenevix-Trench, Antonis C Antoniou
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  ABSTRACT: BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10(-8), HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4×10(-8), HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2×10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.
  PLoS Genetics 03/2013; 9(3):e1003212. · 8.69 Impact Factor
• Article: Melanoma Genetic Testing, Counseling, and Adherence to Skin Cancer Prevention and Detection Behaviors.

  Karen L Glanz, Kathryn Volpicelli, Peter A Kanetsky, Michael E Ming, Lynn M Schuchter, Christopher Jepson, Susan M Domchek, Katrina Armstrong
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  ABSTRACT: BACKGROUND: Little is known about the impact of knowledge of CDKN2A and MC1R genotype on melanoma prevention behaviors like sun avoidance and skin examination in the context of familial melanoma. METHODS: A total of 73 adults with a family history of melanoma were randomly assigned to be offered individualized CDKN2A and MC1R genotyping results in the context of a genetic counseling session, or the standard practice of not being offered counseling or disclosure of genotyping results. Mixed effects or longitudinal logistic models were used to determine whether the intervention affected change in sun protection habits, skin examinations and perception and beliefs related to melanoma risk, prevention, and genetic counseling. RESULTS: All participants in the intervention group who attended genetic counseling sessions chose to receive their test results. From baseline to follow-up, participants in the intervention group reported an increase in the frequency of skin self-examinations compared to a slight decrease in the control group (p=0.002). Participants in the intervention group reported a smaller decrease in frequency of wearing a shirt with long sleeves than did participants in the control group (p =0.047). No effect of the intervention was noted for other outcomes. CONCLUSIONS: It is noteworthy that feedback of CDKN2A and MC1R genotype among families without known pathogenic CDKN2A mutations does not appear to decrease sun protection behaviors. Because of the limited number of families with known pathogenic CDKN2A mutations in this study, it is difficult to interpret the results as demonstrating a positive benefit of the intervention.
  Cancer Epidemiology Biomarkers &amp Prevention 02/2013; · 4.12 Impact Factor
• Article: Biallelic Deleterious BRCA1 Mutations in a Woman with Early-Onset Ovarian Cancer.

  Susan M Domchek, Jiang-Bo Tang, Jill Stopfer, Dana R Lilli, Nancy Hamel, Marc Tischkowitz, Alvaro N A Monteiro, Troy E Messick, Jacquelyn Powers, Alexandria Yonker, Fergus J Couch, David E Goldgar, H Rosemarie Davidson, Katherine L Nathanson, William Foulkes, Roger A Greenberg
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  ABSTRACT: BRCA1 and BRCA2 are the most important breast and ovarian cancer susceptibility genes. Biallelic mutations in BRCA2 can lead to Fanconi Anemia and predisposition to cancers, while biallelic BRCA1 mutations have not been confirmed, presumably because one wild-type BRCA1 allele is required during embryogenesis. This study describes an individual who was diagnosed with ovarian carcinoma at age 28 and found to have one allele with a deleterious mutation in BRCA1, c.2457delC (p.Asp821Ilefs*25), and a second allele with a variant of unknown significance (VUS) in BRCA1, c.5207T>C (p.Val1736Ala). Medical records revealed short stature, microcephaly, developmental delay and significant toxicity from chemotherapy. BRCA1 p.Val1736Ala co-segregated with cancer in multiple families, associated tumors demonstrated loss of wild-type BRCA1, and BRCA1 p.Val1736Ala showed reduced DNA damage localization. These findings represent the first validated example of biallelic deleterious human BRCA1 mutations, and have implications for the interpretation of genetic test results.
  Cancer discovery. 12/2012;
• Article: Risk of metachronous breast cancer after BRCA mutation-associated ovarian cancer.

  Susan M Domchek, Komal Jhaveri, Sujata Patil, Jill E Stopfer, Clifford Hudis, Jacquelyn Powers, Zsofia Stadler, Laura Goldstein, Noah Kauff, Mustafa Khasraw, Kenneth Offit, Katherine L Nathanson, Mark Robson
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  ABSTRACT: BACKGROUND: This study sought to estimate the risk of breast cancer (BC) after a diagnosis of ovarian cancer (OC) associated with mutation of the BRCA1/2 (breast cancer, early onset) genes (BRCA-OC). METHODS: The Memorial Sloan-Kettering Cancer Center and the University of Pennsylvania, clinical genetics databases were searched to identify women with BRCA-OC who participated in genetic testing and follow-up studies from 1995 to 2009. The primary objective was to determine the risk of developing BC after BRCA-OC. Overall survival (OS) and BC-free survival (BCFS) were determined by the Kaplan-Meier method; patients were censored at the time of last follow-up. RESULTS: A total of 164 patients had BRCA-OC (115 with BRCA1; 49 with BRCA2). Of these 164 patients, 152 developed OC prior to BRCA testing (median time to testing, 2.4 years [0.01-55 years]). Median follow-up from OC for those not developing BC was 5.8 years (0.25-55.6 years). There were 46 deaths, but none were due to BC. The 5- and 10-year OS were 85% (95% confidence interval [CI] = 0.78, 0.90) and 68% (95% CI = 0.59, 0.76), respectively. There were 18 metachronous BC diagnoses. The 5- and 10-year BCFS were 97% (95% CI = 0.92, 0.99) and 91% (95% CI = 0.82, 0.95), respectively. A subset of 64 women were tested either before or within 12 months of BRCA-OC. In this pseudo-incident subset, 5- and 10- year OS was 71% (95% CI = 0.53, 0.83) and 62% (95% CI = 0.44, 0.75), respectively, and 5- and 10-year BCFS were 100% and 87% (95% CI = 0.56, 0.96), respectively. CONCLUSIONS: OS was dominated by OC deaths. Metachronous BC risk was lower than reported for unaffected BRCA mutation carriers. These results support nonsurgical management of BC risk in women with BRCA-OC. Cancer 2012. © 2012 American Cancer Society.
  Cancer 11/2012; · 4.77 Impact Factor
• Article: A classification model for BRCA2 DNA binding domain missense variants based on homology directed repair activity.

  Lucia Guidugli, V Shane Pankratz, Namit Singh, James Thompson, Catherine A Erding, Christoph Engel, Rita K Schmutzler, Susan M Domchek, Katherine L Nathanson, Paolo Radice, Christian F Singer, Patricia N Tonin, Noralane M Lindor, David E Goldgar, Fergus J Couch
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  ABSTRACT: The relevance of many BRCA2 variants of uncertain significance (VUS) to breast cancer has not been determined due to limited genetic information from families carrying these alterations. Here we classified six new variants as pathogenic or non-pathogenic by analysis of genetic information from families carrying 65 individual BRCA2 DBD missense mutations using a multifactorial likelihood model of cancer causality. Next, we evaluated the utility of a homology directed DNA break repair (HDR) functional assay as a method for inferring the clinical relevance of VUS in the DNA binding domain (DBD) of BRCA2 using 18 established non-pathogenic missense variants and all 13 established pathogenic missense mutations from the BRCA2 DBD. Compared to the known status of these variants based on the multifactorial likelihood model, the sensitivity of the HDR assay for pathogenic mutations was estimated at 100% (95%CI: 75.3%-100%), and specificity was estimated at 100% (95%CI: 81.5%-100%). A statistical classifier for predicting the probability of pathogenicity of BRCA2 DBD variants was developed using these functional results. When applied to 33 additional VUS, the classifier identified eight with >99% probability of non-pathogenicity and 18 with ≥ 99% probability of pathogenicity. Thus, in the absence of genetic evidence a cell based HDR assay can provide a probability of pathogenicity for all VUS in the BRCA2 DBD, suggesting that the assay can be used in combination with other information to determine the cancer relevance of BRCA2 VUS.
  Cancer Research 10/2012; · 7.86 Impact Factor
• Article: Frequency of Triple-Negative Breast Cancer in BRCA1 Mutation Carriers: Comparison Between Common Ashkenazi Jewish and Other Mutations.

  Nadine Tung, Judy E Garber, Anne Lincoln, Susan M Domchek
  Journal of Clinical Oncology 10/2012; · 18.37 Impact Factor
• Source

  Available from: Sandrine Caputo

  Dataset: 2012 Spurdle J Med Genet-2012-Spurdle-525-32 supp

  Anna A Kattentidt-Mouravieva, Susan M Domchek, Christoph Engel, Alfons Meindl, Ans M W van den Ouweland, Amanda E Toland, Elizabeth J Van Rensburg, Amanda B Spurdle, Barbara Wappenschmidt, Sandrine Caputo, [......], Mads Thomassen, Dutch Belgium Uv Consortium, Diana M Eccles, Rita K Schmutzler, Christopher Pettigrew, Maritta H Pigg, Kathy Tucker, Christi J Van Asperen, Margreet G E M Ausems, Javier Benitez
• Source

  Available from: Gary K Chen

  Article: A genome-wide association study of breast cancer in women of African ancestry.

  Fang Chen, Gary K Chen, Daniel O Stram, Robert C Millikan, Christine B Ambrosone, Esther M John, Leslie Bernstein, Wei Zheng, Julie R Palmer, Jennifer J Hu, [......], Ulrike Peters, Suhn K Rhie, Peggy Wan, Xin Sheng, Loreall C Pooler, David J Van Den Berg, Loic Le Marchand, Laurence N Kolonel, Brian E Henderson, Christopher A Haiman
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  ABSTRACT: Genome-wide association studies (GWAS) in diverse populations are needed to reveal variants that are more common and/or limited to defined populations. We conducted a GWAS of breast cancer in women of African ancestry, with genotyping of >1,000,000 SNPs in 3,153 African American cases and 2,831 controls, and replication testing of the top 66 associations in an additional 3,607 breast cancer cases and 11,330 controls of African ancestry. Two of the 66 SNPs replicated (p < 0.05) in stage 2, which reached statistical significance levels of 10(-6) and 10(-5) in the stage 1 and 2 combined analysis (rs4322600 at chromosome 14q31: OR = 1.18, p = 4.3 × 10(-6); rs10510333 at chromosome 3p26: OR = 1.15, p = 1.5 × 10(-5)). These suggestive risk loci have not been identified in previous GWAS in other populations and will need to be examined in additional samples. Identification of novel risk variants for breast cancer in women of African ancestry will demand testing of a substantially larger set of markers from stage 1 in a larger replication sample.
  Human Genetics 08/2012; · 5.07 Impact Factor
• Source

  Available from: Sandrine Caputo

  Article: BRCA1 R1699Q variant displaying ambiguous functional abrogation confers intermediate breast and ovarian cancer risk.

  Amanda B Spurdle, Phillip J Whiley, Bryony Thompson, Bingjian Feng, Sue Healey, Melissa A Brown, Christopher Pettigrew, Christi J Van Asperen, Margreet G E M Ausems, Anna A Kattentidt-Mouravieva, [......], Diana M Eccles, Kathy Tucker, Javier Benitez, Susan M Domchek, Amanda E Toland, Elizabeth J Van Rensburg, Barbara Wappenschmidt, Åke Borg, Maaike P G Vreeswijk, David E Goldgar
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  ABSTRACT: Clinical classification of rare sequence changes identified in the breast cancer susceptibility genes BRCA1 and BRCA2 is essential for appropriate genetic counselling of individuals carrying these variants. We previously showed that variant BRCA1 c.5096G>A p.Arg1699Gln in the BRCA1 transcriptional transactivation domain demonstrated equivocal results from a series of functional assays, and proposed that this variant may confer low to moderate risk of cancer. Measures of genetic risk (report of family history, segregation) were assessed for 68 BRCA1 c.5096G>A p.Arg1699Gln (R1699Q) families recruited through family cancer clinics, comparing results with 34 families carrying the previously classified pathogenic BRCA1 c.5095C>T p.Arg1699Trp (R1699W) mutation at the same residue, and to 243 breast cancer families with no BRCA1 pathogenic mutation (BRCA-X). Comparison of BRCA1 carrier prediction scores of probands using the BOADICEA risk prediction tool revealed that BRCA1 c.5096G>A p.Arg1699Gln variant carriers had family histories that were less 'BRCA1-like' than BRCA1 c.5095C>T p.Arg1699Trp mutation carriers (p<0.00001), but more 'BRCA1-like' than BRCA-X families (p=0.0004). Further, modified segregation analysis of the subset of 30 families with additional genotyping showed that BRCA1 c.5096G >A p.Arg1699Gln had reduced penetrance compared with the average truncating BRCA1 mutation penetrance (p=0.0002), with estimated cumulative risks to age 70 of breast or ovarian cancer of 24%. Our results provide substantial evidence that the BRCA1 c.5096G>A p.Arg1699Gln (R1699Q) variant, demonstrating ambiguous functional deficiency across multiple assays, is associated with intermediate risk of breast and ovarian cancer, highlighting challenges for risk modelling and clinical management of patients of this and other potential moderate-risk variants.
  Journal of Medical Genetics 08/2012; 49(8):525-32. · 6.36 Impact Factor
• Article: Cancer treatment according to BRCA1 and BRCA2 mutations.

  Kara N Maxwell, Susan M Domchek
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  ABSTRACT: Identification of germline mutations associated with significant cancer susceptibility has the potential to change all aspects of an individual's care, from screening to cancer treatment. For example, women with germline mutations in BRCA1 and BRCA2 have markedly elevated risks of breast and ovarian cancer and the identification of these germline mutations has led to specific screening and prevention strategies. More recently, advances in the understanding of the biological function of BRCA1 and BRCA2 have led to clinical trials testing targeted therapies in this population, particularly poly(ADP-ribose) polymerase (PARP) inhibitors. Unfortunately, the development of PARP inhibitors has not been as rapid as anticipated and has been more challenging than expected. Somatic mutations identified in many cancer types have allowed the development of therapeutics that target these mutated genes, and many of these agents obtained rapid regulatory approval and are currently in widespread clinical practice. Diagnostic testing has a central role in targeted cancer therapeutics for both somatic and germline mutations. Although the era of molecular medicine and targeted therapies has led to significant changes in the practice of oncology, new challenges continue to arise.
  Nature Reviews Clinical Oncology 07/2012; 9(9):520-8. · 11.96 Impact Factor
• Article: How genetic variant libraries effectively extend gene testing patents: implications for intellectual property and good clinical care.

  Sean McElligott, Robert I Field, Mirar Bristol-Demeter, Susan M Domchek, David A Asch
  Journal of Clinical Oncology 07/2012; 30(24):2943-5. · 18.37 Impact Factor
• Source

  Available from: Sheila Seal

  Article: Breast Cancer Risk and 6q22.33: Combined Results from Breast Cancer Association Consortium and Consortium of Investigators on Modifiers of BRCA1/2

  Tomas Kirchhoff, Mia M. Gaudet, Antonis C. Antoniou, Lesley McGuffog, Manjeet K. Humphreys, Alison M. Dunning, Stig E. Bojesen, Børge G. Nordestgaard, Henrik Flyger, Daehee Kang, [......], Fiona Douglas, Shirley Hodgson, D. Gareth Evans, Rosalind Eeles, Bert Gold, Paul D.P. Pharoah, Kenneth Offit, Georgia Chenevix-Trench, Douglas F. Easton, on behalf of BCAC/CIMBA
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  ABSTRACT: Recently, a locus on chromosome 6q22.33 (rs2180341) was reported to be associated with increased breast cancer risk in the Ashkenazi Jewish (AJ) population, and this association was also observed in populations of non-AJ European ancestry. In the present study, we performed a large replication analysis of rs2180341 using data from 31,428 invasive breast cancer cases and 34,700 controls collected from 25 studies in the Breast Cancer Association Consortium (BCAC). In addition, we evaluated whether rs2180341 modifies breast cancer risk in 3,361 BRCA1 and 2,020 BRCA2 carriers from 11 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Based on the BCAC data from women of European ancestry, we found evidence for a weak association with breast cancer risk for rs2180341 (per-allele odds ratio (OR) = 1.03, 95% CI 1.00–1.06, p = 0.023). There was evidence for heterogeneity in the ORs among studies (I2 = 49.3%; p =
  PLoS ONE 06/2012; 7(6). · 4.09 Impact Factor
• Article: A nonsynonymous polymorphism in IRS1 modifies risk of developing breast and ovarian cancers in BRCA1 and ovarian cancer in BRCA2 mutation carriers.

  Yuan C Ding, Lesley McGuffog, Sue Healey, Eitan Friedman, Yael Laitman, Shani- Paluch-Shimon, Bella Kaufman, Annelie Liljegren, Annika Lindblom, Håkan Olsson, [......], Hilmi Ozcelik, Anne-Marie Gerdes, Mads Thomassen, Uffe Birk Jensen, Anne-Bine Skytte, Maria A Caligo, Andrew Lee, Georgia Chenevix-Trench, Antonis C Antoniou, Susan L Neuhausen
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  ABSTRACT: 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 (HR, 1.43; 95% confidence interval (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 II mutations than class I mutations (class II HR, 1.86; 95% CI, 1.28-2.70; class I HR, 0.86; 95%CI, 0.69-1.09; P(difference), 0.0006). Rs13306465 was associated with ovarian cancer risk in BRCA1 class II mutation carriers (HR, 2.42; P = 0.03). The IRS1 Gly972Arg single-nucleotide polymorphism, 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 II mutation carriers. These findings may prove useful for risk prediction for breast and ovarian cancers in BRCA1 and BRCA2 mutation carriers.
  Cancer Epidemiology Biomarkers &amp Prevention 06/2012; 21(8):1362-70. · 4.12 Impact Factor
• Source

  Available from: Pilar Zamora

  Article: Breast Cancer Risk and 6q22.33: Combined Results from Breast Cancer Association Consortium and Consortium of Investigators on Modifiers of BRCA1/2

  Tomas Kirchhoff, Mia M Gaudet, Antonis C Antoniou, Lesley Mcguffog, Manjeet K Humphreys, Alison M Dunning, Stig E Bojesen, Børge G Nordestgaard, Henrik Flyger, Daehee Kang, [......], Jackie Cook, Fiona Douglas, Shirley Hodgson, D Gareth Evans, Rosalind Eeles, Bert Gold, Paul D P Pharoah, Kenneth Offit, Georgia Chenevix-Trench, Douglas F Easton
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  ABSTRACT: AM), 9 Gene Environment Interaction and Breast Cancer in Germany (GENICA): Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, and University Tü bingen, Stuttgart and Tü bingen, Germany (HB, Christina Justenhoven); Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum, Heidelberg, Germany (UH); Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany (YDK,); Institute of Pathology, Medical Faculty of the University of Bonn, Bonn, Germany (Hans-Peter Fischer); Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Bochum, Germany (Thomas Brü ning, Beate Pesch, Volker Harth, Sylvia Rabstein), 10 Amsterdam Breast Cancer Study (ABCS): Netherlands Cancer Institute, Departments of Experimental Therapy, Epidemiology and Molecular Pathology, Amsterdam, The Netherlands (AB, MKS, LJVV, LMB), 11 British Breast Cancer Study (BBCS):
  PLoS ONE 06/2012; 6(7). · 4.09 Impact Factor
• Article: CD25 blockade depletes and selectively reprograms regulatory T cells in concert with immunotherapy in cancer patients.

  Andrew J Rech, Rosemarie Mick, Sunil Martin, Adri Recio, Nicole A Aqui, Daniel J Powell, Theresa A Colligon, Jennifer A Trosko, Leah I Leinbach, Charles H Pletcher, Carol K Tweed, Angela DeMichele, Kevin R Fox, Susan M Domchek, James L Riley, Robert H Vonderheide
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  ABSTRACT: Regulatory T cells (T(regs)) are key mediators of immune tolerance and feature prominently in cancer. Depletion of CD25(+) FoxP3(+) T(regs) in vivo may promote T cell cancer immunosurveillance, but no strategy to do so in humans while preserving immunity and preventing autoimmunity has been validated. We evaluated the Food and Drug Administration-approved CD25-blocking monoclonal antibody daclizumab with regard to human T(reg) survival and function. In vitro, daclizumab did not mediate antibody-dependent or complement-mediated cytotoxicity but rather resulted in the down-regulation of FoxP3 selectively among CD25(high) CD45RA(neg) T(regs). Moreover, daclizumab-treated CD45RA(neg) T(regs) lost suppressive function and regained the ability to produce interferon-γ, consistent with reprogramming. To understand the impact of daclizumab on T(regs) in vivo, we performed a clinical trial of daclizumab in combination with an experimental cancer vaccine in patients with metastatic breast cancer. Daclizumab administration led to a marked and prolonged decrease in T(regs) in patients. Robust CD8 and CD4 T cell priming and boosting to all vaccine antigens were observed in the absence of autoimmunity. We conclude that CD25 blockade depletes and selectively reprograms T(regs) in concert with active immune therapy in cancer patients. These results suggest a mechanism to target cancer-associated T(regs) while avoiding autoimmunity.
  Science translational medicine 05/2012; 4(134):134ra62. · 7.80 Impact Factor