New Candidate Predisposition Genes for Hereditary Breast Cancer: SLIT3, CREB3, USP39

Breast cancer is the most common type of malignant neoplasm in women. BRCA1 and BRCA2 are the most commonly mutated genes, but only up to 30% of hereditary breast cancer cases are attributed to alterations in these genes. A large proportion of genetic causes of hereditary breast cancer remains unknown. Thus, the search for new hereditary mutations and establishing a genetic alteration in each case of hereditary breast cancer is a clinically significant task; be the goal of our research. Next-generation sequencing (NGS) allows for simultaneous analysis of hundreds to thousands of genes at one time. We analyzed the genetic material of 49 patients of the northwest Russian population with clinical signs of hereditary breast cancer and identified new mutations associated with hereditary breast cancer. Research results show two missense mutations - SLIT3 p.Arg154Cys, CREB3 p.Lys157Glu, and truncating mutation - USP39 c.*208G>C. Research conclusion; The identified mutations can explain only a tiny fraction of hereditary breast cancer cases (0.7% to 1.1%). The next step to increase the practical value of the detected alterations should be the analysis of biological characteristics of tumors in carriers of these mutations that can potentially become a target for chemotherapy

Response to : The GPRC5A frameshift variant c.183del is not associated with increased breast cancer risk in BRCA1 mutation carriers

Non peer reviewe

PALB2 mutations in German and Russian patients with bilateral breast cancer

Since germline mutations in the PALB2 (Partner and Localizer of BRCA2) gene have been identified as breast cancer (BC) susceptibility alleles, the geographical spread and risks associated with PALB2 mutations are subject of intense investigation. Patients with bilateral breast cancer constitute a valuable group for genetic studies. We have thus scanned the whole coding region of PALB2 in a total of 203 German or Russian bilateral breast cancer patients using an approach based on high-resolution melting analysis and direct sequencing of genomic DNA samples. Truncating PALB2 mutations were identified in 4/203 (2%) breast cancer patients with bilateral disease. The two nonsense mutations, p.E545X and p.Q921X, have not been previously described whereas the two other mutations, p.R414X and c.509_510delGA, are recurrent. Our results indicate that PALB2 germline mutations account for a small, but not negligible, proportion of bilateral breast carcinomas in German and Russian populations

BRCA1 4153delA founder mutation in Russian ovarian cancer patients

The BRCA1 4153delA allele is frequently referred to as the Russian founder mutation, as it was initially detected in several cancer families from Moscow. Our earlier studies have demonstrated 1% occurrence of BRCA1 4153delA heterozygosity in familial and/or early-onset and/or bilateral Russian breast cancer (BC) patients. Since literature data suggest that the 4153delA variant is more associated with ovarian cancer (OC) than with BC, we expected to reveal a highly elevated frequency of this genotype in Russian ovarian cancer series. However, real-time allele-specific PCR genotyping has detected only two BRCA1 4153delA carriers out of 177 unselected OC patients (1.1%). Both these carriers were early-onset and had serous carcinomas of grade 3. Thus, our study supports neither the Russian origin of BRCA1 4153delA mutation, nor its selectivity towards ovarian versus breast cancer predisposition

Large family with both parents affected by distinct BRCA1 mutations: implications for genetic testing

Although the probability of both parents being affected by BRCA1 mutations is not negligible, such families have not been systematically described in the literature. Here we present a large breast-ovarian cancer family, where 3 sisters and 1 half-sister inherited maternal BRCA1 5382insC mutation while the remaining 2 sisters carried paternal BRCA1 1629delC allele. No BRCA1 homozygous mutations has been detected, that is consistent with the data on lethality of BRCA1 knockout mice. This report exemplifies that the identification of a single cancer-predisposing mutation within the index patient may not be sufficient in some circumstances. Ideally, all family members affected by breast or ovarian tumor disease have to be subjected to the DNA testing, and failure to detect the mutation in any of them calls for the search of the second cancer-associated allele

Rapid selection of BRCA1-proficient tumor cells during neoadjuvant therapy for ovarian cancer in BRCA1 mutation carriers

Ovarian carcinomas (OC) often demonstrate rapid tumor shrinkage upon neoadjuvant chemotherapy (NACT). However, complete pathologic responses are very rare and the mechanisms underlying the emergence of residual tumor disease remain elusive. We hypothesized that the change of somatic BRCA1 status may contribute to this process. The loss-of-heterozygosity (LOH) at the BRCA1 locus was determined for 23 paired tumor samples obtained from BRCA1 germ-line mutation carriers before and after NACT. We observed a somatic loss of the wild-type BRCAI allele in 74% (17/23) of OCs before NACT. However, a retention of the wild-type BRCA1 copy resulting in a reversion of LOH status was detected in 65% (11/17) of those patients after NACT. Furthermore, we tested 3 of these reversion samples for LOH at intragenic BRCA1single nucleotide polymorphisms (SNPs) and confirmed a complete restoration of the SNP heterozygosity in all instances. The neoadjuvant chemotherapy for BRCA1-associated OC is accompanied by a rapid expansion of pre-existing BRCA1-proficient tumor clones suggesting that continuation of the same therapy after NACT and surgery may not be justified even in patients initially experiencing a rapid tumor regression. (C) 2017 Elsevier B.V. All rights reserved.Peer reviewe

High frequency of BRCA1, but not CHEK2 or NBS1 (NBN), founder mutations in Russian ovarian cancer patients

<p>Abstract</p> <p>Background</p> <p>A significant portion of ovarian cancer (OC) cases is caused by germ-line mutations in BRCA1 or BRCA2 genes. BRCA testing is cheap in populations with founder effect and therefore recommended for all patients with OC diagnosis. Recurrent mutations constitute the vast majority of BRCA defects in Russia, however their impact in OC morbidity has not been yet systematically studied. Furthermore, Russian population is characterized by a relatively high frequency of CHEK2 and NBS1 (NBN) heterozygotes, but it remains unclear whether these two genes contribute to the OC risk.</p> <p>Methods</p> <p>The study included 354 OC patients from 2 distinct, geographically remote regions (290 from North-Western Russia (St.-Petersburg) and 64 from the south of the country (Krasnodar)). DNA samples were tested by allele-specific PCR for the presence of 8 founder mutations (BRCA1 5382insC, BRCA1 4153delA, BRCA1 185delAG, BRCA1 300T>G, BRCA2 6174delT, CHEK2 1100delC, CHEK2 IVS2+1G>A, NBS1 657del5). In addition, literature data on the occurrence of BRCA1, BRCA2, CHEK2 and NBS1 mutations in non-selected ovarian cancer patients were reviewed.</p> <p>Results</p> <p>BRCA1 5382insC allele was detected in 28/290 (9.7%) OC cases from the North-West and 11/64 (17.2%) OC patients from the South of Russia. In addition, 4 BRCA1 185delAG, 2 BRCA1 4153delA, 1 BRCA2 6174delT, 2 CHEK2 1100delC and 1 NBS1 657del5 mutation were detected. 1 patient from Krasnodar was heterozygous for both BRCA1 5382insC and NBS1 657del5 variants.</p> <p>Conclusion</p> <p>Founder BRCA1 mutations, especially BRCA1 5382insC variant, are responsible for substantial share of OC morbidity in Russia, therefore DNA testing has to be considered for every OC patient of Russian origin. Taken together with literature data, this study does not support the contribution of CHEK2 in OC risk, while the role of NBS1 heterozygosity may require further clarification.</p

Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10-8, HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10-8, HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4×10-8, HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific associat

Polygenic Risk Modelling for Prediction of Epithelial Ovarian Cancer Risk

Funder: Funding details are provided in the Supplementary MaterialAbstractPolygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally-efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, “select and shrink for summary statistics” (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestry; 7,669 women of East Asian ancestry; 1,072 women of African ancestry, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestry. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38(95%CI:1.28–1.48,AUC:0.588) per unit standard deviation, in women of European ancestry; 1.14(95%CI:1.08–1.19,AUC:0.538) in women of East Asian ancestry; 1.38(95%CI:1.21-1.58,AUC:0.593) in women of African ancestry; hazard ratios of 1.37(95%CI:1.30–1.44,AUC:0.592) in BRCA1 pathogenic variant carriers and 1.51(95%CI:1.36-1.67,AUC:0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.</jats:p