William D Foulkes

McGill University, Montréal, Quebec, Canada

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Publications (431)3655.34 Total impact

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    ABSTRACT: Specific germline mutations in the hereditary breast-ovarian cancer susceptibility (HBC/HBOC) genes, BRCA1, BRCA2 and PALB2, have been shown to recur in French Canadians of Quebec, Canada, and this has been attributed to common ancestors. Germline TP53 mutation carriers are known to segregate in Li-Fraumeni syndrome families, which feature young age of onset breast cancer. We have reported rare TP53 mutation carriers in French Canadian HBC families, though none recurred possibly due to the limited number of cancer families investigated. Here we describe TP53 germline mutations found in French Canadian cancer families provided from hereditary cancer clinics; investigate 37 new BRCA1 and BRCA2 mutation-negative HBC/HBOC families for the TP53 mutations; and assess the frequency of TP53 mutations in a 1235 French Canadian breast cancer cases not selected for family history of cancer. TP53 mutation-positive pedigrees from French Canadian cancer families were provided from local hereditary cancer clinics. Bidirectional Sanger sequencing of all protein encoding exons of TP53 was performed using peripheral blood lymphocyte DNA from breast/ovarian cancer probands from 37 HBC/HBOC families of French Canadian descent. Targeted bidirectional Sanger sequencing assay of regions containing the identified TP53 mutations was performed on 1235 French Canadian breast cancer cases not selected for family history cancer. Five new TP53 mutations were identified in six pedigrees from hereditary cancer clinics. No deleterious mutations were identified in cancer probands from 37 HBC/HBOC families. A targeted mutation screen of the 1235 breast cancer cases identified a c.844C>T [p.Arg282Trp] mutation carrier. This mutation was also found among the six mutation-positive cancer families provided by the local hereditary cancer clinics. The targeted screen also uncovered a new TP53 mutation, c.685T>C [p.Cys229Arg] that was found in two breast cancer cases. All TP53 mutation carriers were among the 656 women with breast cancer diagnosed less than 50 years of age. In all six new TP53 mutations were identified in French Canadians, where two each occurred in independently ascertained cases/families. Although all newly identified breast cancer mutation carriers reported a family history of cancer, none were consistent with features of Li-Fraumeni syndrome families.
    BMC Medical Genetics 12/2015; 16(1):24. DOI:10.1186/s12881-015-0169-y · 2.45 Impact Factor
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    ABSTRACT: Given the adverse effect of alcohol in the development of breast cancer among women in the general population, we evaluated whether a similar association exists among women with a BRCA1 or BRCA2 mutation. Information regarding baseline daily alcohol consumption was abstracted from a research questionnaire for 3067 BRCA mutation carriers enrolled in a prospective cohort study. Women were followed biennially until the date of the last follow-up questionnaire, date of breast cancer diagnosis, date of prophylactic bilateral mastectomy, or date of death. Cox proportional hazards models were used to estimate relative risks (RRs) and 95 % confidence intervals (CIs) for invasive breast cancer associated with alcohol consumed at or prior to completion of the baseline questionnaire. After a mean of 5.4 years of follow-up, we observed 259 incident cases of primary invasive breast cancer. Compared with non-users, the adjusted RRs were 1.06 (95 % CI 0.78-1.44) for ever use and 1.08 (0.79-1.47) for current alcohol use. For women in the highest versus lowest quintile of cumulative alcohol consumption, the RR was 0.94 (95 % CI 0.63-1.40; P trend = 0.65). Our findings suggest that alcohol consumption is not a risk factor for breast cancer among women with a BRCA1 or BRCA2 mutation.
    Breast Cancer Research and Treatment 05/2015; DOI:10.1007/s10549-015-3393-4 · 4.20 Impact Factor
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    ABSTRACT: The DICER1 gene encodes an endoribonuclease involved in the production of mature microRNAs which regulates gene expression through several mechanisms. Recent studies have demonstrated somatic mutations in DICER1 in approximately 60% of ovarian Sertoli-Leydig cell tumors. Furthermore, patients with germline mutations in DICER1 are predisposed to developing a range of rare neoplasms including ovarian sex cord-stromal tumors most of which have been classified as Sertoli-Leydig cell tumor. However, the histologic features of these tumors have not been reported in detail. We describe the morphologic and immunophenotypic findings of 4 sex cord-stromal tumors arising in patients with proven or likely germline DICER1 mutations including 3 individuals from 1 family. Three tumors showed similar appearances characterized by marked architectural and cytologic heterogeneity including sertoliform, juvenile granulosa cell tumor-like, and unclassifiable elements. The remaining case mainly showed heterologous mucinous epithelial and neuroendocrine differentiation with only a minor intermediate-grade Sertoli cell component. This tumor and one of the 3 former cases arose in related patients with identical germline DICER1 mutations indicating that additional factors influence tumor morphology. All tumors were positive for steroidogenic factor-1 and FOXL2 on immunohistochemical analysis, whereas there was more variable expression of inhibin, calretinin, CD56, CD99, and hormone receptors. The present small series suggests that some ovarian Sertoli-Leydig cell tumor associated with germline DICER1 mutations may show distinctive histologic features in particular admixed Sertoli cell and juvenile granulosa cell tumor-like features. Larger studies are required to establish whether heterologous elements are also a more common feature of these tumors.
    International journal of gynecological pathology: official journal of the International Society of Gynecological Pathologists 05/2015; 34(3):266-274. DOI:10.1097/PGP.0000000000000150 · 1.63 Impact Factor
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    04/2015; 12. DOI:10.1016/j.gore.2015.02.002
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    ABSTRACT: Several moderate- and high-risk breast cancer susceptibility genes have been discovered, but more are likely to exist. To discover new breast cancer susceptibility genes, we used 2 populations (from Poland and Quebec, Canada) and applied whole-exome sequencing in a discovery phase (n = 195), followed by validation. We identified rare recurrent RECQL mutations in each population. In Quebec, 7 of 1,013 higher-risk breast cancer cases and 1 of 7,136 newborns carried the c.634C>T (p.Arg215*) variant (P = 0.00004). In Poland, 30 of 13,136 unselected breast cancer cases and 2 of 4,702 controls carried the c.1667_1667+3delAGTA (p.K555delinsMYKLIHYSFR) variant (P = 0.008). RECQL is implicated in resolving stalled DNA replication forks to prevent double-stranded DNA (dsDNA) breaks. This function is related to that of other known breast cancer susceptibility genes, many of which are involved in repairing dsDNA breaks. We conclude that RECQL is a breast cancer susceptibility gene.
    Nature Genetics 04/2015; DOI:10.1038/ng.3284 · 29.65 Impact Factor
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    ABSTRACT: Genome-wide association studies have identified multiple genetic variants associated with prostate cancer (PrCa) risk which explain a substantial proportion of familial relative risk. These variants can be used to stratify individuals by their risk of PrCa. We genotyped 25 PrCa susceptibility loci in 40,414 individuals and derived a polygenic risk score (PRS). We estimated empirical Odds Ratios for PrCa associated with different risk strata defined by PRS and derived age-specific absolute risks of developing PrCa by PRS stratum and family history. The PrCa risk for men in the top 1% of the PRS distribution was 30.6 (95% CI 16.4-57.3) fold compared with men in the bottom 1%, and 4.2 (95% CI 3.2-5.5) fold compared with the median risk. The absolute risk of PrCa by age 85 was 65.8% for a man with family history in the top 1% of the PRS distribution, compared with 3.7% for a man in the bottom 1%. The PRS was only weakly correlated with serum PSA level (correlation=0.09). Risk profiling can identify men at substantially increased or reduced risk of PrCa. The effect size, measured by OR per unit PRS, was higher in men at younger ages and in men with family history of PrCa. Incorporating additional newly identified loci into a PRS should improve the predictive value of risk profiles. We demonstrate that the risk profiling based on SNPs can identify men at substantially increased or reduced risk that could have useful implications for targeted prevention and screening programs. Copyright © 2015, American Association for Cancer Research.
    Cancer Epidemiology Biomarkers & Prevention 04/2015; DOI:10.1158/1055-9965.EPI-14-0317 · 4.32 Impact Factor
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    ABSTRACT: The purpose of this study was to compare the risks of radiation in screening strategies using chest radiographs and CT to detect a rare cancer in a genetically predisposed population against the risks of undetected disease. A decision analytic model of diagnostic imaging screening strategies was built to predict outcomes and cumulative radiation doses for children with DICER1 mutations screened for pleuropulmonary blastoma. Screening strategies compared were chest radiographs followed by chest CT for a positive radiographic result and CT alone. Screening frequencies ranged from once in 3 years to once every 3 months. BEIR VII (model VII proposed by the Committee on the Biological Effects of Ionizing Radiation) risk tables were used to predict excess cancer mortality for each strategy, and the corresponding loss of life expectancy was calculated using Surveillance Epidemiologic and End Results (SEER) statistics. Loss of life expectancy owing to undetected progressive pleuropulmonary blastoma was estimated on the basis of data from the International Pleuropulmonary Blastoma Registry. Sensitivity analysis was performed for all model parameters. Loss of life expectancy owing to undetected disease in an unscreened population exceeded that owing to radiation-induced cancer for all screening scenarios investigated. Increases in imaging frequency decreased loss of life expectancy for the combined (chest radiographs and CT) screening strategy but increased that for the CT-only strategy. This was because loss of life expectancy for combined screening is dominated by undetected disease, whereas loss of life expectancy for CT screening is dominated by radiation-induced cancers. Even for a rare disease such as pleuropulmonary blastoma, radiographic screening of infants and young children with cancer-predisposing mutations may result in improved life expectancy compared with the unscreened population. The benefit of screening will be greater for diseases with a higher screening yield.
    American Journal of Roentgenology 04/2015; 204(4):W475-W482. DOI:10.2214/AJR.14.12802 · 2.74 Impact Factor
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    ABSTRACT: Enrolling patients in studies of pancreatic ductal adenocarcinoma (pdac) is challenging because of the high fatality of the disease. We hypothesized that a prospective clinic-based study with rapid ascertainment would result in high participation rates. Using that strategy, we established the Quebec Pancreas Cancer Study (qpcs) to investigate the genetics and causes of pdac and other periampullary tumours (pats) that are also rare and underrepresented in research studies. Patients diagnosed with pdac or pat were introduced to the study at their initial clinical encounter, with a strategy to enrol participants within 2 weeks of diagnosis. Patient self-referrals and referrals of unaffected individuals with an increased risk of pdac were also accepted. Family histories, epidemiologic and clinical data, and biospecimens were collected. Additional relatives were enrolled in families at increased genetic risk. The first 346 completed referrals led to 306 probands being enrolled, including 190 probands affected with pdac, who represent the population focus of the qpcs. Participation rates were 88.4% for all referrals and 89.2% for pdac referrals. Family history, epidemiologic and clinical data, and biospecimens were ascertained from 91.9%, 54.6%, and 97.5% respectively of patients with pdac. Although demographics and trends in risk factors in our patients were consistent with published statistics for patients with pdac, the qpcs is enriched for families with French-Canadian ancestry (37.4%), a population with recurrent germ-line mutations in hereditary diseases. Using rapid ascertainment, a pdac and pat research registry with high participation rates can be established. The qpcs is a valuable research resource and its enrichment with patients of French-Canadian ancestry provides a unique opportunity for studies of heredity in these diseases.
    Current Oncology 04/2015; 22(2):113-21. DOI:10.3747/co.22.2300 · 1.64 Impact Factor
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    ABSTRACT: Background Inherited mutations in DNA mismatch repair genes predispose to different cancer syndromes depending on whether they are mono-allelic or bi-allelic. This supports a causal relationship between expression level in the germline and phenotype variation. As a model to study this relationship, our study aimed to define the pathogenic characteristics of a recurrent homozygous coding variant in PMS2 displaying an attenuated phenotype identified by clinical genetic testing in seven Inuit families from Northern Quebec. Methods Pathogenic characteristics of the PMS2 mutation NM_000535.5:c.2002A>G were studied using genotype–phenotype correlation, single-molecule expression detection and single genome microsatellite instability analysis. Results This PMS2 mutation generates a de novo splice site that competes with the authentic site. In homozygotes, expression of the full-length protein is reduced to a level barely detectable by conventional diagnostics. Median age at primary cancer diagnosis is 22 years among 13 NM_000535.5:c.2002A>G homozygotes, versus 8 years in individuals carrying biallelic truncating mutations. Residual expression of fulllength PMS2 transcript was detected in normal tissues from homozygotes with cancers in their 20s. Conclusions Our genotype–phenotype study of c.2002A>G illustrates that an extremely low level of PMS2 expression likely delays cancer onset, a feature that could be exploited in cancer preventive intervention.
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    03/2015; 233. DOI:10.1016/j.gore.2015.03.005
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    ABSTRACT: Embryonal rhabdomyosarcoma (ERMS), a soft tissue sarcoma, is one of the most common pediatric cancers. Certain ERMSs are associated with the DICER1 syndrome, a tumor predisposition syndrome caused by germ-line DICER1 mutations. Characteristic somatic mutations have also been identified in DICER1-associated tumor types. These "hotspot" mutations affect the catalytic activity of the DICER1 ribonuclease IIIb domain. Primary ovarian ERMS (oERMS) is extremely rare. We present a case of a 6-year-old girl with an oERMS harboring 2 DICER1 mutations. The girl also exhibited other DICER1 phenotypes: cystic nephroma (CN) and multinodular goiter. Somatic investigations of the CN identified a hotspot DICER1 mutation different from that in the oERMS. Significantly, the CN presented at 12 years of age, which is much older than the previously reported age range of susceptibility. This report documents the occurrence of DICER1 mutations in a case of oERMS, expanding the spectrum of DICER1-associated tumors. Copyright © 2015. Published by Elsevier Inc.
    Human pathology 03/2015; 46(6). DOI:10.1016/j.humpath.2015.02.008 · 2.81 Impact Factor
  • Ester Castellsagué, William D Foulkes
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    ABSTRACT: Despite the great advances that have occurred in the century following the first description of a Lynch syndrome (LS) family and more especially, in the more than 20 years since the discovery of causal mutations in the mismatch repair genes (MMR), long-standing clinical questions remain unanswered. Moreover, as a result of novel technologies, new questions have arisen. With this commentary we aim to briefly cover of some of these aspects of LS. We will focus on current challenges regarding the definition of LS-related tumors, their prevention and early detection, the role of next-generation sequencing (NGS) in the molecular diagnostics of LS and advances in the treatment of LS tumors. This article is protected by copyright. All rights reserved.
    Clinical Genetics 03/2015; 87(6). DOI:10.1111/cge.12580 · 3.65 Impact Factor
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    ABSTRACT: Inherited mutations in DNA mismatch repair genes predispose to different cancer syndromes depending on whether they are mono-allelic or bi-allelic. This supports a causal relationship between expression level in the germline and phenotype variation. As a model to study this relationship, our study aimed to define the pathogenic characteristics of a recurrent homozygous coding variant in PMS2 displaying an attenuated phenotype identified by clinical genetic testing in seven Inuit families from Northern Quebec. Pathogenic characteristics of the PMS2 mutation NM_000535.5:c.2002A>G were studied using genotype-phenotype correlation, single-molecule expression detection and single genome microsatellite instability analysis. This PMS2 mutation generates a de novo splice site that competes with the authentic site. In homozygotes, expression of the full-length protein is reduced to a level barely detectable by conventional diagnostics. Median age at primary cancer diagnosis is 22 years among 13 NM_000535.5:c.2002A>G homozygotes, versus 8 years in individuals carrying bi-allelic truncating mutations. Residual expression of full-length PMS2 transcript was detected in normal tissues from homozygotes with cancers in their 20s. Our genotype-phenotype study of c.2002A>G illustrates that an extremely low level of PMS2 expression likely delays cancer onset, a feature that could be exploited in cancer preventive intervention. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
    Journal of Medical Genetics 02/2015; DOI:10.1136/jmedgenet-2014-102934 · 5.64 Impact Factor
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    ABSTRACT: Importance Women who carry a germline mutation in either the BRCA1 or BRCA2 gene face a lifetime risk of breast cancer of up to 70%, and once they receive a diagnosis of breast cancer, they face high risks of both second primary breast and ovarian cancers. Preventive bilateral salpingo-oophorectomy is recommended to women with a BRCA mutation at age 35 years or thereafter to prevent breast and ovarian cancer, but it is unclear whether oophorectomy has an impact on survival in women with BRCA-associated breast cancer.Objective To estimate the impact of oophorectomy on survival in women with breast cancer with a BRCA1 or BRCA2 mutation.Design, Setting, and Participants Retrospective analysis of patients selected by pedigree review of families who received counseling at 1 of 12 participating clinical genetics centers. Patients were 676 women with stage I or II breast cancer and a BRCA1 or BRCA2 mutation who were observed for up to 20 years after receiving a diagnosis between 1975 and 2008. Survival experience was compared for women who did and who did not undergo oophorectomy.Main Outcomes and Measures In all analyses, the primary end point was death due to breast cancer.Results Of the 676 women, 345 underwent oophorectomy after the diagnosis of breast cancer and 331 retained both ovaries. The 20-year survival for the entire patient cohort was 77.4%. The adjusted hazard ratio for death attributed to breast cancer in women who underwent oophorectomy was 0.38 (95% CI, 0.19-0.77; P = .007) for BRCA1 carriers and 0.57 (95% CI, 0.23-1.43; P = .23) for BRCA2 carriers. The hazard ratio for breast cancer-specific mortality was 0.76 (95% CI, 0.32-1.78; P = .53) for women with estrogen receptor-positive breast cancer and 0.07 (95% CI, 0.01-0.51; P = .009) for women with estrogen receptor-negative breast cancer.Conclusions and Relevance Oophorectomy is associated with a decrease in mortality in women with breast cancer and a BRCA1 mutation. Women with estrogen receptor-negative breast cancer and a BRCA1 mutation should undergo oophorectomy shortly after diagnosis.
    01/2015; DOI:10.1001/jamaoncol.2015.0658
  • Cancer Research 12/2014; 74(23 Supplement):IA03-IA03. DOI:10.1158/1538-7445.CANSUSC14-IA03 · 9.28 Impact Factor
  • Antonis C Antoniou, William D Foulkes, Marc Tischkowitz
    New England Journal of Medicine 10/2014; 371(17):1651-2. DOI:10.1056/NEJMc1410673 · 54.42 Impact Factor
  • Cancer Research 10/2014; 74(19 Supplement):LB-89-LB-89. DOI:10.1158/1538-7445.AM2014-LB-89 · 9.28 Impact Factor
  • W D Foulkes
    Current Oncology 10/2014; 21(5):205-7. DOI:10.3747/co.21.2253 · 1.64 Impact Factor
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    ABSTRACT: Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare, aggressive tumor that primarily affects young women. SCCOHT has recently been identified as a monogenic disorder caused by germline and/or somatic SMARCA4 mutations. We describe a 15-year-old Caucasian female with a SCCOHT harboring a previously unreported somatic mutation in the SMARCA4 gene (c.1757delA; p.K586.fs) with loss of heterozygosity. No germline mutation was identified. Subsequent immunohistochemical staining confirmed loss of SMARCA4 protein. These molecular findings will aid with SCCOHT diagnosis through immunohistochemical staining for SMARCA4 and in the future may have implications for the management of this disease. Pediatr Blood Cancer © 2014 Wiley Periodicals, Inc.
    Pediatric Blood & Cancer 10/2014; 62(4). DOI:10.1002/pbc.25279 · 2.56 Impact Factor

Publication Stats

15k Citations
3,655.34 Total Impact Points

Institutions

  • 1995–2015
    • McGill University
      • • Department of Oncology
      • • Department of Human Genetics
      • • Department of Medicine
      Montréal, Quebec, Canada
  • 2001–2013
    • Lady Davis Institute for Medical Research
      Montréal, Quebec, Canada
    • Universität Ulm
      • Clinic of Gynecology and Obstetrics
      Ulm, Baden-Wuerttemberg, Germany
    • University of Vermont
      • Department of Medicine
      Burlington, Vermont, United States
  • 2000–2013
    • McGill University Health Centre
      • Department of Oncology
      Montréal, Quebec, Canada
    • Institut Paoli Calmettes
      • Cancer Research Center of Marseille (CRCM)
      Marsiglia, Provence-Alpes-Côte d'Azur, France
  • 2011
    • Creighton University
      Omaha, Nebraska, United States
    • Memorial Sloan-Kettering Cancer Center
      • Department of Medicine
      New York City, NY, United States
  • 1997–2011
    • Jewish General Hospital
      Montréal, Quebec, Canada
  • 2010
    • University of Michigan
      • Department of Internal Medicine
      Ann Arbor, MI, United States
    • University of Oxford
      • Nuffield Department of Clinical Medicine
      Oxford, ENG, United Kingdom
  • 2009
    • Sultan Qaboos University
      Masqaţ, Masqaţ, Oman
  • 1998–2009
    • Institute of Cancer Research
      Londinium, England, United Kingdom
  • 2008
    • St. James University
      Сент-Джеймс, New York, United States
  • 2007
    • University of Utah
      • Division of Genetic Epidemiology
      Salt Lake City, UT, United States
  • 1996–2006
    • University of Toronto
      Toronto, Ontario, Canada
    • University of Southampton
      Southampton, England, United Kingdom
  • 1995–2006
    • Centre hospitalier de l'Université de Montréal (CHUM)
      • Département Chirurgie
      Montréal, Quebec, Canada
  • 2005
    • Haukeland University Hospital
      • Department of Pathology
      Bergen, Hordaland Fylke, Norway
  • 2003–2005
    • University of Bergen
      Bergen, Hordaland, Norway
    • Tufts University
      • Department of Medicine
      Georgia, United States
  • 2004
    • Lund University
      • Department of Oncology
      Lund, Skane, Sweden
  • 2001–2004
    • Sunnybrook Health Sciences Centre
      • Division of Medical Oncology and Hematology
      Toronto, Ontario, Canada