Evaluation of RAD51C as cancer susceptibility gene in a large breast-ovarian cancer patient population referred for genetic testing (original) (raw)
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Mutation analysis of RAD51D in non-BRCA1/2 ovarian and breast cancer families
British journal of cancer, 2012
Recent data show that mutations in RAD51D have an aetiological role in ovarian carcinoma, yet mutations do not appear to be associated with an increased risk for breast cancer. We studied ovarian and breast cancer families having at least one woman affected by ovarian carcinoma, to assess the importance of RAD51D mutations in such families. The coding region of the RAD51D gene was analysed in 175 BRCA1/2-negative families with family histories of both ovarian and breast cancer ascertained from two Canadian and two Belgian institutions. We identified one previously reported deleterious mutation, p.Arg186(*) (c.556C>T), and two novel variants; missense substitution p.Cys119Arg and an intronic variant c.83-26A>G. p.Arg186(*) segregated with the disease in the family and two ovarian carcinomas available for analysis showed loss of the wild-type allele, but the novel variants are likely neutral. RAD51D should be included in genetic screening of ovarian cancer families that do not h...
Breast Cancer Research and Treatment, 2014
BRCA1 and BRCA2 are the most well-known breast and ovarian cancer susceptibility genes. Additional genes involved in DNA repair have been identified as predisposing to breast cancer. Recently, RAD51C, a new Fanconi Anemia gene, essential for homologous recombination repair, has been reported to be a rare hereditary breast and ovarian cancer susceptibility gene. Indeed, several pathogenic mutations have been identified in BRCA1/BRCA2-negative hereditary breast and ovarian cancer families. Here, we present the results of the screening of RAD51C mutations in a large series of 516 BRCA1/BRCA2-negative Spanish patients from breast and/ or ovarian cancer families, and the evaluation of these results in the context of all RAD51C carriers. RAD51C mutation screening was performed by DNA analysis for all index cases. All the genetic variants identified were analyzed in silico for splicing and protein predictions. cDNA analysis was performed for three selected variants. All previous RAD51C mutation studies on breast and/or ovarian cancer were reviewed. We identified three inactivating RAD51C mutations. Two mutations were found in breast and ovarian cancer families and one mutation in a site-specific breast cancer family. Based on the mean age of ovarian cancer diagnosis in RAD51C carriers, we would recommend prophylactic bilateral salpingo-ophorectomy in premenopausal RAD51C mutation carriers. Our results support that RAD51C is a rare breast and ovarian cancer susceptibility gene and may contribute to a small fraction of families including breast and ovarian cancer cases and families with only breast cancer. Thus, RAD51C testing should be offered to hereditary breast and/or ovarian cancer families without selecting for specific cancer origin.
2020
Background: RAD51 from the cluster genes which have a vital role in the pathogenesis of squamous cell carcinoma. Present study aimed to analysed polymorphisms of RAD5 single nucleotide 1(rs2619679, rs2928140 and rs1801320) and their relationship to breast cancer (BC) and ovarian cancer (OC) in Iraqi population. Methods: This study included, 35 females with BC, 35 females with OC, who were diagnostic histopathologicaly, and 30 healthy females as control. Three SNPs (rs2619679, rs2928140 and rs1801320) of RAD51 were selected for genotyping by using the polymerase chain reactionrestriction fragment length polymorphism (PCR-RFLP). Results: Statistically differences were found in the distribution of AA and TT genotypes and A/T alleles for rs2619679 in BC (p<0.05) so GG and CC genotypes and G/C alleles for rs2928140. Whereas distribution of genotypes and alleles for rs1801320 not reflect significant differences (p>0.05) between BC and control but mutant genotype GG and mutant allele G appeared in highest frequency (42%, 57%) in BC. Statistically changes of RAD51 SNPs for OC were found in the incidence of AA and T alleles for rs2619679 (p<0.05) so, GG and CC genotypes and G/C alleles for rs2928140 but distribution of genotypes and alleles for rs1801320 not reproduce significant differences (p>0.05) between OC and control but mutant genotype GG and mutant allele G appeared in OC with highest rate (45%, 59%). Mutant genotype/allele of rs2619679 (TT/T), rs2928140(CC/C) and rs1801320 (GG/G) appeared as effective factors for cancer with acceptable rate for diagnosis of BC and OC. Conclusion: mutation in RAD51 SNPs (rs2619679, rs2928140 , rs1801320) associated with increases the possibility of BC and OC.
International journal of cancer. Journal international du cancer, 2004
Six SNPs have been detected in the DNA repair genes RAD51C and RAD51D, not previously characterized. The novel variant E233G in RAD51D is more highly represented in high-risk, site-specific, familial breast cancer cases that are not associated with the BRCA1/2 genes, with a frequency of 5.74% (n ؍ 174) compared to a control population (n ؍ 567) and another subset of breast cancer patients (n ؍ 765) with a prevalence of around 2% only (comparison to controls, OR ؍ 2.6, 95% CI 1.12-6.03; p < 0.021). We found that the immunohistochemical profile detected in available tumors from these patients differs slightly from those described in non-BRCA1/2 tumors. Finally, the structural prediction of the putative functional consequence of this change indicates that it can diminish protein stability and structure. This suggests a role for E233G as a low-penetrance susceptibility gene in the specific subgroup of high-risk familial breast cancer cases that are not related to BRCA1/2.
PLoS ONE, 2012
Background: Although inherited breast cancer has been associated with germline mutations in genes that are functionally involved in the DNA homologous recombination repair (HRR) pathway, including BRCA1, BRCA2, TP53, ATM, BRIP1, CHEK2 and PALB2, about 70% of breast cancer heritability remains unexplained. Because of their critical functions in maintaining genome integrity and already well-established associations with breast cancer susceptibility, it is likely that additional genes involved in the HRR pathway harbor sequence variants associated with increased risk of breast cancer. RAD51 plays a central biological function in DNA repair and despite the fact that rare, likely dysfunctional variants in three of its five paralogs, RAD51C, RAD51D, and XRCC2, have been associated with breast and/or ovarian cancer risk, no population-based casecontrol mutation screening data are available for the RAD51 gene. We thus postulated that RAD51 could harbor rare germline mutations that confer increased risk of breast cancer. Methodology/Principal Findings: We screened the coding exons and proximal splice junction regions of the gene for germline sequence variation in 1,330 early-onset breast cancer cases and 1,123 controls from the Breast Cancer Family Registry, using the same population-based sampling and analytical strategy that we developed for assessment of rare sequence variants in ATM and CHEK2. In total, 12 distinct very rare or private variants were characterized in RAD51, with 10 cases (0.75%) and 9 controls (0.80%) carrying such a variant. Variants were either likely neutral missense substitutions (3), silent substitutions (4) or non-coding substitutions (5) that were predicted to have little effect on efficiency of the splicing machinery. Conclusion: Altogether, our data suggest that RAD51 tolerates so little dysfunctional sequence variation that rare variants in the gene contribute little, if anything, to breast cancer susceptibility.
Human Molecular Genetics, 2012
RAD51C was defined by Meindl et al. in 2010 as a high-risk gene involved in hereditary breast and ovarian cancers. Although this role seems to be clear, nowadays there is controversy about the indication of including the gene in routine clinical genetic testing, due to the lower prevalence or the absence of mutations found in subsequent studies. Here, we present the results of a comprehensive mutational screening of the RAD51C gene in a large series of 785 Spanish breast and/or ovarian cancer families, which, in contrast to the various subsequent studies published to date, includes the functional characterization of suspicious missense variants as reported in the initial study. We have detected 1.3% mutations of RAD51C in breast and ovarian cancer families, while mutations in breast cancer only families seem to be very rare. More than half of the deleterious variants detected were of missense type, which highlights their significance in the gene, and suggest that RAD51C mutations may have been so far partially disregarded and their prevalence underestimated due to the lack of functional complementation assays. Our results provide new evidences, suggesting that the genetic testing of RAD51C should be considered for inclusion into the clinical setting, at least for breast and ovarian cancer families, and encourage re-evaluating its role incorporating functional assays.
Germline mutations in RAD51D confer susceptibility to ovarian cancer
Recently, RAD51C mutations were identified in families with breast and ovarian cancer1. This observation prompted us to investigate the role of RAD51D in cancer susceptibility. We identified eight inactivating RAD51D mutations in unrelated individuals from 911 breast-ovarian cancer families compared with one inactivating mutation identified in 1,060 controls (P = 0.01). The association found here was principally with ovarian cancer, with three mutations identified in the 59 pedigrees with three or more individuals with ovarian cancer (P = 0.0005). The relative risk of ovarian cancer for RAD51D mutation carriers was estimated to be 6.30 (95% CI 2.86–13.85, P = 4.8 × 10−6). By contrast, we estimated the relative risk of breast cancer to be 1.32 (95% CI 0.59–2.96, P = 0.50). These data indicate that RAD51D mutation testing may have clinical utility in individuals with ovarian cancer and their families. Moreover, we show that cells deficient in RAD51D are sensitive to treatment with a PARP inhibitor, suggesting a possible therapeutic approach for cancers arising in RAD51D mutation carriers.
The American Journal of Human Genetics, 2007
on behalf of the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) † RAD51 is an important component of double-stranded DNA-repair mechanisms that interacts with both BRCA1 and BRCA2. A single-nucleotide polymorphism (SNP) in the 5 untranslated region (UTR) of RAD51, 135GrC, has been suggested as a possible modifier of breast cancer risk in BRCA1 and BRCA2 mutation carriers. We pooled genotype data for 8,512 female mutation carriers from 19 studies for the RAD51 135GrC SNP. We found evidence of an increased breast cancer risk in CC homozygotes (hazard ratio [HR] 1.92 [95% confidence interval {CI} 1.25-2.94) but not in heterozygotes (HR 0.95 [95% CI 0.83-1.07];
Proceedings of the National Academy of Sciences, 2001
BRCA1 and BRCA2 carriers are at increased risk for both breast and ovarian cancer, but estimates of lifetime risk vary widely, suggesting their penetrance is modified by other genetic and͞or environmental factors. The BRCA1 and BRCA2 proteins function in DNA repair in conjunction with RAD51. A preliminary report suggested that a single nucleotide polymorphism in the 5 untranslated region of RAD51 (135C͞G) increases breast cancer risk in BRCA1 and BRCA2 carriers. To investigate this effect we studied 257 female Ashkenazi Jewish carriers of one of the common BRCA1 (185delAG, 5382insC) or BRCA2 (6174delT) mutations. Of this group, 164 were affected with breast and͞or ovarian cancer and 93 were unaffected. RAD51 genotyping was performed on all subjects. Among BRCA1 carriers, RAD51-135C frequency was similar in healthy and affected women [6.1% (3 of 49) and 9.9% (12 of 121), respectively], and RAD-135C did not influence age of cancer diagnosis [Hazard ratio (HR) ؍ 1.18 for disease in RAD51-135C heterozygotes, not significant]. However, in BRCA2 carriers, RAD51-135C heterozygote frequency in affected women was 17.4% (8 of 46) compared with 4.9% (2 of 41) in unaffected women (P ؍ 0.07). Survival analysis in BRCA2 carriers showed RAD51-135C increased risk of breast and͞or ovarian cancer with an HR of 4.0 [95% confidence interval 1.6 -9.8, P ؍ 0.003]. This effect was largely due to increased breast cancer risk with an HR of 3.46 (95% confidence interval 1.3-9.2, P ؍ 0.01) for breast cancer in BRCA2 carriers who were RAD51-135C heterozygotes. RAD51 status did not affect ovarian cancer risk. These results show RAD51-135C is a clinically significant modifier of BRCA2 penetrance, specifically in raising breast cancer risk at younger ages.