Abstract PS16-25: Comparison of the genetic mutations in sporadic and BRCA1 carrier breast cancer through targeted next generation sequencing
Authors: Barron Cynthia Reyes , Hicks David , Wang Xi 
Published: February 2021

Abstract
IntroductionWomen who carry a germline mutation in BRCA1 (breast cancer type 1 susceptibility protein) have an increased risk of developing breast cancer in their lifetimes. Carriers tend to develop breast cancer at a younger age and their tumors are generally aggressive. Although BRCA1 breast cancers have been researched, many questions remain. The purpose of this study was to analyze the mutational landscape of tumors from BRCA1 carriers and compare them to tumors of sporadic breast cancer. MethodsPathology reports were reviewed to identify cases of breast cancer (BC) and the ER/PR/HER2 status was noted as well as the Ki67 proliferation index and patient age. Next generation sequencing (NGS) was performed on 72 BC tumors; 26 from BRCA1 carriers and 46 sporadic BC tumors. Two targeted panels were used for sequencing, the Oncomine Comprehensive Assay by Thermo Fisher Scientific on an Ion Torrent S5 XL sequencer and the AmpliSeq for Illumina Cancer HotSpot Panel. Mutations in a total of 44 cancer associated genes common to both panels were analyzed including TP53, RB1, PTEN, NRAS, ERBB2, PIK3CA, and BRAF. Missense and nonsense single nucleotide variants with a variant allele frequency &gt;3% and coverage &gt;150 reads were considered as well as insertions/deletions. Pathogenicity was determined using ClinVar and Varsome. Mutations were classified as benign, likely benign, variants of uncertain significance, likely pathogenic, and pathogenic.ResultsPathogenic/likely pathogenic variants were identified in 15 genes. TP53 was the most commonly mutated gene with pathogenic/likely pathogenic variants in 13 (50%) BRCA1 carriers’ tumors and 18 (39%) sporadic tumors. Having a TP53 mutation did not increase the likelihood of having other pathogenic mutations in either BRCA1 carriers or sporadic tumors; 74% of all tumors with p53 mutations had no additional pathogenic mutations overall. PIK3CA pathogenic/likely pathogenic mutations were significantly more common in sporadic tumors (26%) than BRCA1 carrier tumors (8%). PIK3CA mutation did not increase the likelihood of other gene mutations and did not correlate with TP53 mutations. BRCA1 pathogenic mutations were identified in four cases with no germline testing and likely represent somatic mutations. No pathogenic mutations were found in 12 (46%) of the BRCA1 carriers’ tumors and 10 (22%) sporadic tumors. There were four BRCA1 carriers with bilateral BCs; two pairs had the same mutations, one pair had different TP53 pathogenic mutations and another pair had different PIK3CA pathogenic mutations. A total of twenty-four cases were triple negative, 13 sporadic and 11 BRCA1 carriers (see table below). As expected, BRCA1 carriers were diagnosed with BC at a younger age with 21 (81%) cases diagnosed at age &lt; 60 years while 22 (48%) of sporadic cases were in this age group.
Conclusion
TP53 is the most commonly mutated gene in BCs, even though more common in BRCA1 carriers’ tumors; however, they are not required for tumor development as seen in the 57% of cases in our study with normal TP53 (50% of BRCA1 carriers). No specific additional pathogenic mutation was commonly seen in BRCA1 tumors with TP53 mutations. PIK3CA was frequently mutated in sporadic cases and not in BRCA1 carriers. BRCA1 tumors were less likely to have other pathogenic mutations than sporadic tumors in this study of 44 genes. Additional studies will help further elucidate the molecular basis of BRCA1 tumor carcinogenesis.
Citation Format: Cynthia Reyes Barron, David Hicks, Xi Wang. Comparison of the genetic mutations in sporadic and BRCA1 carrier breast cancer through targeted next generation sequencing [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS16-25.