Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene

Meindl, Alfons; Hellebrand, Heide; Wiek, Constanze; Erven, Verena; Wappenschmidt, Barbara; Niederacher, Dieter; Freund, Marcel; Lichtner, Peter; Hartmann, Linda; Schaal, Heiner; Ramser, Juliane; Honisch, Ellen; Kubisch, Christian; Wichmann, Hans; Kast, Karin; Deissler, Helmut; Engel, Christoph; Müller‐Myhsok, Bertram; Neveling, Kornelia; Kiechle, Marion; Mathew, Christopher G.; Schindler, Detlev; Schmutzler, Rita K.; Hanenberg, Helmut

doi:10.1038/ng.569

Cited by 648 publications

(604 citation statements)

References 35 publications

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“…Similarly, whole genome exon sequencing (WES) detected biallelic XRCC2 mutations in a consanguineous FA family [9]; however, because of FA genes that predispose to breast and ovarian cancer influence ovarian cancers more than breast cancer [18,19], and are linked to other tumors such as head and neck cancer [20,21]. RAD51C and FANCM were initially associated to FA before they were candidates for FBOC in monoallelic carriers [22,23] highlighting the role of FA research in molecular oncology.…”

Section: Fa Genes (Fanca B C D1 D2 E F G I J L N P Q) Fmentioning

confidence: 99%

Fanconi anemia: a model disease for studies on human genetics and advanced therapeutics

Bogliolo

Surrallés

2015

Current Opinion in Genetics & Development

160

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Section: Fa Genes (Fanca B C D1 D2 E F G I J L N P Q) Fmentioning

confidence: 99%

Fanconi anemia: a model disease for studies on human genetics and advanced therapeutics

Bogliolo

Surrallés

2015

Current Opinion in Genetics & Development

160

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“…210,211 In addition, germline mutations in RAD51C and RAD51D, more recently shown to interact with the Fanconi pathway 212 as well as RAD51 and the BRCA1 co-factor BARD, have all been associated with predisposition to breast and/or ovarian cancer. [213][214][215] These findings, revealing defects in the Fanconi pathway beyond BRCA1/2 mutations to be associated with cancer risk, advocate disturbances in other Fanconi complex components to be examined with respect to drug sensitivity/resistance as well (see below).…”

Section: Homologous Recombination Repairmentioning

confidence: 99%

Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

Lønning

Knappskog

2013

Oncogene

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Although new agents are implemented to cancer therapy, we lack fundamental understandings of the mechanisms of chemoresistance, the main obstacle to cure in cancer. Here we review clinical evidence linking molecular defects to drug resistance across different tumour forms and discuss contemporary experimental evidence exploring these mechanisms. Although evidence, in general, is sparse and fragmentary, merging knowledge links drug resistance, and also sensitivity, to defects in functional pathways having a key role in cell growth arrest or death and DNA repair. As these pathways may act in concert, there is a need to explore multiple mechanisms in parallel. Taking advantage of massive parallel sequencing and other novel high-throughput technologies and base research on biological hypotheses, we now have the possibility to characterize functional defects related to these key pathways and to design a new generation of studies identifying the mechanisms controlling resistance to different treatment regimens in different tumour forms.

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“…Numerous other genes have been shown to be involved in the genetic determinism of breast or ovarian cancers, but their respective contribution and the penetrance of their mutations remain, for most of them, to be characterized. Mutations within TP53, PTEN, STK11 and CDH1 resulting in Li Fraumeni (LFS), Cowden, Peutz-Jeghers syndrome and hereditary diffuse gastric cancer, respectively, are associated to an increased risk of breast cancer; [12][13][14][15] mutations within RAD51 paralogs, such as RAD51C, confer an increased risk of ovarian cancer; 16 and variations within ATM, BRIP1, PALB2 and CHEK2 have been shown to be associated with a moderate increase of breast cancer. 17 Next-generation sequencing (NGS), based on massively parallel sequencing after clonal amplification of DNA templates in emulsion PCR or solid phase, allows molecular diagnostic laboratories to increase their throughput, to reduce the delay of analysis and to analyze simultaneously the different genes involved in a specific disease or a group of diseases.…”

Section: Introductionmentioning

confidence: 99%

Next-generation sequencing for the diagnosis of hereditary breast and ovarian cancer using genomic capture targeting multiple candidate genes

et al. 2014

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To optimize the molecular diagnosis of hereditary breast and ovarian cancer (HBOC), we developed a next-generation sequencing (NGS)-based screening based on the capture of a panel of genes involved, or suspected to be involved in HBOC, on pooling of indexed DNA and on paired-end sequencing in an Illumina GAIIx platform, followed by confirmation by Sanger sequencing or MLPA/QMPSF. The bioinformatic pipeline included CASAVA, NextGENe, CNVseq and Alamut-HT. We validated this procedure by the analysis of 59 patients' DNAs harbouring SNVs, indels or large genomic rearrangements of BRCA1 or BRCA2. We also conducted a blind study in 168 patients comparing NGS versus Sanger sequencing or MLPA analyses of BRCA1 and BRCA2. All mutations detected by conventional procedures were detected by NGS. We then screened, using three different versions of the capture set, a large series of 708 consecutive patients. We detected in these patients 69 germline deleterious alterations within BRCA1 and BRCA2, and 4 TP53 mutations in 468 patients also tested for this gene. We also found 36 variations inducing either a premature codon stop or a splicing defect among other genes: 5/708 in CHEK2, 3/708 in RAD51C, 1/708 in RAD50, 7/708 in PALB2, 3/708 in MRE11A, 5/708 in ATM, 3/708 in NBS1, 1/708 in CDH1, 3/468 in MSH2, 2/468 in PMS2, 1/708 in BARD1, 1/468 in PMS1 and 1/468 in MLH3. These results demonstrate the efficiency of NGS in performing molecular diagnosis of HBOC. Detection of mutations within other genes than BRCA1 and BRCA2 highlights the genetic heterogeneity of HBOC. In BRCA1 and BRCA2 mutation carriers, the cumulative risk of breast cancer at 70 years has been estimated to 65 and 45%, respectively, and the risk of ovarian cancer to 39 and 10%, respectively. 3 The identification of a deleterious BRCA1/BRCA2 mutation within a family is crucial for the medical follow-up, as mutation carriers should be offered annual MRI or, alternatively, prophylactic mastectomy and prophylactic salpingooophorectomy. Furthermore, in a breast cancer patient, the detection of a germline BRCA1 or BRCA2 mutation may have important therapeutic consequences: complete mastectomy instead of partial mastectomy and, in the future, the prescription of specific targeted therapies, such as PARP inhibitors. 4,5 Considering the medical consequences of the identification of a germline BRCA1 or BRCA2 mutation and the frequency of mutation carriers, which has

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Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene

Cited by 648 publications

References 35 publications

Fanconi anemia: a model disease for studies on human genetics and advanced therapeutics

Fanconi anemia: a model disease for studies on human genetics and advanced therapeutics

Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

Next-generation sequencing for the diagnosis of hereditary breast and ovarian cancer using genomic capture targeting multiple candidate genes

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