Germline RAD51C mutations confer susceptibility to ovarian cancer

Loveday, Chey; Turnbull, Clare; Ruark, Elise; Xicola, Rosa M.; Ramsay, Emma; Hughes, Deborah; Warren-Perry, Margaret; Snape, Katie; Eccles, Diana; Evans, D. Gareth; Gore, Martin; Renwick, Anthony; Seal, Sheila; Antoniou, Antonis C.; Rahman, Nazneen

doi:10.1038/ng.2224

Cited by 219 publications

(169 citation statements)

References 15 publications

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“…The variants c.494G>A (p.Arg165Gln; 11,14,22 (Table 1). Both the c.26G>C and the c.715C>T variants (this last occurring in all the carriers of the deleterious c.694C>T variant) were predicted to be damaging by two of the four programs used to analyze the variant effect on the protein (Table 1).…”

Section: Resultsmentioning

confidence: 99%

About 1% of the breast and ovarian Spanish families testing negative for BRCA1 and BRCA2 are carriers of RAD51D pathogenic variants

Gutiérrez‐Enríquez

Bonache

Garibay

et al. 2013

Intl Journal of Cancer

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RAD51D mutations have been recently identified in breast (BC) and ovarian cancer (OC) families. Although an etiological role in OC appears to be present, the association of RAD51D mutations and BC risk is more unclear. We aimed to determine the prevalence of germline RAD51D mutations in Spanish BC/OC families negative for BRCA1/BRCA2 mutations. We analyzed 842 index patients: 491 from BC/OC families, 171 BC families, 51 OC families and 129 patients without family history but with early-onset BC or OC or metachronous BC and OC. Mutation detection was performed with high-resolution melting, denaturing high-performance liquid chromatography or Sanger sequencing. Three mutations were found in four families with BC and OC cases (0.82%). Two were novel: c.1A>T (p.Met1?) and c.66712_667123del, leading to the exon 7 skipping and one previously described: c.674C>T (p.Arg232*). All were present in BC/OC families with only one OC. The c.66712_667123del cosegregated in the family with one early-onset BC and two bilateral BC cases. We also identified the c.629C>T (p.Ala210Val) variant, which was predicted in silico to be potentially pathogenic. About 1% of the BC and OC Spanish families negative for BRCA1/BRCA2 are carriers of RAD51D mutations. The presence of several BC mutation carriers, albeit in the context of familial OC, suggests an increased risk for BC, which should be taken into account in the follow-up and early detection measures. RAD51D testing should be considered in clinical setting for families with BC and OC, irrespective of the number of OC cases in the family.

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Section: Resultsmentioning

confidence: 99%

About 1% of the breast and ovarian Spanish families testing negative for BRCA1 and BRCA2 are carriers of RAD51D pathogenic variants

Gutiérrez‐Enríquez

Bonache

Garibay

et al. 2013

Intl Journal of Cancer

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“…Although this is the first report on the loss of the Mutp53 allele through LOH in an apparent healthy tissue, Mut-LOH was noticed for other TSGs with a role in DNA repair. [41][42][43][44][45] It is tempting to speculate that LOH can be seen as a physiological genetic repair mechanism. Gene expression, copy number and sequencing analyses (Figures 6f, 2e, f and h) point to the induction of HRDRP events as the mechanism underlie most cases of LOH.…”

Section: Discussionmentioning

confidence: 99%

The onset of p53 loss of heterozygosity is differentially induced in various stem cell types and may involve the loss of either allele

et al. 2014

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1,5 p53 loss of heterozygosity (p53LOH) is frequently observed in Li-Fraumeni syndrome (LFS) patients who carry a mutant (Mut) p53 germ-line mutation. Here, we focused on elucidating the link between p53LOH and tumor development in stem cells (SCs). Although adult mesenchymal stem cells (MSCs) robustly underwent p53LOH, p53LOH in induced embryonic pluripotent stem cells (iPSCs) was significantly attenuated. Only SCs that underwent p53LOH induced malignant tumors in mice. These results may explain why LFS patients develop normally, yet acquire tumors in adulthood. Surprisingly, an analysis of single-cell sub-clones of iPSCs, MSCs and ex vivo bone marrow (BM) progenitors revealed that p53LOH is a bi-directional process, which may result in either the loss of wild-type (WT) or Mut p53 allele. Interestingly, most BM progenitors underwent Mutp53LOH. Our results suggest that the bi-directional p53LOH process may function as a cell-fate checkpoint. The loss of Mutp53 may be regarded as a DNA repair event leading to genome stability. Indeed, gene expression analysis of the p53LOH process revealed upregulation of a specific chromatin remodeler and a burst of DNA repair genes. However, in the case of loss of WTp53, cells are endowed with uncontrolled growth that promotes cancer.

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“…Thus, we recommend excluding FANCM as an FA gene, although, together with FAAP100, FAAP25, and other FA-core complex interacting proteins, FANCM is involved in the FA ICL repair (ICLR) pathway (see below). 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

167

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Germline RAD51C mutations confer susceptibility to ovarian cancer

Cited by 219 publications

References 15 publications

About 1% of the breast and ovarian Spanish families testing negative for BRCA1 and BRCA2 are carriers of RAD51D pathogenic variants

About 1% of the breast and ovarian Spanish families testing negative for BRCA1 and BRCA2 are carriers of RAD51D pathogenic variants

The onset of p53 loss of heterozygosity is differentially induced in various stem cell types and may involve the loss of either allele

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

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