Peter Rogan will be presenting:
Seeking the “Missing Heritability” in High-Risk Hereditary Breast and Ovarian Cancer (HBOC) Patients By Prioritizing Coding and Non-Coding Variants in 21 Genes. Natasha Caminsky G, Eliseos Mucaki J, Amelia Perri M, Ruipeng Lu, Matthew Halvorsen, Alain Laederach, Joan Knoll HM, Peter Rogan K
on Tuesday, November 10 from 12-2 PM in the poster session: Genomics, Proteomics, and Bioinformatics
in Montréal – Hôtel Bonaventure.
Scientific Program: link
Abstract:
Current BRCA1 and BRCA2 genetic testing for hereditary breast and ovarian cancer (HBOC) is often uninformative. The “missing heritability” may be due to variants in uninvestigated regions of these genes or variants in other genes. We have applied a unified framework based on information theory (IT) to predict and prioritize non-coding variants of uncertain significance. We captured complete gene sequences of 21 diseaserelevant genes in HBOC patients with uninformative hereditary predisposition testing (N=336) by hybridization enrichment using ab initio single copy probes that comprehensively span non-coding regions and flanking sequences of ATM, ATP8B1, BARD1, BRCA1, BRCA2, CDH1, CHEK2, EPCAM, MLH1, MRE11A, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, PTEN, RAD51B, STK11, TP53, and XRCC2. We identified 38,538 unique variants. Eight were likely pathogenic BRCA1/2 mutations previously undetected by clinical testing. Eight proteintruncating mutations were identified in non-BRCA genes, the majority of which were in PALB2 (N=5), and 148 missense variants were flagged. Information weight matrices were derived for transcription factor (TFBS), splicing regulatory (SRBS), and RNA-binding (RBBS) protein binding sites from high-throughput sequencing data. IT analysis prioritized 12 variants affecting splicing (6 natural, 6 cryptic), 71 TFBS, 218 SRBS, and 29 RBBS. Co-segregation analysis found the relative risk of breast cancer for likely pathogenic BRCA variants torange from 1.55 to 75.78. According to clinically accepted guidelines, twenty-three were possibly pathogenic (13 confirmed by Sanger sequencing to date), 472 were of uncertain significance, and all remaining were likely not pathogenic. Complete gene analysis of BRCA1/2 and other genes is a successful strategy for identifying probable mutations in previously uninformative HBOC patients.