Understanding BRCA1 and BRCA2 mutated breast cancer cases in Romania: First report on founder mutations in Romanians

Abstract

Background: First systematic analysis of BRCA 1(B1) or BRCA2(B2) mutations in high-risk Romanian breast cancer patients (pts) aiming at defining founder mutations. Methods: This prospective study evaluated the germline B1/B2 mutations in 250 highrisk breast cancer pts tested between 02.2015-12.2016 at IOCN. Inclusion criteria selected pts diagnosed with triple negative breast cancer under the age of 50, or having conventional family history criteria. All pts signed an informed consent. B1/B2 testing was performed using an AmpliSeq-based sequencing analysis, on the Ion Torrent Personal Genome Machine at RCFG. Pathogenic mutations were validated using Sanger technology. MLPA was performed for all pts. Results: Of the 250 pts with breast cancer, 44 (17.6%) carried pathogenic mutations, 29 pts (11.6%) in B1 and 15 (6%)in B2, while 18 patients (7.2%) carried a Variant of Uncertain Significance (VUS). Patient features analysis confirmed the prevalence of younger age, higher grade, hormone receptor negative and Her2 negative status among mutated patients (data not shown). Out of the 16 distinct deleterious mutations identified, 7 (43.75%) occurred in B1 and 9 (56.25%) in B2. The founder mutations identified in B1 gene were: c.5329-5330insC (c.5266dupC) 11 pts (37.93%), c.3607C>T 9 pts (31.03%) and c.181T>G 4 pts (13.79%). Other B1 mutations where c.1687C>T 2 pts (6.89%), and c.4218delG (3.44%), c.212+1G>T (3.44%), c.68-69delAG (3.44%) in one patient respectively. For B2 gene, c.9371A>T (46.66%) was identified as founder mutation (7 pts, 46.66%). Other mutations were found each in one patient (6.66%): c.1528G>T, c.4022C>G, c.7007G>A, c.8695C>T, c.9253delA, c.8680C>T, c.8755- 1G>A, c.8695C>T. Of the founder mutations identified, two (c.3607C>T and c.9371A>T) have not been previously identified as founder mutations in any Eastern European country. Conclusions: This prospective study presents the first extensive results of germline B1/ B2 mutations in Romanian high-risk breast cancer pts. Our results indicate that at least four recurrent B1/B2 mutations qualify as founder mutations; two being newly identified as carrying a founder effect.