Gene Summary

Gene:RAD51D; RAD51 paralog D
Aliases: TRAD, R51H3, BROVCA4, RAD51L3
Summary:The protein encoded by this gene is a member of the RAD51 protein family. RAD51 family members are highly similar to bacterial RecA and Saccharomyces cerevisiae Rad51, which are known to be involved in the homologous recombination and repair of DNA. This protein forms a complex with several other members of the RAD51 family, including RAD51L1, RAD51L2, and XRCC2. The protein complex formed with this protein has been shown to catalyze homologous pairing between single- and double-stranded DNA, and is thought to play a role in the early stage of recombinational repair of DNA. Alternative splicing results in multiple transcript variants. Read-through transcription also exists between this gene and the downstream ring finger and FYVE-like domain containing 1 (RFFL) gene. [provided by RefSeq, Jan 2011]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:DNA repair protein RAD51 homolog 4
Source:NCBIAccessed: 11 March, 2017


What does this gene/protein do?
Show (8)

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 11 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Base Sequence
  • Registries
  • Sequence Homology
  • RNA Helicases
  • Mutation
  • DNA Repair
  • Genetic Predisposition
  • Rad51 Recombinase
  • Risk Factors
  • BRCA2
  • DNA Helicases
  • Nuclear Proteins
  • Ubiquitin-Protein Ligases
  • Risk Assessment
  • Age Factors
  • Heterozygote
  • BRCA2 Protein
  • Ovarian Cancer
  • ras Proteins
  • Homologous Recombination
  • Breast Cancer
  • Germ-Line Mutation
  • Triple Negative Breast Cancer
  • Cancer Gene Expression Regulation
  • Single Nucleotide Polymorphism
  • Hereditary Breast and Ovarian Cancer Syndrome
  • Case-Control Studies
  • Genetic Testing
  • DNA Mutational Analysis
  • Platinum Compounds
  • Pedigree
  • Drug Resistance
  • Chromosome 17
  • Exons
  • High-Throughput Nucleotide Sequencing
  • BRCA1
  • Rad52 DNA Repair and Recombination Protein
  • TP53
  • BRCA1 Protein
  • DNA-Binding Proteins
Tag cloud generated 11 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: RAD51D (cancer-related)

Pritchard CC, Mateo J, Walsh MF, et al.
Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer.
N Engl J Med. 2016; 375(5):443-53 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Inherited mutations in DNA-repair genes such as BRCA2 are associated with increased risks of lethal prostate cancer. Although the prevalence of germline mutations in DNA-repair genes among men with localized prostate cancer who are unselected for family predisposition is insufficient to warrant routine testing, the frequency of such mutations in patients with metastatic prostate cancer has not been established.
METHODS: We recruited 692 men with documented metastatic prostate cancer who were unselected for family history of cancer or age at diagnosis. We isolated germline DNA and used multiplex sequencing assays to assess mutations in 20 DNA-repair genes associated with autosomal dominant cancer-predisposition syndromes.
RESULTS: A total of 84 germline DNA-repair gene mutations that were presumed to be deleterious were identified in 82 men (11.8%); mutations were found in 16 genes, including BRCA2 (37 men [5.3%]), ATM (11 [1.6%]), CHEK2 (10 [1.9% of 534 men with data]), BRCA1 (6 [0.9%]), RAD51D (3 [0.4%]), and PALB2 (3 [0.4%]). Mutation frequencies did not differ according to whether a family history of prostate cancer was present or according to age at diagnosis. Overall, the frequency of germline mutations in DNA-repair genes among men with metastatic prostate cancer significantly exceeded the prevalence of 4.6% among 499 men with localized prostate cancer (P<0.001), including men with high-risk disease, and the prevalence of 2.7% in the Exome Aggregation Consortium, which includes 53,105 persons without a known cancer diagnosis (P<0.001).
CONCLUSIONS: In our multicenter study, the incidence of germline mutations in genes mediating DNA-repair processes among men with metastatic prostate cancer was 11.8%, which was significantly higher than the incidence among men with localized prostate cancer. The frequencies of germline mutations in DNA-repair genes among men with metastatic disease did not differ significantly according to age at diagnosis or family history of prostate cancer. (Funded by Stand Up To Cancer and others.).

González-Rivera M, Lobo M, López-Tarruella S, et al.
Frequency of germline DNA genetic findings in an unselected prospective cohort of triple-negative breast cancer patients participating in a platinum-based neoadjuvant chemotherapy trial.
Breast Cancer Res Treat. 2016; 156(3):507-15 [PubMed] Related Publications
We describe the status and frequency of germline DNA genetic findings in an unselected prospective cohort of triple negative breast cancer patients participating in a platinum-based neoadjuvant chemotherapy trial. Study population includes 124 consecutive patients with stage II-III TNBC from a trial exploring the antitumor activity of neoadjuvant carboplatin/docetaxel chemotherapy enrolled between 2012 and March 2015, to determine the frequency of germline DNA genetic mutations. 17.1 % of the patients with germline DNA tested had deleterious mutations in any of the analyzed genes (12.38 % in BRCA1, 1.9 % in BRCA2 and BARD1 and 0.95 % in RAD51D). Attending the intrinsic subtype, all the BRCA1/2 carriers tested had basal-like subtype. Among wild-type (WT) patients, 70.11 % had basal subtype, 16.09 % HER2 enriched, 1.15 % Luminal B, and 4.60 % Normal-like. Mean age at diagnosis was significantly lower in mutation-carriers compared with no carriers (43.72 vs 53.10, p = 0.004). 3 BRCA1/2 carriers were detected between 51 and 60 years, and only one deleterious mutation (BARD1) over 60 years. A positive familiar history of breast and ovarian cancer was more frequent in patients with deleterious mutations (39.39 vs 17.94 %, p = 0.043). Our study confirms the prevalence of BRCA1/2 mutations in TNBC patients. TNBC should therefore be considered by itself as a criterion for BRCA1/2 genetic testing. Determination of other breast cancer predisposition genes implicated in homologous recombination should also be discussed in this population. However, no definitive conclusions can be reached due to the low prevalence and the uncertain clinical impact of most of the genes included.

Frimer M, Levano KS, Rodriguez-Gabin A, et al.
Germline mutations of the DNA repair pathways in uterine serous carcinoma.
Gynecol Oncol. 2016; 141(1):101-7 [PubMed] Related Publications
OBJECTIVE: Treatment options are limited for patients with uterine serous carcinoma (USC). Knowledge of USC's somatic mutation landscape is rapidly increasing, but its role in hereditary cancers remains unclear. We aim to evaluate the frequency and characteristics of germline mutations in genes commonly implicated in carcinogenesis, including those within homologous recombination (HR) and mismatch repair (MMR) pathways in patients with pure USC.
METHODS: By using targeted capture exome sequencing, 43 genes were analyzed in a cohort of 7 consecutive patients with paired tumor and non-tumor USC samples in our institutional tumor repository. Mutations predicted to have damaging effects on protein function are validated by Sanger Sequencing.
RESULTS: We found 21 germline mutations in 11 genes in our USC cohort. Five patients harbored 7 germline mutations (33.3%) within genes involved in the HR pathway, RAD51D being the most common. Four patients had 9 (42.8%) germline mutations in hereditary colon cancer genes, most commonly MLH. All patients (42.7%) who are platinum-sensitive had HR germline mutations (RAD50, NBN, ATM). Patients with HER2 overexpression (2/7, 28.6%) had germline HR mutations and were platinum-sensitive. Three patients in our cohort reported a personal history of breast cancer, one with HR germline mutation, and 2 in patients with germline mutations in HCC genes. In addition, 5 out of 7 patients had germline mutations in genes associated with growth factor signaling pathway.
CONCLUSIONS: A significant proportion of our cohort harbor germline mutations in DNA repair genes. This may be associated with the high rate of breast cancer in our patients and their family, and suggests a targeted cohort for genetic counseling. If validated in a larger cohort, our findings may allow clinicians to expand therapeutic options to include targeted therapies and inclusion of USC patient in preventative and genetic counseling.

Tung N, Lin NU, Kidd J, et al.
Frequency of Germline Mutations in 25 Cancer Susceptibility Genes in a Sequential Series of Patients With Breast Cancer.
J Clin Oncol. 2016; 34(13):1460-8 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
PURPOSE: Testing for germline mutations in BRCA1/2 is standard for select patients with breast cancer to guide clinical management. Next-generation sequencing (NGS) allows testing for mutations in additional breast cancer predisposition genes. The frequency of germline mutations detected by using NGS has been reported in patients with breast cancer who were referred for BRCA1/2 testing or with triple-negative breast cancer. We assessed the frequency and predictors of mutations in 25 cancer predisposition genes, including BRCA1/2, in a sequential series of patients with breast cancer at an academic institution to examine the utility of genetic testing in this population.
METHODS: Patients with stages I to III breast cancer who were seen at a single cancer center between 2010 and 2012, and who agreed to participate in research DNA banking, were included (N = 488). Personal and family cancer histories were collected and germline DNA was sequenced with NGS to identify mutations.
RESULTS: Deleterious mutations were identified in 10.7% of women, including 6.1% in BRCA1/2 (5.1% in non-Ashkenazi Jewish patients) and 4.6% in other breast/ovarian cancer predisposition genes including CHEK2 (n = 10), ATM (n = 4), BRIP1 (n = 4), and one each in PALB2, PTEN, NBN, RAD51C, RAD51D, MSH6, and PMS2. Whereas young age (P < .01), Ashkenazi Jewish ancestry (P < .01), triple-negative breast cancer (P = .01), and family history of breast/ovarian cancer (P = .01) predicted for BRCA1/2 mutations, no factors predicted for mutations in other breast cancer predisposition genes.
CONCLUSION: Among sequential patients with breast cancer, 10.7% were found to have a germline mutation in a gene that predisposes women to breast or ovarian cancer, using a panel of 25 predisposition genes. Factors that predict for BRCA1/2 mutations do not predict for mutations in other breast/ovarian cancer susceptibility genes when these genes are analyzed as a single group. Additional cohorts will be helpful to define individuals at higher risk of carrying mutations in genes other than BRCA1/2.

Catts ZA, Baig MK, Milewski B, et al.
Statewide Retrospective Review of Familial Pancreatic Cancer in Delaware, and Frequency of Genetic Mutations in Pancreatic Cancer Kindreds.
Ann Surg Oncol. 2016; 23(5):1729-35 [PubMed] Related Publications
BACKGROUND: Considering the typical rapid progression and high mortality of pancreatic cancer (PC), early detection may lead to an improved outcome. To date, there is no safe, sensitive, and cost-effective screening strategy to detect PC. Currently, screening is focused on individuals at the highest risk of developing PC based on family history. A high-risk individual is defined as having two or more first-degree relatives with PC, or one first- or second-degree relative with PC with a confirmed mutation in a gene associated with PC. The BRCA2 gene is one of the most common genes linked to pancreatic-only cancer families; however, other hereditary cancer syndromes have also been associated with an increased risk for PC.
METHODS: We conducted a retrospective review of pedigrees of families with a pancreatic adenocarcinoma cancer diagnosis held in the statewide Ruth Ann Minner High Risk Family Cancer Registry at the Helen F. Graham Cancer Center and Research Institute, Christiana Care Health System, Newark, DE, USA, from 2002 to 2013. The registry was queried based on how many first-, second-, or third-degree relatives of the proband were affected with PC, genetic testing status, and (if applicable) the results. These data were then categorized into families that meet familial PC (FPC) criteria, defined as two first-degree relatives with PC (FPC families), families that did not meet the FPC definition but had one first-degree relative affected with PC (first-degree families), and probands with PC (probands). Each family was counted only once in the analysis, even if multiple family members were tested.
RESULTS: Our analysis revealed that 175 of 597 families fitting any of the above criteria completed genetic testing. Of this cohort, 52 had pathogenic alterations with nine different genes implicated. Overall, 164 of the 175 families that fitted into any of the three categories previously identified had BRCA1 or BRCA2 testing, either by DNA sequencing or next-generation sequencing via a panel test that included BRCA1/2. BRCA1 pathogenic alterations were noted in 17/164 (10.4 %) and BRCA2 pathogenic alterations were noted in 23/164 (14.0 %). FPC families (n = 46) 42/46 of the FPC families underwent BRCA1/2 testing, and 11/42 (26 % [95 % CI 12.89-39.49]) had pathogenic alterations. Specifically, 4/42 = BRCA1 (9.5 %) and 7/42 = BRCA2 (16.7 %). Additionally, 16/46 of the FPC families underwent exclusively Lynch syndrome (LS) testing, and pathogenic mutations in a mismatch repair protein were identified in 2/16. Specifically, 1/16 = MLH1 (6.3 %) and 1/16 = MSH2 (3.6 %). Overall, a genetic mutation within any gene associated with an increased PC risk was found in 28 % of FPC families. First-degree families (n = 106) 99/106 of the families with one first-degree relative underwent BRCA1/2 testing, and 21/99 (21.2 % [95 % CI 13.16-29.27]) had pathogenic alterations. Specifically, 11/99 = BRCA1 (11.1 %) and 10/99 = BRCA2 (10.1 %). 32/99 first-degree families underwent exclusively LS testing, and pathogenic mutations were identified in 4/32. Specifically, 3/32 = MLH1 (9 %) and 1/32 = MSH6 (3 %). 25/99 of the families pursued panel testing, and pathogenic alterations in any gene were identified in 3/25. Specifically, the mutations were found in 1/25 = ATM (4 %), 1/25 = CHEK2 (4 %), and 1/25 = RAD51D (4 %). Affected probands (n = 23) Lastly, all 23 probands affected with PC pursued genetic testing. Of these, 11/23 were found to have pathogenic alterations. All 23 underwent BRCA1/2 testing, and pathogenic alterations were identified in 8/23 (35 % [95 % CI 15.32-54.25]), specifically 2/23 = BRCA1 (9 %), and 6/23 = BRCA2 (26 %). 10/23 patients underwent panel testing and pathogenic alterations were found in 3/10 (30 %) patients, of whom 1/10 = MSH6 (10 %), 1/10 = ATM (10 %), and 1/10 = TP53 (10 %).
CONCLUSIONS: This study demonstrates that a statewide high-risk family cancer registry is an important instrument in studying the risk of PC in families. Our analysis revealed 14 mutations associated with FPC, among which hereditary breast and ovarian cancer and LS were most prevalent. BRCA1 was found to have the same association with PC as BRCA2, which appears unique to our population. We plan to use our knowledge of these mutations in developing a PC screening program.

Norquist BM, Harrell MI, Brady MF, et al.
Inherited Mutations in Women With Ovarian Carcinoma.
JAMA Oncol. 2016; 2(4):482-90 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
IMPORTANCE: Germline mutations in BRCA1 and BRCA2 are relatively common in women with ovarian, fallopian tube, and peritoneal carcinoma (OC) causing a greatly increased lifetime risk of these cancers, but the frequency and relevance of inherited mutations in other genes is less well characterized.
OBJECTIVE: To determine the frequency and importance of germline mutations in cancer-associated genes in OC.
DESIGN, SETTING, AND PARTICIPANTS: A study population of 1915 woman with OC and available germline DNA were identified from the University of Washington (UW) gynecologic tissue bank (n = 570) and from Gynecologic Oncology Group (GOG) phase III clinical trials 218 (n = 788) and 262 (n = 557). Patients were enrolled at diagnosis and were not selected for age or family history. Germline DNA was sequenced from women with OC using a targeted capture and multiplex sequencing assay.
MAIN OUTCOMES AND MEASURES: Mutation frequencies in OC were compared with the National Heart, Lung, and Blood Institute GO Exome Sequencing Project (ESP) and the Exome Aggregation Consortium (ExAC). Clinical characteristics and survival were assessed by mutation status.
RESULTS: Overall, the median (range) age at diagnosis was 60 (28-91) years in patients recruited from UW and 61 (23-87) years in patients recruited from the GOG trials. A higher number of black women were recruited from the GOG trials (4.3% vs 1.4%; P = .009); but in patients recruited from UW, there was a higher proportion of fallopian tube carcinomas (13.3% vs 5.7%; P < .001); stage I and II disease (14.6% vs 0% [GOG trials were restricted to advanced-stage cancer]); and nonserous carcinomas (29.9% vs 13.1%, P < .001). Of 1915 patients, 280 (15%) had mutations in BRCA1 (n = 182), or BRCA2 (n = 98), and 8 (0.4%) had mutations in DNA mismatch repair genes. Mutations in BRIP1 (n = 26), RAD51C (n = 11), RAD51D (n = 11), PALB2 (n = 12), and BARD1 (n = 4) were significantly more common in patients with OC than in the ESP or ExAC, present in 3.3%. Race, histologic subtype, and disease site were not predictive of mutation frequency. Patients with a BRCA2 mutation from the GOG trials had longer progression-free survival (hazard ratio [HR], 0.60; 95% CI, 0.45-0.79; P < .001) and overall survival (HR, 0.39; 95% CI, 0.25-0.60; P < .001) compared with those without mutations.
CONCLUSIONS AND RELEVANCE: Of 1915 patients with OC, 347 (18%) carried pathogenic germline mutations in genes associated with OC risk. PALB2 and BARD1 are suspected OC genes and together with established OC genes (BRCA1, BRCA2, BRIP1, RAD51C, RAD51D, MSH2, MLH1, PMS2, and MSH6) bring the total number of genes suspected to cause hereditary OC to 11.

Bernards SS, Norquist BM, Harrell MI, et al.
Genetic characterization of early onset ovarian carcinoma.
Gynecol Oncol. 2016; 140(2):221-5 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
OBJECTIVE: Ovarian carcinoma (OC) is rare in young women and the fraction of early onset OC attributable to inherited mutations in known OC genes is uncertain. We sought to characterize the fraction of OC that is heritable in women diagnosed with ovarian, fallopian tube, or peritoneal carcinoma at forty years of age or younger.
METHODS: We sequenced germline DNA from forty-seven women diagnosed with OC at age 40 or younger ascertained through a gynecologic oncology tissue bank or referred from outside providers using BROCA, a targeted capture and massively parallel sequencing platform that can detect all mutation classes. We evaluated 11 genes associated with ovarian carcinoma (BARD1, BRCA1, BRCA2, BRIP1, MLH1, MSH2, MSH6, PALB2, PMS2, RAD51D, and RAD51C) and additional candidate genes in DNA repair (ATM, BAP1, CHEK2, MRE11A, NBN, PTEN, TP53). We counted only clearly damaging mutations.
RESULTS: Damaging mutations in OC genes were identified in 13 of 47 (28%) subjects, of which 10 (77%) occurred in BRCA1 and one each occurred in BRCA2, MSH2, and RAD51D. Women with a strong family history were no more likely to have an OC gene mutation (8/17, 47%) than those without a strong family history (9/30, 30%, P=0.35). Additionally, damaging mutations in non-OC genes were identified, one in NBN and one in CHEK2.
CONCLUSIONS: A high proportion of young women with invasive OC have mutations in BRCA1, and a smaller fraction have mutations in other known OC genes. Family history was not associated with mutation status in these early onset cases.

Qu J, Yu H, Li F, et al.
Molecular basis of antibody binding to mucin glycopeptides in lung cancer.
Int J Oncol. 2016; 48(2):587-94 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Glycopeptides bearing Tn epitopes are emerging targets for cancer diagnosis and immunotherapy. In this study, we analyzed membrane proteins containing O-glycosylated tandem repeat (TR) sequences in lung cancer patients of different types and stages, using gene microarray data in public domain. The expression of Tn and glycopeptide epitopes on the surface of lung cancer cell lines were studied by monoclonal IgG antibodies 14A, 16A, and B72.3. The binding of mAbs to synthetic glycopeptides were studied by surface plasmon resonance. Nine mucin mRNAs were found to be expressed in lung cancer patients but at similar level to healthy individuals. At protein level, a glycopeptide epitope on cancer cell surface is preferably recognized by mAb 16A, as compared to peptide-alone (14A) or sugar-alone epitopes (B72.3). 14A and 16A favor clustered TR containing more than three TR sequences, with 10-fold lower Kd than two consecutive TR. B72.3 preferrably recognized clustered sialyl-Tn displayed on MUC1 but not other O-glycoproteins, with 100-fold stronger binding when MUC1 is transfected as a sugar carrier, while the total sugar epitopes remain unchanged. These findings indicate that clusters of both TR backbones and sugars are essential for mAb binding to mucin glycopeptides. Three rules of antibody binding to mucin glycopeptides at molecular level are presented here: first, the peptide backbone of a glycopeptide is preferentially recognized by B cells through mutations in complementarity determining regions (CDRs) of B cell receptor, and the sugar-binding specificity is acquired through mutations in frame work of heavy chain; secondly, consecutive tandem repeats (TR) of peptides and glycopeptides are preferentially recognized by B cells, which favor clustered TR containing more than three TR sequences; thirdly, certain sugar-specific B cells recognize and accommodate clustered Tn and sialyl-Tn displayed on the surface of a mucin but not other membrane proteins.

Li J, Meeks H, Feng BJ, et al.
Targeted massively parallel sequencing of a panel of putative breast cancer susceptibility genes in a large cohort of multiple-case breast and ovarian cancer families.
J Med Genet. 2016; 53(1):34-42 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
INTRODUCTION: Gene panel testing for breast cancer susceptibility has become relatively cheap and accessible. However, the breast cancer risks associated with mutations in many genes included in these panels are unknown.
METHODS: We performed custom-designed targeted sequencing covering the coding exons of 17 known and putative breast cancer susceptibility genes in 660 non-BRCA1/2 women with familial breast cancer. Putative deleterious mutations were genotyped in relevant family members to assess co-segregation of each variant with disease. We used maximum likelihood models to estimate the breast cancer risks associated with mutations in each of the genes.
RESULTS: We found 31 putative deleterious mutations in 7 known breast cancer susceptibility genes (TP53, PALB2, ATM, CHEK2, CDH1, PTEN and STK11) in 45 cases, and 22 potential deleterious mutations in 31 cases in 8 other genes (BARD1, BRIP1, MRE11, NBN, RAD50, RAD51C, RAD51D and CDK4). The relevant variants were then genotyped in 558 family members. Assuming a constant relative risk of breast cancer across age groups, only variants in CDH1, CHEK2, PALB2 and TP53 showed evidence of a significantly increased risk of breast cancer, with some supportive evidence that mutations in ATM confer moderate risk.
CONCLUSIONS: Panel testing for these breast cancer families provided additional relevant clinical information for <2% of families. We demonstrated that segregation analysis has some potential to help estimate the breast cancer risks associated with mutations in breast cancer susceptibility genes, but very large case-control sequencing studies and/or larger family-based studies will be needed to define the risks more accurately.

Pelttari LM, Kinnunen L, Kiiski JI, et al.
Screening of HELQ in breast and ovarian cancer families.
Fam Cancer. 2016; 15(1):19-23 [PubMed] Related Publications
Several high and moderate risk alleles have been identified for breast and ovarian cancer predisposition and most of them encode proteins that function in DNA repair. A prospective candidate for breast and ovarian cancer susceptibility is the HELQ helicase that has a role in the resolution of DNA interstrand cross-links. HELQ interacts with the RAD51 paralog complex BCDX2. Two components of the complex, RAD51C and RAD51D, increase the risk of ovarian cancer especially, and the other two, RAD51B and XRCC2 have been associated with breast cancer risk. To investigate the role of HELQ in cancer predisposition, we screened the gene for germline variation in 185 Finnish breast or ovarian cancer families and performed haplotype analyses for 1517 breast cancer cases, 308 ovarian cancer cases, and 1234 population controls using five common polymorphisms at the HELQ gene locus. No truncating mutations were identified among the families. One putatively pathogenic missense mutation c.1309A>G was identified but no additional carriers were observed in the subsequent genotyping of 332 familial breast or ovarian cancer patients. Furthermore, the haplotype distribution did not differ between breast or ovarian cancer cases and population controls. Our results indicate that HELQ is not a major breast and ovarian cancer susceptibility gene in the Finnish population. However, we cannot rule out rare risk-variants in the Finnish or other populations and larger datasets are needed to further assess the role of HELQ especially in ovarian cancer predisposition.

Frey MK, Kim SH, Bassett RY, et al.
Rescreening for genetic mutations using multi-gene panel testing in patients who previously underwent non-informative genetic screening.
Gynecol Oncol. 2015; 139(2):211-5 [PubMed] Related Publications
OBJECTIVE: The availability of next-generation sequencing and identification of multiple cancer-related genes has caused a shift away from single gene testing towards multi-gene panel testing for hereditary cancer syndromes. However, the utility of panels in individuals who previously underwent non-informative genetic screening has yet to be evaluated. We aim to evaluate the use of rescreening and results of multi-gene panels in this rescreened population.
METHODS: We reviewed the medical records for patients who had previously undergone genetic testing and then underwent multi-gene panel testing at a single institution between 9/2013 and 11/2014.
RESULTS: One hundred and twenty-seven patients with prior genetic testing underwent multi-gene panels. One hundred and four patients (82%) had a history of cancer and 118 (93%) had at least one family member with cancer. On primary testing, no pathogenic mutations were detected and 10 patients (8%) were found to have variants of uncertain significance (VUS). On repeat multi-gene panel testing, nine patients (7%) were found to have a pathogenic mutation and 53 patients (42%) were VUS not identified on prior testing.
CONCLUSIONS: Seven percent of patients with non-informative primary testing were found to have a pathogenic mutation with multi-gene panels, suggesting that there is a potential benefit to be gained from rescreening. However, 42% of patients were found to have new VUS with panels, a result that can cause patients anxiety without clear clinical implications.

Song H, Dicks E, Ramus SJ, et al.
Contribution of Germline Mutations in the RAD51B, RAD51C, and RAD51D Genes to Ovarian Cancer in the Population.
J Clin Oncol. 2015; 33(26):2901-7 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
PURPOSE: The aim of this study was to estimate the contribution of deleterious mutations in the RAD51B, RAD51C, and RAD51D genes to invasive epithelial ovarian cancer (EOC) in the population and in a screening trial of individuals at high risk of ovarian cancer.
PATIENTS AND METHODS: The coding sequence and splice site boundaries of the three RAD51 genes were sequenced and analyzed in germline DNA from a case-control study of 3,429 patients with invasive EOC and 2,772 controls as well as in 2,000 unaffected women who were BRCA1/BRCA2 negative from the United Kingdom Familial Ovarian Cancer Screening Study (UK_FOCSS) after quality-control analysis.
RESULTS: In the case-control study, we identified predicted deleterious mutations in 28 EOC cases (0.82%) compared with three controls (0.11%; P < .001). Mutations in EOC cases were more frequent in RAD51C (14 occurrences, 0.41%) and RAD51D (12 occurrences, 0.35%) than in RAD51B (two occurrences, 0.06%). RAD51C mutations were associated with an odds ratio of 5.2 (95% CI, 1.1 to 24; P = .035), and RAD51D mutations conferred an odds ratio of 12 (95% CI, 1.5 to 90; P = .019). We identified 13 RAD51 mutations (0.65%) in unaffected UK_FOCSS participants (RAD51C, n = 7; RAD51D, n = 5; and RAD51B, n = 1), which was a significantly greater rate than in controls (P < .001); furthermore, RAD51 mutation carriers were more likely than noncarriers to have a family history of ovarian cancer (P < .001).
CONCLUSION: These results confirm that RAD51C and RAD51D are moderate ovarian cancer susceptibility genes and suggest that they confer levels of risk of EOC that may warrant their use alongside BRCA1 and BRCA2 in routine clinical genetic testing.

Domagala P, Jakubowska A, Jaworska-Bieniek K, et al.
Prevalence of Germline Mutations in Genes Engaged in DNA Damage Repair by Homologous Recombination in Patients with Triple-Negative and Hereditary Non-Triple-Negative Breast Cancers.
PLoS One. 2015; 10(6):e0130393 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
PURPOSE: This study sought to assess the prevalence of common germline mutations in several genes engaged in the repair of DNA double-strand break by homologous recombination in patients with triple-negative breast cancers and hereditary non-triple-negative breast cancers. Tumors deficient in this type of DNA damage repair are known to be especially sensitive to DNA cross-linking agents (e.g., platinum drugs) and to poly(ADP-ribose) polymerase (PARP) inhibitors.
METHODS: Genetic testing was performed for 36 common germline mutations in genes engaged in the repair of DNA by homologous recombination, i.e., BRCA1, BRCA2, CHEK2, NBN, ATM, PALB2, BARD1, and RAD51D, in 202 consecutive patients with triple-negative breast cancers and hereditary non-triple-negative breast cancers.
RESULTS: Thirty five (22.2%) of 158 patients in the triple-negative group carried mutations in genes involved in DNA repair by homologous recombination, while 10 (22.7%) of the 44 patients in the hereditary non-triple-negative group carried such mutations. Mutations in BRCA1 were most frequent in patients with triple-negative breast cancer (18.4%), and mutations in CHEK2 were most frequent in patients with hereditary non-triple-negative breast cancers (15.9%). In addition, in the triple-negative group, mutations in CHEK2, NBN, and ATM (3.8% combined) were found, while mutations in BRCA1, NBN, and PALB2 (6.8% combined) were identified in the hereditary non-triple-negative group.
CONCLUSIONS: Identifying mutations in genes engaged in DNA damage repair by homologous recombination other than BRCA1/2 can substantially increase the proportion of patients with triple-negative breast cancer and hereditary non-triple-negative breast cancer who may be eligible for therapy using PARP inhibitors and platinum drugs.

Janatova M, Soukupova J, Stribrna J, et al.
Mutation Analysis of the RAD51C and RAD51D Genes in High-Risk Ovarian Cancer Patients and Families from the Czech Republic.
PLoS One. 2015; 10(6):e0127711 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Recent studies have conferred that the RAD51C and RAD51D genes, which code for the essential proteins involved in homologous recombination, are ovarian cancer (OC) susceptibility genes that may explain genetic risks in high-risk patients. We performed a mutation analysis in 171 high-risk BRCA1 and BRCA2 negative OC patients, to evaluate the frequency of hereditary RAD51C and RAD51D variants in Czech population. The analysis involved direct sequencing, high resolution melting and multiple ligation-dependent probe analysis. We identified two (1.2%) and three (1.8%) inactivating germline mutations in both respective genes, two of which (c.379_380insG, p.P127Rfs*28 in RAD51C and c.879delG, p.C294Vfs*16 in RAD51D) were novel. Interestingly, an indicative family cancer history was not present in four carriers. Moreover, the ages at the OC diagnoses in identified mutation carriers were substantially lower than those reported in previous studies (four carriers were younger than 45 years). Further, we also described rare missense variants, two in RAD51C and one in RAD51D whose clinical significance needs to be verified. Truncating mutations and rare missense variants ascertained in OC patients were not detected in 1226 control samples. Although the cumulative frequency of RAD51C and RAD51D truncating mutations in our patients was lower than that of the BRCA1 and BRCA2 genes, it may explain OC susceptibility in approximately 3% of high-risk OC patients. Therefore, an RAD51C and RAD51D analysis should be implemented into the comprehensive multi-gene testing for high-risk OC patients, including early-onset OC patients without a family cancer history.

Couch FJ, Hart SN, Sharma P, et al.
Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer.
J Clin Oncol. 2015; 33(4):304-11 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
PURPOSE: Recent advances in DNA sequencing have led to the development of breast cancer susceptibility gene panels for germline genetic testing of patients. We assessed the frequency of mutations in 17 predisposition genes, including BRCA1 and BRCA2, in a large cohort of patients with triple-negative breast cancer (TNBC) unselected for family history of breast or ovarian cancer to determine the utility of germline genetic testing for those with TNBC.
PATIENTS AND METHODS: Patients with TNBC (N = 1,824) unselected for family history of breast or ovarian cancer were recruited through 12 studies, and germline DNA was sequenced to identify mutations.
RESULTS: Deleterious mutations were identified in 14.6% of all patients. Of these, 11.2% had mutations in the BRCA1 (8.5%) and BRCA2 (2.7%) genes. Deleterious mutations in 15 other predisposition genes were detected in 3.7% of patients, with the majority observed in genes involved in homologous recombination, including PALB2 (1.2%) and BARD1, RAD51D, RAD51C, and BRIP1 (0.3% to 0.5%). Patients with TNBC with mutations were diagnosed at an earlier age (P < .001) and had higher-grade tumors (P = .01) than those without mutations.
CONCLUSION: Deleterious mutations in predisposition genes are present at high frequency in patients with TNBC unselected for family history of cancer. Mutation prevalence estimates suggest that patients with TNBC, regardless of age at diagnosis or family history of cancer, should be considered for germline genetic testing of BRCA1 and BRCA2. Although mutations in other predisposition genes are observed among patients with TNBC, better cancer risk estimates are needed before these mutations are used for clinical risk assessment in relatives.

Oji Y, Tatsumi N, Kobayashi J, et al.
Wilms' tumor gene WT1 promotes homologous recombination-mediated DNA damage repair.
Mol Carcinog. 2015; 54(12):1758-71 [PubMed] Related Publications
The Wilms' tumor gene WT1 is overexpressed in leukemia and various types of solid tumors and plays an oncogenic role in these malignancies. Alternative splicing at two sites yields four major isoforms, 17AA(+)KTS(+), 17AA(+)KTS(-), 17AA(-)KTS(+), and 17AA(-)KTS(-), and all the isoforms are expressed in the malignancies. However, among the four isoforms, function of WT1[17AA(-)KTS(+)] isoform still remains undetermined. In the present study, we showed that forced expression of WT1[17AA(-)KTS(+)] isoform significantly inhibited apoptosis by DNA-damaging agents such as Doxorubicin, Mitomycin, Camptothesisn, and Bleomycin in immortalized fibroblast MRC5SV and cervical cancer HeLa cells. Knockdown of Rad51, an essential factor for homologous recombination (HR)-mediated DNA repair canceled the resistance to Doxorubicin induced by WT1[17AA(-)KTS(+)] isoform. GFP recombination assay showed that WT1[17AA(-)KTS(+)] isoform alone promoted HR, but that three other WT1 isoforms did not. WT1[17AA(-)KTS(+)] isoform significantly upregulated the expression of HR genes, XRCC2, Rad51D, and Rad54. Knockdown of XRCC2, Rad51D, and Rad54 inhibited the HR activity and canceled resistance to Doxorubicin in MRC5SV cells with forced expression of WT1[17AA(-)KTS(+)] isoform. Furthermore, chromatin immunoprecipitation (ChIP) assay showed the binding of WT1[17AA(-)KTS(+)] isoform protein to promoters of XRCC2 and Rad51D. Immunohistochemical study showed that Rad54 and XRCC2 proteins were highly expressed in the majority of non-small-cell lung cancer (NSCLC) and gastric cancer, and that expression of these two proteins was significantly correlated with that of WT1 protein in NSCLCs. Our results presented here showed that WT1[17AA(-)KTS(+)] isoform had a function to promote HR-mediated DNA repair.

Tabone T, Abuhusain HJ, Nowak AK, et al.
Multigene profiling to identify alternative treatment options for glioblastoma: a pilot study.
J Clin Pathol. 2014; 67(7):550-5 [PubMed] Related Publications
UNLABELLED: Glioblastoma (GBM) is a highly aggressive malignancy and the most effective treatment regime has a high relapse rate. Increasingly, the development of therapies involves defining drug-diagnostic combinations where the presence of a molecular target or marker identifies patients who are most likely to respond to a specific therapy. Trials in other solid cancers have demonstrated clear utility in the incorporation of biomarkers to stratify patients to targeted treatment, however, there are no mutations that are currently used to inform treatment options for GBM.
AIMS: We piloted the use of high-throughput next-generation sequencing technology to identify genetic mutations in 44 GBM specimens that may be amenable to current or future targeted therapeutic strategies.
METHOD: Somatic mutation profiling was performed using the AmpliSeq Cancer Hotspot Panel v2 and semiconductor sequencing technology.
RESULTS: A total of 66 mutations were detected in 35/44 (80%) patients. The number of mutations per tumour ranged from 0 to 4 (average per tumour=1.5). The most frequent mutations were in TP53 (n=12), PTEN (n=9), EGFR (n=8) and PIK3CA (n=5). Clinically actionable somatic mutations were detected in 24/35 (69%) patients.
CONCLUSIONS: This study demonstrates that the use of an 'off-the-shelf' oncogene primer panel and benchtop next-generation sequencer can identify mutations and potentially actionable targets in the majority of GBM patients. Data from this pilot highlights the potential for targeted genetic resequencing to identify mutations that may inform treatment options and predict outcomes.

Paulíková S, Chmelařová M, Petera J, et al.
Hypermethylation of RAD51L3 and XRCC2 genes to predict late toxicity in chemoradiotherapy-treated cervical cancer patients.
Folia Biol (Praha). 2013; 59(6):240-5 [PubMed] Related Publications
Cervical cancer affects women worldwide, especially in developing countries. Approximately 500,000 cases of this disease are diagnosed per year. The method of choice in the treatment of advanced cervical cancers (in accordance with the International Federation of Gynecology and Obstetrics staging system (FIGO) starting from stage IIB) is combined radiotherapy with concomitant chemotherapy. This treatment provides good tumour control, but it carries a risk of late complications in the irradiated area in 10-15 % of cases. Methylation is one of the methods of epigenetic control, which has an important role in gene expression. Aberrant methylation of normal CpG islands in promoters of tumour suppressor genes such as RB, p53 or DNA reparation genes ATM, BRCA1,2, and RAD51 gene family causes silencing of their function and cell cycle deregulation, which is one of the efficient ways of neoplastic transformation. The significantly decreased expression of molecules involved in DNA response may cause facilitated radiosensitivity in predisposed individuals. We looked for the relationship between hypermethylation of 18 DNA reparation genes and late toxicity occurrence in cervical cancer patients treated by chemoradiotherapy using methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA). The cut-off value for the hypermethylation was set at 10 %. We confirmed significant association between promoter hypermethylation in the XRCC2 gene and occurrence of late grade III-IV toxicity in cervical cancer patients (P = 0.0357). This finding could be useful in the late toxicity prediction in radiotherapy-treated patients.

Pennington KP, Walsh T, Harrell MI, et al.
Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas.
Clin Cancer Res. 2014; 20(3):764-75 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
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.

Golmard L, Caux-Moncoutier V, Davy G, et al.
Germline mutation in the RAD51B gene confers predisposition to breast cancer.
BMC Cancer. 2013; 13:484 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
BACKGROUND: Most currently known breast cancer predisposition genes play a role in DNA repair by homologous recombination. Recent studies conducted on RAD51 paralogs, involved in the same DNA repair pathway, have identified rare germline mutations conferring breast and/or ovarian cancer predisposition in the RAD51C, RAD51D and XRCC2 genes. The present study analysed the five RAD51 paralogs (RAD51B, RAD51C, RAD51D, XRCC2, XRCC3) to estimate their contribution to breast and ovarian cancer predisposition.
METHODS: The study was conducted on 142 unrelated patients with breast and/or ovarian cancer either with early onset or with a breast/ovarian cancer family history. Patients were referred to a French family cancer clinic and had been previously tested negative for a BRCA1/2 mutation. Coding sequences of the five genes were analysed by EMMA (Enhanced Mismatch Mutation Analysis). Detected variants were characterized by Sanger sequencing analysis.
RESULTS: Three splicing mutations and two likely deleterious missense variants were identified: RAD51B c.452 + 3A > G, RAD51C c.706-2A > G, RAD51C c.1026 + 5_1026 + 7del, RAD51B c.475C > T/p.Arg159Cys and XRCC3 c.448C > T/p.Arg150Cys. No RAD51D and XRCC2 gene mutations were detected. These mutations and variants were detected in families with both breast and ovarian cancers, except for the RAD51B c.475C > T/p.Arg159Cys variant that occurred in a family with 3 breast cancer cases.
CONCLUSIONS: This study identified the first RAD51B mutation in a breast and ovarian cancer family and is the first report of XRCC3 mutation analysis in breast and ovarian cancer. It confirms that RAD51 paralog mutations confer breast and ovarian cancer predisposition and are rare events. In view of the low frequency of RAD51 paralog mutations, international collaboration of family cancer clinics will be required to more accurately estimate their penetrance and establish clinical guidelines in carrier individuals.

Gutiérrez-Enríquez S, Bonache S, de Garibay GR, et al.
About 1% of the breast and ovarian Spanish families testing negative for BRCA1 and BRCA2 are carriers of RAD51D pathogenic variants.
Int J Cancer. 2014; 134(9):2088-97 [PubMed] Related Publications
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.667+2_667+23del, 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.667+2_667+23del 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.

Huang JW, Wang Y, Dhillon KK, et al.
Systematic screen identifies miRNAs that target RAD51 and RAD51D to enhance chemosensitivity.
Mol Cancer Res. 2013; 11(12):1564-73 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
UNLABELLED: Homologous recombination mediates error-free repair of DNA double-strand breaks (DSB). RAD51 is an essential protein for catalyzing homologous recombination and its recruitment to DSBs is mediated by many factors including RAD51, its paralogs, and breast/ovarian cancer susceptibility gene products BRCA1/2. Deregulation of these factors leads to impaired DNA repair, genomic instability, and cellular sensitivity to chemotherapeutics such as cisplatin and PARP inhibitors. microRNAs (miRNA) are short, noncoding RNAs that posttranscriptionally regulate gene expression; however, the contribution of miRNAs in the regulation of homologous recombination is not well understood. To address this, a library of human miRNA mimics was systematically screened to pinpoint several miRNAs that significantly reduce RAD51 foci formation in response to ionizing radiation in human osteosarcoma cells. Subsequent study focused on two of the strongest candidates, miR-103 and miR-107, as they are frequently deregulated in cancer. Consistent with the inhibition of RAD51 foci formation, miR-103 and miR-107 reduced homology-directed repair and sensitized cells to various DNA-damaging agents, including cisplatin and a PARP inhibitor. Mechanistic analyses revealed that both miR-103 and miR-107 directly target and regulate RAD51 and RAD51D, which is critical for miR-103/107-mediated chemosensitization. Furthermore, endogenous regulation of RAD51D by miR-103/107 was observed in several tumor subtypes. Taken together, these data show that miR-103 and miR-107 overexpression promotes genomic instability and may be used therapeutically to chemosensitize tumors.
IMPLICATIONS: These findings demonstrate a role for miR-103 and -107 in regulating DNA damage repair, thereby identifying new players in the progression of cancer and response to chemotherapy.

Thompson ER, Rowley SM, Sawyer S, et al.
Analysis of RAD51D in ovarian cancer patients and families with a history of ovarian or breast cancer.
PLoS One. 2013; 8(1):e54772 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Mutations in RAD51D have been associated with an increased risk of hereditary ovarian cancer and although they have been observed in the context of breast and ovarian cancer families, the association with breast cancer is unclear. The aim of this current study was to validate the reported association of RAD51D with ovarian cancer and assess for an association with breast cancer. We screened for RAD51D mutations in BRCA1/2 mutation-negative index cases from 1,060 familial breast and/or ovarian cancer families (including 741 affected by breast cancer only) and in 245 unselected ovarian cancer cases. Exons containing novel non-synonymous variants were screened in 466 controls. Two overtly deleterious RAD51D mutations were identified among the unselected ovarian cancers cases (0.82%) but none were detected among the 1,060 families. Our data provide additional evidence that RAD51D mutations are enriched among ovarian cancer patients, but are extremely rare among familial breast cancer patients.

Le Calvez-Kelm F, Oliver J, Damiola F, et al.
RAD51 and breast cancer susceptibility: no evidence for rare variant association in the Breast Cancer Family Registry study.
PLoS One. 2012; 7(12):e52374 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
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 case-control 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.

Covell DG, Wallqvist A, Kenney S, Vistica DT
Bioinformatic analysis of patient-derived ASPS gene expressions and ASPL-TFE3 fusion transcript levels identify potential therapeutic targets.
PLoS One. 2012; 7(11):e48023 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Gene expression data, collected from ASPS tumors of seven different patients and from one immortalized ASPS cell line (ASPS-1), was analyzed jointly with patient ASPL-TFE3 (t(X;17)(p11;q25)) fusion transcript data to identify disease-specific pathways and their component genes. Data analysis of the pooled patient and ASPS-1 gene expression data, using conventional clustering methods, revealed a relatively small set of pathways and genes characterizing the biology of ASPS. These results could be largely recapitulated using only the gene expression data collected from patient tumor samples. The concordance between expression measures derived from ASPS-1 and both pooled and individual patient tumor data provided a rationale for extending the analysis to include patient ASPL-TFE3 fusion transcript data. A novel linear model was exploited to link gene expressions to fusion transcript data and used to identify a small set of ASPS-specific pathways and their gene expression. Cellular pathways that appear aberrantly regulated in response to the t(X;17)(p11;q25) translocation include the cell cycle and cell adhesion. The identification of pathways and gene subsets characteristic of ASPS support current therapeutic strategies that target the FLT1 and MET, while also proposing additional targeting of genes found in pathways involved in the cell cycle (CHK1), cell adhesion (ARHGD1A), cell division (CDC6), control of meiosis (RAD51L3) and mitosis (BIRC5), and chemokine-related protein tyrosine kinase activity (CCL4).

Wickramanayake A, Wickramanyake A, Bernier G, et al.
Loss of function germline mutations in RAD51D in women with ovarian carcinoma.
Gynecol Oncol. 2012; 127(3):552-5 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
OBJECTIVE: RAD51D, a gene in the Fanconi Anemia-BRCA homologous recombination pathway, has recently been shown to harbor germline mutations responsible for ovarian carcinoma in multiply affected families. We aimed to extend these results to ovarian carcinoma in the general population.
METHODS: We sequenced RAD51D in germline DNA from 360 individuals with primary ovarian, peritoneal or fallopian tube carcinoma who were not selected for age of cancer onset or family history. We also sequenced RAD51D in 459 probands from 226 high risk breast cancer families who were wild type for 21 breast and ovarian cancer genes.
RESULTS: Of 360 cases, three (0.8%) carried loss-of-function mutations in RAD51D. All three subjects had ovarian carcinoma; one was also diagnosed with a synchronous endometrial carcinoma. Only one of the three subjects had a family history of breast or ovarian cancer. Combined with previous data for this series, 23.9% of women with unselected ovarian, fallopian tube, or peritoneal carcinoma carried a germline loss-of-function mutation in any of 13 tumor suppressor genes. Among the 449 women and 10 men with familial breast cancer, none carried a loss of function mutation in RAD51D.
CONCLUSIONS: These data support the previous observation that loss-of-function mutations in RAD51D predispose to ovarian carcinoma but not to breast carcinoma. We conclude that inherited ovarian cancer is highly heterogeneous genetically, and that approximately one in four ovarian carcinoma patients carry a germline mutation in a known tumor suppressor gene that confers high risk.

Weissman SM, Weiss SM, Newlin AC
Genetic testing by cancer site: ovary.
Cancer J. 2012 Jul-Aug; 18(4):320-7 [PubMed] Related Publications
Approximately 1 in every 4 to 5 women with a diagnosis of ovarian cancer has a hereditary gene mutation that is responsible for the development of her cancer. Identifying women at increased risk of developing ovarian cancer due to a hereditary cancer syndrome can allow for early detection or prevention of not only ovarian cancer, but also other cancers, depending on the causative gene. This review focuses on 3 of the most common hereditary ovarian cancer syndromes, hereditary breast and ovarian cancer syndrome (the BRCA1 and BRCA2 genes), Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer syndrome), and Peutz-Jeghers syndrome, including key features, genetics, and management of these syndromes. In addition, newly discovered genes (eg, RAD51C and RAD51D) linked to ovarian cancer are discussed.

Pelttari LM, Kiiski J, Nurminen R, et al.
A Finnish founder mutation in RAD51D: analysis in breast, ovarian, prostate, and colorectal cancer.
J Med Genet. 2012; 49(7):429-32 [PubMed] Related Publications
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.

Osher DJ, De Leeneer K, Michils G, et al.
Mutation analysis of RAD51D in non-BRCA1/2 ovarian and breast cancer families.
Br J Cancer. 2012; 106(8):1460-3 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSION: RAD51D should be included in genetic screening of ovarian cancer families that do not have BRCA1/BRCA2 mutations. We show that mutations are more likely to be found in families with two or more ovarian cancers, or in probands with first-degree relatives with ovarian cancer, and we feel testing should be preferentially offered to affected women from such families.

Pennington KP, Swisher EM
Hereditary ovarian cancer: beyond the usual suspects.
Gynecol Oncol. 2012; 124(2):347-53 [PubMed] Related Publications
In the past, hereditary ovarian carcinoma was attributed almost entirely to mutations in BRCA1 and BRCA2, with a much smaller contribution from mutations in DNA mismatch repair genes. Recently, three new ovarian cancer susceptibility genes have been identified: RAD51C, RAD51D, and BRIP1. In addition, germline mutations in women with ovarian carcinoma have been recently identified in many of the previously identified breast cancer genes in the Fanconi anemia (FA)-BRCA pathway. While mutations in genes other than BRCA1 and BRCA2 are each individually rare, together they make up a significant proportion of cases. With at least 16 genes implicated in hereditary ovarian cancer to date, comprehensive testing for ovarian cancer risk will require assessment of many genes. As the cost of genomic sequencing continues to fall, the practice of evaluating cancer susceptibility one gene at a time is rapidly becoming obsolete. New advances in genomic technologies will likely accelerate the discovery of additional cancer susceptibility genes and increase the feasibility of comprehensive evaluation of multiple genes simultaneously at low cost. Improved recognition of inherited risk will identify individuals who are candidates for targeted prevention. In addition, identifying inherited mutations in a variety of FA-BRCA pathway genes may aid in identifying individuals who will selectively benefit from PARP inhibitors.

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