Dataset Information

A Finnish founder mutation in RAD51D: analysis in breast, ovarian, prostate, and colorectal cancer.

ABSTRACT: RAD51D and RAD54L are involved in homologous recombination, and rare mutations in RAD51D were recently found in breast-ovarian cancer families. This study investigated RAD51D and RAD54L for mutations in breast and ovarian cancer patients in the Finnish population.The study sequenced the RAD51D and RAD54L genes in 95 breast and/or ovarian cancer families and genotyped the identified mutation in an additional 2200 breast and 553 ovarian cancer patients and 2102 population controls. To investigate the role of the mutation in other common cancers, 1094 prostate and 980 colorectal cancer patients were genotyped.In the screening of RAD51D, one deleterious founder mutation c.576+1G>A was identified in two breast-ovarian cancer families. No mutations were found in RAD54L. Altogether, the c.576+1G>A mutation was detected in 5/707 patients with a personal or family history of ovarian cancer (OR 9.16, 95% CI 1.07 to 78.56; p=0.024), with the highest frequency among breast-ovarian cancer families (3/105 vs 1/1287 controls, OR 37.82, 95% CI 3.90 to 366.91; p=0.0016), but no elevated frequency among breast cancer patients/families (2/2105, p=1). The mutation was not found among prostate or colorectal cancer patients.The results of this study on familial and unselected breast, ovarian, colorectal, and prostate cancer patients suggest that RAD51D is primarily a moderate penetrance susceptibility gene for ovarian cancer, with clinical significance for the carriers.

SUBMITTER: Pelttari LM

PROVIDER: S-EPMC5426530 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A Finnish founder mutation in RAD51D: analysis in breast, ovarian, prostate, and colorectal cancer.

Pelttari Liisa M LM Kiiski Johanna J Nurminen Riikka R Kallioniemi Anne A Schleutker Johanna J Gylfe Alexandra A Aaltonen Lauri A LA Leminen Arto A Heikkilä Päivi P Blomqvist Carl C Bützow Ralf R Aittomäki Kristiina K Nevanlinna Heli H

Journal of medical genetics 20120531 7

<h4>Background</h4>RAD51D and RAD54L are involved in homologous recombination, and rare mutations in RAD51D were recently found in breast-ovarian cancer families. This study investigated RAD51D and RAD54L for mutations in breast and ovarian cancer patients in the Finnish population.<h4>Methods</h4>The study sequenced the RAD51D and RAD54L genes in 95 breast and/or ovarian cancer families and genotyped the identified mutation in an additional 2200 breast and 553 ovarian cancer patients and 2102 p ...[more]

PMID: 22652533

Similar Datasets

Project description:INTRODUCTION:Two major high-penetrance breast cancer genes, BRCA1 and BRCA2, are responsible for approximately 20% of hereditary breast cancer (HBC) cases in Finland. Additionally, rare mutations in several other genes that interact with BRCA1 and BRCA2 increase the risk of HBC. Still, a majority of HBC cases remain unexplained which is challenging for genetic counseling. We aimed to analyze additional mutations in HBC-associated genes and to define the sensitivity of our current BRCA1/2 mutation analysis protocol used in genetic counseling. METHODS:Eighty-two well-characterized, high-risk hereditary breast and/or ovarian cancer (HBOC) BRCA1/2-founder mutation-negative Finnish individuals, were screened for germline alterations in seven breast cancer susceptibility genes, BRCA1, BRCA2, CHEK2, PALB2, BRIP1, RAD50, and CDH1. BRCA1/2 were analyzed by multiplex ligation-dependent probe amplification (MLPA) and direct sequencing. CHEK2 was analyzed by the high resolution melt (HRM) method and PALB2, RAD50, BRIP1 and CDH1 were analyzed by direct sequencing. Carrier frequencies between 82 (HBOC) BRCA1/2-founder mutation-negative Finnish individuals and 384 healthy Finnish population controls were compared by using Fisher's exact test. In silico prediction for novel missense variants effects was carried out by using Pathogenic-Or-Not -Pipeline (PON-P). RESULTS:Three previously reported breast cancer-associated variants, BRCA1 c.5095C > T, CHEK2 c.470T > C, and CHEK2 c.1100delC, were observed in eleven (13.4%) individuals. Ten of these individuals (12.2%) had CHEK2 variants, c.470T > C and/or c.1100delC. Fourteen novel sequence alterations and nine individuals with more than one non-synonymous variant were identified. One of the novel variants, BRCA2 c.72A > T (Leu24Phe) was predicted to be likely pathogenic in silico. No large genomic rearrangements were detected in BRCA1/2 by multiplex ligation-dependent probe amplification (MLPA). CONCLUSIONS:In this study, mutations in previously known breast cancer susceptibility genes can explain 13.4% of the analyzed high-risk BRCA1/2-negative HBOC individuals. CHEK2 mutations, c.470T > C and c.1100delC, make a considerable contribution (12.2%) to these high-risk individuals but further segregation analysis is needed to evaluate the clinical significance of these mutations before applying them in clinical use. Additionally, we identified novel variants that warrant additional studies. Our current genetic testing protocol for 28 Finnish BRCA1/2-founder mutations and protein truncation test (PTT) of the largest exons is sensitive enough for clinical use as a primary screening tool.

Dataset Information

A Finnish founder mutation in RAD51D: analysis in breast, ovarian, prostate, and colorectal cancer.

Publications

A Finnish founder mutation in RAD51D: analysis in breast, ovarian, prostate, and colorectal cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets