Abstract P2-09-18: Exploration of the diagnostic utility of next generation sequencing with TruSight cancer panel for BRCA negative hereditary breast and ovarian cancer patients

Abstract

Abstract Background. Breast cancer is the most commonly diagnosed malignancy and the most frequent cause of death in women due to cancer. About 5% to 10% of breast cancers are thought to be hereditary. Pathogenic mutations in BRCA1/2 genes across Hereditary Breast and Ovarian Cancer (HBOC) patients estimates are at around 15-20%. Other less common genes have also been associated with an increased risk of developing breast cancer, such as mutations in the TP53, PTEN, RAD51C, CDH1, ATM, CHEK2 or PALB2 tumor suppression genes. NGS based sequencing panels allow fast and simultaneous screening of large number of high- and low-penetrance susceptibility genes in these patients. Methods. In the current study we included a group of 31 Bulgarian female breast cancer patients, selected following the strict BCLC and NCCN criteria for hereditary cancer. All of them were prescreened by direct sequencing and MLPA analysis, and tested negative for pathogenic mutations in BRCA1 and BRCA2 genes. Next generation target resequencing using a panel of 94 cancer related genes (Illumina TruSight cancer panel) was performed to explore the hereditary component beyond BRCA1/2 genes in these patients. All detected mutations and variants of unknown clinical significance (VUSs) were confirmed by Sanger sequencing method. Results. Pathogenic and likely pathogenic mutations were found in 14 out of 31 BRCA1/2 negative patients: 1 new frameshift mutation in ATM gene; 6 new likely pathogenic missense mutations in PTCH1, RAD51C, MET, MUTYH, ATM and CHEK2; 7 previously reported pathogenic missense variants in WRN, ERCC4, PALB2, PRF1, RET, SDHB and AIP genes. In addition 27 VUSs (one new splice donor variant in ALK gene and 26 missense variants) were found. Conclusions. The use of next generation target resequencing with TruSight Cancer panel lead to identification of clinically relevant pathogenic variants in 45% of the investigated patients. This could be the preferred diagnostic method in HBOC patients, carefully selected according the strict BCLC and NCCN criteria. Citation Format: Dacheva D, Dodova R, Mitkova A, Kamenarova K, Tzveova R, Popov I, Vlahova A, Taushanova – Hadjieva M, Valev S, Dikov T, Timcheva K, Christova S, Mitev V, Kaneva R. Exploration of the diagnostic utility of next generation sequencing with TruSight cancer panel for BRCA negative hereditary breast and ovarian cancer patients. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-09-18.