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ABSTRACT: INTRODUCTION: DNA variants of uncertain significance (VUS) are common outcomes of clinical genetic testing for susceptibility to cancer. A statistically rigorous model that provides a pathogenicity score for each variant has been developed to aid in the clinical management of patients undergoing genetic testing. METHODS: The information in this article is derived from multiple publications on VUS in BRCA genes, distilled for communicating with clinicians who may encounter VUS in their practice. RESULTS: The posterior probability scores for BRCA1 or BRCA2 VUS, calculated from a multifactorial likelihood model, are explained, and links for looking up specific VUS are provided. The International Agency on Cancer Research (IARC) of the World Health Organization has proposed a simple five-tier system for clinical management that is not widely known to clinicians. Classes 1 and 2 in this system are managed as neutral variants, classes 4 and 5 are managed as pathogenic variants, and class 3 variants still have insufficient evidence to move to either end of this scale and, thus, cannot be used in medical management. Development of models that integrate multiple independent lines of evidence has allowed classification of a growing number of VUS in the BRCA1 and BRCA2 genes. The pathogenicity score that is generated by this model maps to the IARC system for clinical management, which will assist clinicians in the medical management of those patients who obtain a VUS result upon testing.
The Oncologist 04/2013; · 3.91 Impact Factor
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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
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Evelina Mocci,
Roger L Milne,
Elena Yuste Méndez-Villamil,
John L Hopper,
Esther M John,
Irene L Andrulis,
Wendy K Chung,
Mary B Daly,
Saundra S Buys,
Nuria Malats, David E Goldgar
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ABSTRACT: BACKGROUND: Increased risk of pancreatic cancer (PC) has been reported in breast cancer (BC) families carrying BRCA1and BRCA2 mutations; however, PC risk in mutation-negative (BRCAX) families has not been explored to date. The aim of this study was to estimate PC risk in high-risk BC families according to the BRCA mutation status. METHODS: A retrospective cohort analysis was applied to estimate standardized incidence ratios (SIR) for PC. A total of 5,799 families with ≥1 BC case tested for mutations in BRCA1 and/or BRCA2 were eligible. Families were divided into four classes: BRCA1, BRCA2, BRCAX with ≥2 BC diagnosed before age 50 (class 3), and the remaining BRCAX families (class 4). RESULTS: BRCA1 mutation carriers were at increased risk of PC (SIR= 4.11; 95% confidence interval [CI], 2.94-5.76) as were BRCA2 mutation carriers (SIR=5.79; 95% CI, 4.28-7.84). BRCAX family members were also at increased PC risk, which did not appear to vary by number of members with early-onset breast cancer (SIR=1.31; 95%CI, 1.06-1.63 for Class 3 and SIR=1.30; 95%CI, 1.13-1.49 for class 4). CONCLUSIONS: Germline mutations in BRCA1 and BRCA2 are associated with an increased risk of PC. Members of BRCAX families are also at increased risk of PC, pointing to the existence of other genetic factors that increase the risk of both PC and BC. Impact:This study clarifies the relationship between familial breast cancer and pancreatic cancer. Given its high mortality, PC should be included in risk assessment in familial breast cancer counseling.
Cancer Epidemiology Biomarkers & Prevention 03/2013; · 4.12 Impact Factor
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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
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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
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Zhi L Teo,
Daniel J Park,
Elena Provenzano,
Catherine A Chatfield,
Fabrice A Odefrey,
Tu Nguyen-Dumont,
K Confab,
James G Dowty,
John L Hopper,
Ingrid Winship, David E Goldgar,
Melissa C Southey
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ABSTRACT: INTRODUCTION: Population-based studies of breast cancer have estimated that some PALB2 mutations confer a breast cancer risk (penetrance) comparable to the average pathogenic mutation in BRCA2. As this risk is of clinical relevance, we sought to identify mono-allelic PALB2 mutations and determine their frequencies in multiple-case breast cancer families attending Familial Cancer Clinics in Australia and New Zealand. METHODS: The youngest affected woman, not known to carry a mutation in BRCA1 or BRCA2, from 747 multiple-case breast cancer families participating in kConFab were selected for PALB2 mutation screening. The coding and flanking intronic regions of PALB2 in DNA extracted from blood were screened using high resolution melt curve analysis with Sanger sequencing confirmation. Where possible, relatives of women found to carry PALB2 mutations were genotyped for the family-specific mutation, mutant transcripts were characterised and breast tumours arising in mutation carriers were recalled and reviewed. Missense mutations were assessed for potential to disrupt protein function via SIFT, Align GVGD and Polyphen-2. RESULTS: The mutation screen identified two nonsense mutations (PALB2 c.3113G>A in eight women and PALB2 c.196C>T in one woman), two frameshift mutations (PALB2 c.1947_1948insA and PALB2 c.2982_2983insT each in one woman), ten missense variants, eight synonymous variants and four variants in intronic regions. Of the four PALB2 mutations identified that were predicted to produce truncated protein products, only PALB2 c.1947_1948insA had not previously been reported. PALB2 c.3113G>A and PALB2 c.196C>T were previously identified in the Australian population whereas PALB2 c.2982_2983insT was previously reported in the UK population. Transcripts derived from three of these mutant PALB2 alleles were vulnerable to nonsense mediated decay. One missense mutation (PALB2 c.2993G>A) was predicted to disrupt protein function via the three in silico assessment methods applied. The majority of breast cancers arising in carriers that were available for review were high grade invasive ductal carcinomas. CONCLUSIONS: About 1.5% (95% CI 0.6 to 2.4) of Australasian multiple-case breast cancer families attending clinics are segregating protein truncating mutations in PALB2, most being PALB2 c.3113G>A, p.Trp1038*. Given the prevalence, breast cancer risk, and tumour grade associated with this mutation, consideration of clinical PALB2 testing is warranted.
Breast cancer research: BCR 02/2013; 15(1):R17. · 5.24 Impact Factor
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ABSTRACT: BACKGROUND: Characterising genetic diversity through the analysis of massively parallel sequencing (MPS) data offers enormous potential to significantly improve our understanding of the genetic basis for observed phenotypes, including predisposition to and progression of complex human disease. Great challenges remain in resolving which genetic variants are genuinely associated with disease from the millions of 'bystanders' and artefactual signals. RESULTS: FAVR is a suite of new methods designed to work with commonly used MPS analysis pipelines to assist in the resolution of some of these issues with a focus on relatively rare genetic variants. To the best of our knowledge, no equivalent has previously been described. The most important and novel aspect of FAVR is the use of signatures in comparator sequence alignment files during variant filtering, and annotation of variants potentially shared between individuals. The FAVR methods use these signatures to facilitate filtering of (i) platform-specific artefacts, (ii) common genetic variants, and, where relevant, (iii) artefacts derived from imbalanced paired-end sequencing, as well as annotation of genetic variants based on evidence of co-occurrence in individuals. By comparing conventional variant calling with or without downstream processing by FAVR methods applied to whole-exome sequencing datasets, we demonstrate a 3-fold smaller rare single nucleotide variant shortlist with no detected reduction in sensitivity. This analysis included Sanger sequencing of rare variant signals not evident in dbSNP131, assessment of known variant signal preservation, and comparison of observed and expected rare variant numbers across a range of first cousin pairs. The principles described herein were applied in our recent publication identifying XRCC2 as a new breast cancer risk gene and have been made publically available as a suite of software tools. CONCLUSIONS: FAVR is a platform-agnostic suite of methods that significantly enhances the analysis of large volumes of sequencing data for the study of rare genetic variants and their influence on phenotypes.
BMC Bioinformatics 02/2013; 14(1):65. · 2.75 Impact Factor
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ABSTRACT: Background. A 51-year-old French Canadian man presented to his family physician owing to an extensive family history of prostate cancer in five brothers, his father and two paternal uncles. His serum PSA level was 4.9 ng/ml and a six-core biopsy revealed the presence of a prostate adenocarcinoma with a Gleason score of 7 (3+4). He was treated with radical prostatectomy. Repeat PSA tests revealed a gradual rise in PSA levels despite androgen deprivation therapy with bicalutamide and goserelin over the course of 3 years. Genetic evaluation was undertaken in view of his personal and family history. The proband died at the age of 58 years of widespread metastasis.Investigations. PSA testing, six-core biopsy, genetic counselling and mutation analysis for French Canadian founder mutations in the BRCA1 and BRCA2 genes, histopathological review of tumour tissue from family members, examination of loss of heterozygosity at the BRCA2 gene locus, immunohistochemistry to determine the expression of the ERG nuclear oncoprotein in prostate tumours, genotyping with eight selected risk-associated single nucleotide polymorphisms, Doppler ultrasonography of the leg, CT of the abdomen and pelvis with intravenous and oral contrast, chest CT with intravenous contrast for the assessment of metastatic prostate cancer, genetic testing for the G84E variant in the HOXB13 gene.Diagnosis. Early-onset and aggressive prostate cancer associated with a nonsense French Canadian BRCA2 founder mutation, c.5857G>T (p.Glu1953(*)).Management. Radical prostatectomy, hormone therapy with bicalutamide and goserelin, palliative chemotherapy initially with docetaxel plus prednisone then with mitoxantrone plus prednisone, as well as genetic counselling and testing for the proband and his family members.
Nature Reviews Urology 01/2013; · 4.41 Impact Factor
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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;
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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
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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
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Bryony A Thompson, David E Goldgar,
Carol Paterson,
Mark Clendenning,
Rhiannon Walters,
Sven Arnold,
Michael T Parsons,
D Michael,
Steven Gallinger,
Robert W Haile,
John L Hopper,
Mark A Jenkins,
Loic Lemarchand,
Noralane M Lindor,
Polly A Newcomb,
Stephen N Thibodeau,
Joanne P Young,
Daniel D Buchanan,
Sean V Tavtigian,
Amanda B Spurdle
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ABSTRACT: Mismatch repair (MMR) gene sequence variants of uncertain clinical significance are often identified in suspected Lynch syndrome families, and this constitutes a challenge for both researchers and clinicians. Multifactorial likelihood model approaches provide a quantitative measure of MMR variant pathogenicity, but first require input of likelihood ratios (LRs) for different MMR variation-associated characteristics from appropriate, well-characterized reference datasets. Microsatellite instability (MSI) and somatic BRAF tumor data for unselected colorectal cancer probands of known pathogenic variant status were used to derive LRs for tumor characteristics using the Colon Cancer Family Registry (CFR) resource. These tumor LRs were combined with variant segregation within families, and estimates of prior probability of pathogenicity based on sequence conservation and position, to analyze 44 unclassified variants identified initially in Australasian Colon CFR families. In addition, in vitro splicing analyses were conducted on the subset of variants based on bioinformatic splicing predictions. The LR in favor of pathogenicity was estimated to be ∼12-fold for a colorectal tumor with a BRAF mutation-negative MSI-H phenotype. For 31 of the 44 variants, the posterior probabilities of pathogenicity were such that altered clinical management would be indicated. Our findings provide a working multifactorial likelihood model for classification that carefully considers mode of ascertainment for gene testing.
Human Mutation 09/2012; · 5.69 Impact Factor
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Bryony A Thompson,
Marc S Greenblatt,
Maxime P Vallee,
Johanna C Herkert,
Chloe Tessereau,
Erin L Young,
Ivan A Adzhubey,
Biao Li,
Russell Bell,
Bingjian Feng, [......],
Predrag Radivojac,
Shamil R Sunyaev,
Thierry Frebourg,
Robert M W Hofstra,
Rolf H Sijmons,
Ken Boucher,
Alun Thomas, David E Goldgar,
Amanda B Spurdle,
Sean V Tavtigian
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ABSTRACT: Classification of rare missense substitutions observed during genetic testing for patient management is a considerable problem in clinical genetics. The Bayesian integrated evaluation of unclassified variants is a solution originally developed for BRCA1/2. Here, we take a step toward an analogous system for the mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) that confer colon cancer susceptibility in Lynch syndrome by calibrating in silico tools to estimate prior probabilities of pathogenicity for MMR gene missense substitutions. A qualitative five-class classification system was developed and applied to 143 MMR missense variants. This identified 74 missense substitutions suitable for calibration. These substitutions were scored using six different in silico tools (Align-Grantham Variation Grantham Deviation, multivariate analysis of protein polymorphisms [MAPP], MutPred, PolyPhen-2.1, Sorting Intolerant From Tolerant, and Xvar), using curated MMR multiple sequence alignments where possible. The output from each tool was calibrated by regression against the classifications of the 74 missense substitutions; these calibrated outputs are interpretable as prior probabilities of pathogenicity. MAPP was the most accurate tool and MAPP + PolyPhen-2.1 provided the best-combined model (R(2) = 0.62 and area under receiver operating characteristic = 0.93). The MAPP + PolyPhen-2.1 output is sufficiently predictive to feed as a continuous variable into the quantitative Bayesian integrated evaluation for clinical classification of MMR gene missense substitutions.
Human Mutation 09/2012; · 5.69 Impact Factor
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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
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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 & Prevention 06/2012; 21(8):1362-70. · 4.12 Impact Factor
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Amanda B. Spurdle,
Andrew J. Deans,
David Duffy, David E. Goldgar,
Xiaoqing Chen,
Jonathan Beesley,
kConFaB,
Douglas F. Easton,
Antonis C. Antoniou,
Susan Peock,
Margaret Cook,
EMBRACE Study Collaborators,
Katherine L. Nathanson,
Susan M. Domchek,
Grant A. MacArthur,
Georgia Chenevix-Trench
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ABSTRACT: The p27kip1 protein functions as an inhibitor of cyclin dependent kinase-2, and shows loss of expression in a large percentage of BRCA1 and BRCA2 breast cancer cases. We investigated the association between CDKN1B gene variants and breast cancer risk in 2359 female BRCA1 and BRCA2 mutation carriers from Australia, the UK, and the USA. Samples were genotyped for five single nucleotide polymorphisms, including
coding variant rs2066827 (V109G). Cox regression provided no convincing evidence that any of the polymorphisms modified disease
risk for BRCA1 or BRCA2 carriers, either alone or as a haplotype. Borderline associations were observed for homozygote carriers of the rs3759216
rare allele, but were opposite in effect for BRCA1 and BRCA2 carriers (adjusted hazard ratio (HR) 0.72 (95% CI=0.53–0.99; P=0.04 for BRCA1, HR 1.47 (95% CI=0.99–2.18; P=0.06 for BRCA2). The 95% confidence intervals for per allele risk estimates excluded a twofold risk, indicating that common CDKN1B polymorphisms do not markedly modify breast cancer risk among BRCA1 or BRCA2 carriers.
Breast Cancer Research and Treatment 04/2012; 115(2):307-313. · 4.43 Impact Factor
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Sharon E. Johnatty,
Jonathan Beesley,
Xiaoqing Chen,
John L. Hopper,
Melissa C. Southey,
Graham G. Giles, David E. Goldgar,
Georgia Chenevix-Trench,
Amanda B. Spurdle,
The Australian Ovarian Cancer Study Group,
The Kathleen Cuningham Consortium for Research in Familial Breast Cancer
[show abstract]
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ABSTRACT: BARD1 was first identified as a BRCA1-interacting protein with tumour-suppressor functions. Some association studies suggested
that the BARD1 Cys557Ser variant might be associated with increased risk of breast cancer, but the evidence remains uncertain. We found
that the BARD1 Cys557Ser variant was carried by 50 of 1,136 cases (4.4%) and 30 of 623 controls (5.0%) from the population-based Australian
Breast Cancer Family Study, 14 of 324 (4.3%) cases from the Kathleen Cuningham Foundation Consortium for Research into Familial
Breast Cancer (kConFab), and 30 of 760 controls (4.0%) from the Australian Ovarian Cancer Study. Case–control comparisons
showed no evidence that the variant frequency differed by case–control status (P≥0.3). Segregation analysis of 14 kConFab variant-carrying families containing 157 genotyped individuals provided no evidence
of segregation with disease. We conclude that the BARD1 Cys557Ser variant is not associated with breast cancer risk.
Breast Cancer Research and Treatment 04/2012; 115(1):145-150. · 4.43 Impact Factor
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Fergus J Couch,
Mia M Gaudet,
Antonis C Antoniou,
Susan J Ramus,
Karoline B Kuchenbaecker,
Penny Soucy,
Jonathan Beesley,
Xiaoqing Chen,
Xianshu Wang,
Tomas Kirchhoff, [......],
Alessandra Viel,
Giuseppe Giannini,
Liliana Varesco,
Paolo Radice,
Mark H Greene,
Phuong L Mai,
Douglas F Easton,
Georgia Chenevix-Trench,
Kenneth Offit,
Jacques Simard
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ABSTRACT: Genome-wide association studies (GWAS) identified variants at 19p13.1 and ZNF365 (10q21.2) as risk factors for breast cancer among BRCA1 and BRCA2 mutation carriers, respectively. We explored associations with ovarian cancer and with breast cancer by tumor histopathology for these variants in mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA).
Genotyping data for 12,599 BRCA1 and 7,132 BRCA2 mutation carriers from 40 studies were combined.
We confirmed associations between rs8170 at 19p13.1 and breast cancer risk for BRCA1 mutation carriers [HR, 1.17; 95% confidence interval (CI), 1.07-1.27; P = 7.42 × 10(-4)] and between rs16917302 at ZNF365 (HR, 0.84; 95% CI, 0.73-0.97; P = 0.017) but not rs311499 at 20q13.3 (HR, 1.11; 95% CI, 0.94-1.31; P = 0.22) and breast cancer risk for BRCA2 mutation carriers. Analyses based on tumor histopathology showed that 19p13 variants were predominantly associated with estrogen receptor (ER)-negative breast cancer for both BRCA1 and BRCA2 mutation carriers, whereas rs16917302 at ZNF365 was mainly associated with ER-positive breast cancer for both BRCA1 and BRCA2 mutation carriers. We also found for the first time that rs67397200 at 19p13.1 was associated with an increased risk of ovarian cancer for BRCA1 (HR, 1.16; 95% CI, 1.05-1.29; P = 3.8 × 10(-4)) and BRCA2 mutation carriers (HR, 1.30; 95% CI, 1.10-1.52; P = 1.8 × 10(-3)).
19p13.1 and ZNF365 are susceptibility loci for ovarian cancer and ER subtypes of breast cancer among BRCA1 and BRCA2 mutation carriers.
These findings can lead to an improved understanding of tumor development and may prove useful for breast and ovarian cancer risk prediction for BRCA1 and BRCA2 mutation carriers.
Cancer Epidemiology Biomarkers & Prevention 02/2012; 21(4):645-57. · 4.12 Impact Factor
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ABSTRACT: Unclassified sequence variants (UVs) arising from clinical mutation screening of cancer susceptibility genes present a frustrating issue to clinical genetics services and the patients that they serve. We created an open-access database holding missense substitutions from the breast and ovarian cancer susceptibility genes BRCA1 and BRCA2. The main inclusion criterion is that each variant should have been assessed in a published work that used the Bayesian integrated evaluation of unclassified BRCA gene variants. Transfer of data on these substitutions from the original publications to our database afforded an opportunity to analyze the missense substitutions under a single model and to remove inconsistencies that arose during the evolution of the integrated evaluation over the last decade. This analysis also afforded the opportunity to reclassify these missense substitutions according to the recently published IARC 5-Class system. From an initial set of 248 missense substitutions, 31 were set aside due to nonnegligible probability to interfere with splicing. Of the remaining substitutions, 28 fell into one of the two pathogenic classes (IARC Class 4 or 5), 174 fell into one of the two nonpathogenic classes (IARC Class 1 or 2), and 15 remain in IARC Class 3, "Uncertain." The database is available at http://brca.iarc.fr/LOVD.
Human Mutation 01/2012; 33(1):22-8. · 5.69 Impact Factor
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ABSTRACT: Clinical mutation screening of the BRCA1 and BRCA2 genes for the presence of germline inactivating mutations is used to identify individuals at elevated risk of breast and ovarian cancer. Variants identified during screening are usually classified as pathogenic (increased risk of cancer) or not pathogenic (no increased risk of cancer). However, a significant proportion of genetic tests yields variants of uncertain significance (VUS) that have undefined risk of cancer. Individuals carrying these VUS cannot benefit from individualized cancer risk assessment. Recently, a quantitative "posterior probability model" for assessing the clinical relevance of VUS in BRCA1 or BRCA2, which integrates multiple forms of genetic evidence has been developed. Here, we provide a detailed review of this model. We describe the components of the model and explain how these can be combined to calculate a posterior probability of pathogenicity for each VUS. We explain how the model can be applied to public data and provide tables that list the VUS that have been classified as not pathogenic or pathogenic using this method. While we use BRCA1 and BRCA2 VUS as examples, the method can be used as a framework for classification of the pathogenicity of VUS in other cancer genes.
Human Mutation 01/2012; 33(1):8-21. · 5.69 Impact Factor
