Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene
TL;DR: In index cases from 1,100 German families with gynecological malignancies, the first unambiguous evidence of highly penetrant mutations associated with human cancer in a RAD51 paralog is provided and support the 'common disease, rare allele' hypothesis.
Abstract: Germline mutations in a number of genes involved in the recombinational repair of DNA double-strand breaks are associated with predisposition to breast and ovarian cancer. RAD51C is essential for homologous recombination repair, and a biallelic missense mutation can cause a Fanconi anemia-like phenotype. In index cases from 1,100 German families with gynecological malignancies, we identified six monoallelic pathogenic mutations in RAD51C that confer an increased risk for breast and ovarian cancer. These include two frameshift-causing insertions, two splice-site mutations and two nonfunctional missense mutations. The mutations were found exclusively within 480 pedigrees with the occurrence of both breast and ovarian tumors (BC/OC; 1.3%) and not in 620 pedigrees with breast cancer only or in 2,912 healthy German controls. These results provide the first unambiguous evidence of highly penetrant mutations associated with human cancer in a RAD51 paralog and support the 'common disease, rare allele' hypothesis.
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TL;DR: Understanding how the FA pathway links nucleases, helicases and other DNA-processing enzymes should lead to more targeted uses of ICL-inducing agents in cancer treatment and could provide novel insights into drug resistance.
Abstract: Interstrand crosslinks (ICLs) are highly toxic DNA lesions that prevent transcription and replication by inhibiting DNA strand separation. Agents that induce ICLs were one of the earliest, and are still the most widely used, forms of chemotherapeutic drug. Only recently, however, have we begun to understand how cells repair these lesions. Important insights have come from studies of individuals with Fanconi anaemia (FA), a rare genetic disorder that leads to ICL sensitivity. Understanding how the FA pathway links nucleases, helicases and other DNA-processing enzymes should lead to more targeted uses of ICL-inducing agents in cancer treatment and could provide novel insights into drug resistance.
895 citations
Cites background from "Germline mutations in breast and ov..."
...RAD51C , like BRCA1 , BRCA2 and BRCA1-interacting protein 1 ( BRIP1 ; which encodes FANCJ), was recently shown to be a breast and ovarian cancer predisposition gene in heterozygous carriers, and it causes an FA-like syndrome when homozygously mutate...
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TL;DR: Using targeted capture and massively parallel genomic sequencing, this paper screened for germ-line mutations in 21 tumor suppressor genes in genomic DNA from women with primary ovarian, peritoneal, or fallopian tube carcinoma.
Abstract: Inherited loss-of-function mutations in BRCA1 and BRCA2 and other tumor suppressor genes predispose to ovarian carcinomas, but the overall burden of disease due to inherited mutations is not known. Using targeted capture and massively parallel genomic sequencing, we screened for germ-line mutations in 21 tumor suppressor genes in genomic DNA from women with primary ovarian, peritoneal, or fallopian tube carcinoma. Subjects were consecutively enrolled at diagnosis and not selected for age or family history. All classes of mutations, including point mutations and large genomic deletions and insertions, were detected. Of 360 subjects, 24% carried germ-line loss-of-function mutations: 18% in BRCA1 or BRCA2 and 6% in BARD1, BRIP1, CHEK2, MRE11A, MSH6, NBN, PALB2, RAD50, RAD51C, or TP53. Six of these genes were not previously implicated in inherited ovarian carcinoma. Primary carcinomas were generally characterized by genomic loss of normal alleles of the mutant genes. Of women with inherited mutations, >30% had no family history of breast or ovarian carcinoma, and >35% were 60 y or older at diagnosis. More patients with ovarian carcinoma carry cancer-predisposing mutations and in more genes than previously appreciated. Comprehensive genetic testing for inherited carcinoma is warranted for all women with ovarian, peritoneal, or fallopian tube carcinoma, regardless of age or family history. Clinical genetic testing is currently done gene by gene, with each test costing thousands of dollars. In contrast, massively parallel sequencing allows such testing for many genes simultaneously at low cost.
838 citations
Peter MacCallum Cancer Centre1, Garvan Institute of Medical Research2, Queen Mary University of London3, John Radcliffe Hospital4, Cedars-Sinai Medical Center5, University of Oxford6, Stanford University7, Harvard University8, Imperial College London9, University of Cambridge10, Johns Hopkins University11, University Hospital of Lausanne12, University of Pennsylvania13, University of Manchester14, French Institute of Health and Medical Research15, University of Edinburgh16, Walter and Eliza Hall Institute of Medical Research17, University of British Columbia18, University of Chicago19, Memorial Sloan Kettering Cancer Center20, University of Glasgow21, University College London22, University of Toronto23, Indiana University24, Translational Genomics Research Institute25
TL;DR: This 'roadmap' for HGSOC was determined after extensive discussions at an Ovarian Cancer Action meeting in January 2015 and aims to reduce incidence and improve outcomes for women with this disease.
Abstract: High-grade serous ovarian cancer (HGSOC) accounts for 70-80% of ovarian cancer deaths, and overall survival has not changed significantly for several decades. In this Opinion article, we outline a set of research priorities that we believe will reduce incidence and improve outcomes for women with this disease. This 'roadmap' for HGSOC was determined after extensive discussions at an Ovarian Cancer Action meeting in January 2015.
801 citations
TL;DR: Germline or somatic mutations in homologous recombination genes are present in almost one third of ovarian carcinomas, including both serous and nonserous histologies, and the similar rate of homology recombination mutations in nonserous carcinomas supports their inclusion in PARP inhibitor clinical trials.
Abstract: Purpose: Hallmarks of germline BRCA1/2 -associated ovarian carcinomas include chemosensitivity and improved survival. The therapeutic impact of somatic BRCA1/2 mutations and mutations in other homologous recombination DNA repair genes is uncertain. Experimental Design: Using targeted capture and massively parallel genomic sequencing, we assessed 390 ovarian carcinomas for germline and somatic loss-of-function mutations in 30 genes, including BRCA1 , BRCA2 , and 11 other genes in the homologous recombination pathway. Results: Thirty-one percent of ovarian carcinomas had a deleterious germline (24%) and/or somatic (9%) mutation in one or more of the 13 homologous recombination genes: BRCA1 , BRCA2 , ATM , BARD1 , BRIP1 , CHEK1 , CHEK2 , FAM175A , MRE11A , NBN, PALB2 , RAD51C , and RAD51D . Nonserous ovarian carcinomas had similar rates of homologous recombination mutations to serous carcinomas (28% vs. 31%, P = 0.6), including clear cell, endometrioid, and carcinosarcoma. The presence of germline and somatic homologous recombination mutations was highly predictive of primary platinum sensitivity ( P = 0.0002) and improved overall survival ( P = 0.0006), with a median overall survival of 66 months in germline homologous recombination mutation carriers, 59 months in cases with a somatic homologous recombination mutation, and 41 months for cases without a homologous recombination mutation. Conclusions: Germline or somatic mutations in homologous recombination genes are present in almost one third of ovarian carcinomas, including both serous and nonserous histologies. Somatic BRCA1/2 mutations and mutations in other homologous recombination genes have a similar positive impact on overall survival and platinum responsiveness as germline BRCA1/2 mutations. The similar rate of homologous recombination mutations in nonserous carcinomas supports their inclusion in PARP inhibitor clinical trials. Clin Cancer Res; 20(3); 764–75. ©2013 AACR .
767 citations
Cites background from "Germline mutations in breast and ov..."
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University of Helsinki1, University of Oulu2, University of Tampere3, Turku University Hospital4, University of Turku5, Hannover Medical School6, University of Cambridge7, Netherlands Cancer Institute8, Institute of Cancer Research9, University of Melbourne10, University of California, Los Angeles11, University of Erlangen-Nuremberg12, University of London13, King's College London14, Wellcome Trust Centre for Human Genetics15, Heidelberg University16, German Cancer Research Center17, French Institute of Health and Medical Research18, University of Copenhagen19, Copenhagen University Hospital20, Beckman Research Institute21, University of California, Irvine22, Technische Universität München23, University of Cologne24, Bosch25, University of Tübingen26, Ruhr University Bochum27, Karolinska Institutet28, University of Eastern Finland29, QIMR Berghofer Medical Research Institute30, Katholieke Universiteit Leuven31, University of Hamburg32, Mayo Clinic33, Cancer Council Victoria34, University of Southern California35, Laval University36, Oslo University Hospital37, The Breast Cancer Research Foundation38, Vanderbilt University39, Oulu University Hospital40, University of Toronto41, Lunenfeld-Tanenbaum Research Institute42, Leiden University Medical Center43, Erasmus University Rotterdam44, Erasmus University Medical Center45, University of Sheffield46, Pontifical Xavierian University47, Pomeranian Medical University48
TL;DR: It is suggested that loss-of-function mutations in RAD 51B are rare, but common variation at the RAD51B region is significantly associated with familial breast cancer risk.
Abstract: Common variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737 and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of male breast cancer. The aim of this study was to investigate the role of RAD51B variants in breast cancer predisposition, particularly in the context of familial breast cancer in Finland. We sequenced the coding region of RAD51B in 168 Finnish breast cancer patients from the Helsinki region for identification of possible recurrent founder mutations. In addition, we studied the known rs999737, rs2588809, and rs1314913 SNPs and RAD51B haplotypes in 44,791 breast cancer cases and 43,583 controls from 40 studies participating in the Breast Cancer Association Consortium (BCAC) that were genotyped on a custom chip (iCOGS). We identified one putatively pathogenic missense mutation c.541C>T among the Finnish cancer patients and subsequently genotyped the mutation in additional breast cancer cases (n = 5259) and population controls (n = 3586) from Finland and Belarus. No significant association with breast cancer risk was seen in the meta-analysis of the Finnish datasets or in the large BCAC dataset. The association with previously identified risk variants rs999737, rs2588809, and rs1314913 was replicated among all breast cancer cases and also among familial cases in the BCAC dataset. The most significant association was observed for the haplotype carrying the risk-alleles of all the three SNPs both among all cases (odds ratio (OR): 1.15, 95% confidence interval (CI): 1.11-1.19, P = 8.88 x 10-16) and among familial cases (OR: 1.24, 95% CI: 1.16-1.32, P = 6.19 x 10-11), compared to the haplotype with the respective protective alleles. Our results suggest that loss-of-function mutations in RAD51B are rare, but common variation at the RAD51B region is significantly associated with familial breast cancer risk.
715 citations
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TL;DR: Physical exercise and lack of obesity in adolescence were associated with significantly delayed breast cancer onset, and risks appear to be increasing with time.
Abstract: Risks of breast and ovarian cancer were determined for Ashkenazi Jewish women with inherited mutations in the tumor suppressor genes BRCA1 and BRCA2. We selected 1008 index cases, regardless of family history of cancer, and carried out molecular analysis across entire families. The lifetime risk of breast cancer among female mutation carriers was 82%, similar to risks in families with many cases. Risks appear to be increasing with time: Breast cancer risk by age 50 among mutation carriers born before 1940 was 24%, but among those born after 1940 it was 67%. Lifetime risks of ovarian cancer were 54% for BRCA1 and 23% for BRCA2 mutation carriers. Physical exercise and lack of obesity in adolescence were associated with significantly delayed breast cancer onset.
2,043 citations
"Germline mutations in breast and ov..." refers background in this paper
...The occurrence of both breast and ovarian cancers, and the high frequencies, markedly resembles the clinical presentations of people carrying BRCA1 and BRCA2 mutation...
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TL;DR: It is shown that cell lines derived from FA-B and FA-D1 patients have biallelic mutations in BRCA2 and express truncated BRC a2 proteins, which may result in cancer risks similar to those observed in families withBRCA1 or BRCa2 mutations.
Abstract: Fanconi anemia (FA) is a rare autosomal recessive cancer susceptibility disorder characterized by cellular hypersensitivity to mitomycin C (MMC). Six FA genes have been cloned, but the gene or genes corresponding to FA subtypes B and D1 remain unidentified. Here we show that cell lines derived from FA-B and FA-D1 patients have biallelic mutations in BRCA2 and express truncated BRCA2 proteins. Functional complementation of FA-D1 fibroblasts with wild-type BRCA2 complementary DNA restores MMC resistance. Our results link the six cloned FA genes with BRCA1 and BRCA2 in a common pathway. Germ-line mutation of genes in this pathway may result in cancer risks similar to those observed in families with BRCA1 or BRCA2 mutations.
1,144 citations
"Germline mutations in breast and ov..." refers background in this paper
...These features are typical hallmarks of FA cells with defects in BRCA2 ( FANCD1...
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TL;DR: Through complete sequencing of the protein-coding genes in a patient with familial pancreatic cancer, a germline, truncating mutation in PALB2 was identified that appeared responsible for this patient's predisposition to the disease.
Abstract: Through complete sequencing of the protein-coding genes in a patient with familial pancreatic cancer, we identified a germline, truncating mutation in PALB2 that appeared responsible for this patient's predisposition to the disease. Analysis of 96 additional patients with familial pancreatic cancer revealed three distinct protein-truncating mutations, thereby validating the role of PALB2 as a susceptibility gene for pancreatic cancer. PALB2 mutations have been previously reported in patients with familial breast cancer, and the PALB2 protein is a binding partner for BRCA2. These results illustrate that complete, unbiased sequencing of protein-coding genes can lead to the identification of a gene responsible for a hereditary disease.
759 citations
"Germline mutations in breast and ov..." refers background in this paper
...In addition, the high penetrance of mutations impairing RAD51C function, and the causative link with the occurrence of gynecological cancers, justifies testing of other malignancie...
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University College London1, French Institute of Health and Medical Research2, University of Liverpool3, University of Edinburgh4, Netherlands Cancer Institute5, University of Pennsylvania6, University of Melbourne7, University of Cambridge8, Western General Hospital9, University of St Andrews10, University of Aberdeen11, International Agency for Research on Cancer12, University of Utah13, Trinity College, Dublin14, Curie Institute15, St James's University Hospital16, Leiden University17
TL;DR: Key features of the histologic phenotypes of breast cancers in carriers of mutant BRCA1 and BRCa2 genes are identified and this information may improve the classification of breast cancer in individuals with a family history of the disease and may ultimately aid in the clinical management of patients.
Abstract: BACKGROUND: We have previously demonstrated that breast cancers associated with inherited BRCA1 and BRCA2 gene mutations differ from each other in their histopathologic appearances and that each of these types differs from breast cancers in patients unselected for family history (i.e., sporadic cancers). We have now conducted a more detailed examination of cytologic and architectural features of these tumors. METHODS: Specimens of tumor tissue (5-microm-thick sections) were examined independently by two pathologists, who were unaware of the case or control subject status, for the presence of cell mitosis, lymphocytic infiltration, continuous pushing margins, and solid sheets of cancer cells; cell nuclei, cell nucleoli, cell necrosis, and cell borders were also evaluated. The resulting data were combined with previously available information on tumor type and tumor grade and further evaluated by multifactorial analysis. All statistical tests are two-sided. RESULTS: Cancers associated with BRCA1 mutations exhibited higher mitotic counts (P = .001), a greater proportion of the tumor with a continuous pushing margin (P<.0001), and more lymphocytic infiltration (P = .002) than sporadic (i.e., control) cancers. Cancers associated with BRCA2 mutations exhibited a higher score for tubule formation (fewer tubules) (P = .0002), a higher proportion of the tumor perimeter with a continuous pushing margin (P<.0001), and a lower mitotic count (P = .003) than control cancers. CONCLUSIONS: Our study has identified key features of the histologic phenotypes of breast cancers in carriers of mutant BRCA1 and BRCA2 genes. This information may improve the classification of breast cancers in individuals with a family history of the disease and may ultimately aid in the clinical management of patients.
679 citations
"Germline mutations in breast and ov..." refers background in this paper
...It is well established that the breast cancer histology in people with BRCA1 mutations shows an excess of ductal tumors with high mitotic count and negativity for hormone receptors and HER2/neu, compared to individuals with BRCA2 mutations or with sporadic breast cancer...
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TL;DR: The KORA infrastructure, aspects of data management and quality control, and the concept of cooperative research are presented.
Abstract: KORA (Cooperative Health Research in the Region Augsburg) is a regional research platform for population-based surveys and subsequent follow-up studies in the fields of epidemiology, health economics, and health care research. KORA was established in 1996 to continue and expand the MONICA project in Augsburg, including the Acute Myocardial Infarction (AMI) Registry. The available pool of study participants allows for cohort, case-control and family studies. We present the KORA infrastructure, aspects of data management and quality control, and the concept of cooperative research. The increasing use of the MONICA/KORA cohorts for a variety of research topics, with a recent focus on genetic epidemiology, indicates the attractiveness of this concept.
659 citations
"Germline mutations in breast and ov..." refers methods in this paper
...In total, 2,912 age-matched control samples from healthy women were collected in Northrhine-Westphalia or provided by Kooperative Gesundheitsforschung in der Region Augsbur...
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