William D Foulkes

McGill University, Montréal, Quebec, Canada

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Publications (389)

  • [Show abstract] [Hide abstract] ABSTRACT: Background Whether oophorectomy reduces breast cancer risk among BRCA mutation carriers is a matter of debate. We undertook a prospective analysis of bilateral oophorectomy and breast cancer risk in BRCA mutation carriers. Methods Subjects had no history of cancer, had both breasts intact, and had information on oophorectomy status (n = 3722). Women were followed until breast cancer diagnosis, prophylactic bilateral mastectomy, or death. A Cox regression model was used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) of breast cancer associated with oophorectomy (coded as a time-dependent variable). All statistical tests were two-sided. Results Over a mean follow-up of 5.6 years, 350 new breast cancers were diagnosed. Among women with a BRCA1 or BRCA2 mutation, oophorectomy was not associated with breast cancer risk compared with women who did not undergo an oophorectomy. The age-adjusted hazard ratio associated with oophorectomy was 0.96 (95% CI = 0.73 to 1.26, P = .76) for BRCA1 and was 0.65 (95% CI = 0.37 to 1.16, P = .14) for BRCA2 mutation carriers. In stratified analyses, the effect of oophorectomy was statistically significant for breast cancer in BRCA2 mutation carriers diagnosed prior to age 50 years (age-adjusted HR = 0.18, 95% CI = 0.05 to 0.63, P = .007). Oophorectomy was not associated with risk of breast cancer prior to age 50 years among BRCA1 mutation carriers (age-adjusted HR = 0.79, 95% CI = 0.55 to 1.13, P = .51). Conclusions Findings from this large prospective study support a role of oophorectomy for the prevention of premenopausal breast cancer in BRCA2, but not BRCA1 mutation carriers. These findings warrant further evaluation.
    Article · Jan 2017 · JNCI Journal of the National Cancer Institute
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    Leora Witkowski · Nancy Donini · Rebecca Byler-Dann · [...] · William D. Foulkes
    [Show abstract] [Hide abstract] ABSTRACT: Small cell carcinoma of the ovary, hypercalcemic type, (SCCOHT) is the most common undifferentiated ovarian cancer in women aged under 40 years. SCCOHT is a monogenic disease, characterized by germline and somatic SMARCA4 mutations. Recent studies have stressed its morphological and clinical similarity to malignant rhabdoid tumours, which are usually caused by mutations in the related gene, SMARCB1. While familial tumours are rare, the incidence of germline mutations is relatively high, with up to 43% of SCCOHTs and 35% of rhabdoid tumours caused by germline mutations in SMARCA4 and SMARCB1, respectively. We report two new familial cases of SCCOHT. Affected members in both families and the associated tumours were found to carry SMARCA4 germline and somatic mutations, respectively, leading to loss of SMARCA4 protein expression in the tumours. Despite the rarity of familial SCCOHT, the high incidence of germline mutations is important to note, as without a family history of the disease, the hereditary nature of SCCOHT may be missed, especially if the mutation was inherited from the father or acquired de novo. The similarity between SCCOHT and rhabdoid tumours should be recognized, as infant carriers of SMARCA4 mutations may be at risk for these tumours in addition to SCCOHT.
    Full-text available · Article · Nov 2016 · Familial Cancer
  • Leanne de Kock · William D Foulkes
    Article · Nov 2016 · The Lancet Oncology
  • Ester Castellsague · Jian Carrot-Zhang · Isabelle Gamache · [...] · William David Foulkes
    Article · Nov 2016 · Molecular Cancer Research
  • David T. Bonthron · William D. Foulkes
    [Show abstract] [Hide abstract] ABSTRACT: The analytical power of modern methods for DNA analysis has outstripped our capability to interpret and understand the data generated. To make good use of this genomic data in a biomedical setting (whether for research or diagnosis), it is vital that we understand the mechanisms through which mutations affect biochemical pathways and physiological systems. This lies at the centre of what genetics is all about, and it is the reason why genetics and genomics should go hand in hand whenever possible. In this Annual Review Issue of the Journal of Pathology, we have assembled a collection of 16 expert reviews covering a wide range of topics. Through these, we illustrate the power of genetic analysis to improve our understanding of normal physiology and disease pathology, and thereby to think in rational ways about clinical management.
    Article · Nov 2016 · The Journal of Pathology
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    [Show abstract] [Hide abstract] ABSTRACT: Purpose: Cis-acting regulatory SNPs resulting in differential allelic expression (DAE) may, in part, explain the underlying phenotypic variation associated with many complex diseases. To investigate whether common variants associated with DAE were involved in breast cancer susceptibility among BRCA1 and BRCA2 mutation carriers, a list of 175 genes was developed based of their involvement in cancer-related pathways. Methods: Using data from a genome-wide map of SNPs associated with allelic expression, we assessed the association of ~320 SNPs located in the vicinity of these genes with breast and ovarian cancer risks in 15,252 BRCA1 and 8211 BRCA2 mutation carriers ascertained from 54 studies participating in the Consortium of Investigators of Modifiers of BRCA1/2. Results: We identified a region on 11q22.3 that is significantly associated with breast cancer risk in BRCA1 mutation carriers (most significant SNP rs228595 p = 7 × 10(-6)). This association was absent in BRCA2 carriers (p = 0.57). The 11q22.3 region notably encompasses genes such as ACAT1, NPAT, and ATM. Expression quantitative trait loci associations were observed in both normal breast and tumors across this region, namely for ACAT1, ATM, and other genes. In silico analysis revealed some overlap between top risk-associated SNPs and relevant biological features in mammary cell data, which suggests potential functional significance. Conclusion: We identified 11q22.3 as a new modifier locus in BRCA1 carriers. Replication in larger studies using estrogen receptor (ER)-negative or triple-negative (i.e., ER-, progesterone receptor-, and HER2-negative) cases could therefore be helpful to confirm the association of this locus with breast cancer risk.
    Full-text available · Article · Oct 2016 · Breast Cancer Research and Treatment
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    [Show abstract] [Hide abstract] ABSTRACT: The vast majority of coding variants are rare, and assessment of the contribution of rare variants to complex traits is hampered by low statistical power and limited functional data. Improved methods for predicting the pathogenicity of rare coding variants are needed to facilitate the discovery of disease variants from exome sequencing studies. We developed REVEL (rare exome variant ensemble learner), an ensemble method for predicting the pathogenicity of missense variants on the basis of individual tools: MutPred, FATHMM, VEST, PolyPhen, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP, SiPhy, phyloP, and phastCons. REVEL was trained with recently discovered pathogenic and rare neutral missense variants, excluding those previously used to train its constituent tools. When applied to two independent test sets, REVEL had the best overall performance (p < 10⁻¹²) as compared to any individual tool and seven ensemble methods: MetaSVM, MetaLR, KGGSeq, Condel, CADD, DANN, and Eigen. Importantly, REVEL also had the best performance for distinguishing pathogenic from rare neutral variants with allele frequencies <0.5%. The area under the receiver operating characteristic curve (AUC) for REVEL was 0.046–0.182 higher in an independent test set of 935 recent SwissVar disease variants and 123,935 putatively neutral exome sequencing variants and 0.027–0.143 higher in an independent test set of 1,953 pathogenic and 2,406 benign variants recently reported in ClinVar than the AUCs for other ensemble methods. We provide pre-computed REVEL scores for all possible human missense variants to facilitate the identification of pathogenic variants in the sea of rare variants discovered as sequencing studies expand in scale.
    Full-text available · Article · Oct 2016 · The American Journal of Human Genetics
  • William D Foulkes · Kokichi Sugano
    Article · Oct 2016 · Endocrine Related Cancer
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    [Show abstract] [Hide abstract] ABSTRACT: A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. We analyzed 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identified 13 candidate causal SNPs associated with serous OC (P=9.2x10$^{-20}$), ER-negative BC (P=1.1x10$^{-13}$), BRCA1-associated BC (P=7.7x10$^{-16}$) and triple negative BC (P-diff=2x10$^{-5}$). Genotype-gene expression associations were identified for candidate target genes ANKLE1 (P=2x10$^{-3}$) and ABHD8 (P
    Full-text available · Article · Sep 2016 · Nature Communications
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    [Show abstract] [Hide abstract] ABSTRACT: Background The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study. Methods We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant. Results For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10⁻⁵), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10⁻⁸) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p≤0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants. Conclusions This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.
    Full-text available · Article · Sep 2016 · Journal of Medical Genetics
  • Leora Witkowski · W. Glenn McCluggage · William D. Foulkes
    [Show abstract] [Hide abstract] ABSTRACT: The introduction of new sequencing technologies has resulted in the discovery of commonly mutated genes in uncommon cancers, including non-epithelial ovarian neoplasms and other rare gynaecological tumours, such as cervical embryonal rhabdomyosarcoma. In some of these neoplasms, mutations in certain genes are both frequent and specific enough such that the genomic mutations and sometimes their associated protein loss or overexpression can be used as an aid to diagnosis. In this review, we contrast previous gene identification methods with newer ones and discuss how the new sequencing technologies (collectively referred to as “next-generation sequencing”) have permitted the identification of specific molecular events that characterise several rare gynaecological neoplasms. We highlight the value of using sequencing to complement traditional pathological methods when diagnosing certain tumours and provide practical advice to pathologists dealing with these neoplasms. We focus on adult granulosa cell tumours (somatic monoallelic mutations in FOXL2), Sertoli-Leydig cell tumours and gynaecological embryonal rhabdomyosarcomas (germline and somatic mutations in DICER1) and small cell carcinoma of the ovary, hypercalcaemic type (biallelic mutations in SMARCA4). The new genetic findings uncovered by next generation sequencing in these uncommon neoplasms have brought these disorders back into focus and point the way towards new diagnostic, preventive and therapeutic avenues. This article is protected by copyright. All rights reserved.
    Article · Aug 2016 · Histopathology
  • Ester Castellsagué · Barbara Rivera · William D Foulkes
    [Show abstract] [Hide abstract] ABSTRACT: To the Editor: In his review article, Strum (March 17 issue)(1) provides data on the overall prevalence of colorectal adenomas in the United States and risk factors for these lesions. It is well established that patients with Streptococcus bovis-group infective endocarditis are at high risk for colorectal cancer.(2) Although a strong relationship between Enterococcus faecalis endocarditis and colorectal adenomas is suspected, robust data are lacking. Of the 150 patients with a diagnosis of enterococcal endocarditis in our cohort from 1979 through 2013, a total of 108 had E. faecalis endocarditis of unknown origin. Of these patients, 58 (54%) underwent . . .
    Article · Jul 2016 · New England Journal of Medicine
  • [Show abstract] [Hide abstract] ABSTRACT: List of the local Institutional Review Boards that provided ethical approval for this study. (XLSX)
    File available · Data · Jul 2016
  • Data: S1 Fig
    [Show abstract] [Hide abstract] ABSTRACT: Assessment for an independent signal for the association between SNPs in 9p22.2 and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. The colour code indicates the linkage disequilibrium with respect to the variant used for adjustment. (TIFF)
    File available · Data · Jul 2016
  • [Show abstract] [Hide abstract] ABSTRACT: Association of SNPs with ovarian cancer risk in BRCA1 and BRCA2 mutation carriers (p<0.01). (XLSX)
    File available · Data · Jul 2016
  • [Show abstract] [Hide abstract] ABSTRACT: SNPs within 100 times likely of being causal for the association with ovarian cancer in the meta-analysis of BRCA1 and BRCA2 mutation carriers. 'T' corresponds to genotyped; 'Ref' and 'Eff' correspond to reference and effector allele, respectively; 'MAF' to minimum allele frequency, 'HR' hazard ratio and 'CI' confidence interval. Bold cells correspond to the strongest associated SNP in the indicated dataset. Green, violet and orange text indicate those SNPs within 100 times likely of being the causal variant/s in BRCA1 and BRCA2 mutation carriers and their meta-analysis, respectively. (PDF)
    File available · Data · Jul 2016
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    [Show abstract] [Hide abstract] ABSTRACT: Population-based genome wide association studies have identified a locus at 9p22.2 associated with ovarian cancer risk, which also modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. We conducted fine-scale mapping at 9p22.2 to identify potential causal variants in BRCA1 and BRCA2 mutation carriers. Genotype data were available for 15,252 (2,462 ovarian cancer cases) BRCA1 and 8,211 (631 ovarian cancer cases) BRCA2 mutation carriers. Following genotype imputation, ovarian cancer associations were assessed for 4,873 and 5,020 SNPs in BRCA1 and BRCA 2 mutation carriers respectively, within a retrospective cohort analytical framework. In BRCA1 mutation carriers one set of eight correlated candidate causal variants for ovarian cancer risk modification was identified (top SNP rs10124837, HR: 0.73, 95%CI: 0.68 to 0.79, p-value 2× 10-16). These variants were located up to 20 kb upstream of BNC2. In BRCA2 mutation carriers one region, up to 45 kb upstream of BNC2, and containing 100 correlated SNPs was identified as candidate causal (top SNP rs62543585, HR: 0.69, 95%CI: 0.59 to 0.80, p-value 1.0 × 10-6). The candidate causal in BRCA1 mutation carriers did not include the strongest associated variant at this locus in the general population. In sum, we identified a set of candidate causal variants in a region that encompasses the BNC2 transcription start site. The ovarian cancer association at 9p22.2 may be mediated by different variants in BRCA1 mutation carriers and in the general population. Thus, potentially different mechanisms may underlie ovarian cancer risk for mutation carriers and the general population.
    Full-text available · Article · Jul 2016 · PLoS ONE
  • [Show abstract] [Hide abstract] ABSTRACT: Genomic features for selected SNPs associated with ovarian cancer risk in BRCA2 mutation carriers. (XLSX)
    File available · Data · Jul 2016
  • [Show abstract] [Hide abstract] ABSTRACT: SNPs within 100 times likely of being causal for the association with ovarian cancer in BRCA1 and BRCA2 mutation carriers. 'T' corresponds to genotyped; 'Info' measures the accuracy of the imputation; 'Ref' and 'Eff' correspond to reference and effector allele, respectively; 'MAF' to minor allele frequency, 'HR' hazard ratio and 'CI' confidence interval. Bold cells correspond to the strongest associated SNP in the indicated dataset. Green and violet text indicates the set of potentially causal variant/s in BRCA1 and BRCA2 mutation carriers, respectively. (PDF)
    File available · Data · Jul 2016
  • [Show abstract] [Hide abstract] ABSTRACT: Characteristics of study participants. (PDF)
    File available · Data · Jul 2016

Publication Stats

15k Citations


  • 2002-2015
    • McGill University
      • Department of Oncology
      Montréal, Quebec, Canada
  • 1997-2015
    • Jewish General Hospital
      Montréal, Quebec, Canada
  • 2011
    • Creighton University
      Omaha, Nebraska, United States
  • 2001-2006
    • University of Toronto
      Toronto, Ontario, Canada
    • University of Vermont
      • Department of Medicine
      Burlington, Vermont, United States
  • 2003-2005
    • University of Bergen
      • The Gade Institute
      Bergen, Hordaland, Norway
    • Haukeland University Hospital
      • Department of Pathology
      Bergen, Hordaland Fylke, Norway
  • 2004
    • Sunnybrook Health Sciences Centre
      • Division of Medical Oncology and Hematology
      Toronto, Ontario, Canada
  • 2000-2002
    • McGill University Health Centre
      Montréal, Quebec, Canada