Abstract P5-03-08: Breast cancer genomic landscape according to germline BRCA1/2 pathogenicity
Authors: Kim Ju Won , Choi Jung Yoon , Lee Soo Hyeon , Chang Won Jin , Bae Soo Youn , Choi Yoon Ji , Jung Seung Pil , Cho Kyu Ran , Shin Sang Won , Kim Yeul Hong , Park Kyong Hwa 
Published: March 2020

Abstract
Background: BRCA1 and BRCA2 are tumor suppressor genes and their protein products play a key role in DNA repair pathway. Individuals harboring germline mutations in BRCA1/2 genes(gBRCA1/2) confer high risk of developing breast cancer. Although clinical features of BRCA-related breast cancer have been well established, the characteristic of tumor biology and specific somatic mutational profile has not been fully understood. Here we investigated tumor mutational landscape of germline BRCA-mutant or wild type breast cancer. Methods: We collected breast cancer patients who had been confirmed as pathogenic gBRCA1/2 mutation by blood test. Matched cohorts who had wild type or variants of unknown significance(VUS) in BRCA1/2 gene were also selected based on age, TNM stage, and molecular subtype. Formalin-fixed paraffin-embedded (FFPE) tumor samples from all participants were analyzed by Next Generation Sequencing(NGS)-based cancer panel. We used CancerSCAN panel from Samsung Genome Institute, which provides variant genomic data and its own class stratification. All the single nucleotide variants(SNVs) were reported based on classification of clinical importance. If there is no evidence of preclinical evidence, that variant is labeled as ‘novel’. When a variant has some relevance on tumor biology, it is categorized as class 1 to 5 based on evidence level. Results: Each of seven patients were found to be suitable for analysis in groups of ‘pathogenic gBRCA1/2’, ‘wild gBRCA1/2’, and ‘VUS gBRCA’, respectively. (N=21) Detected number of SNV in patients with pathogenic gBRCA1/2 were higher than wild gBRCA1/2. (19.3 vs 15.6 SNVs per tumor sample) The number of SNVs suspected to germline mutation due to high variant allele frequency(VAF) was higher in pathogenic BRCA1/2 group, but the difference was minimal. (11.1 vs 10.0 SNVs with VAF&gt;30% per tumor sample) The mean VAF of all variants also had little difference. (34.2% vs 35.6%) The patients with VUS gBRCA1/2 showed highest number of SNVs and SNVs with elevated VAF. (21.0 SNVs 14.1 SNVs with VAF&gt;30% per tumor sample, mean VAF 36.8%) The rate of SNVs denoted as class 1 to 5 were similar in pathogenic and wild type gBRCA1/2 patients. (20.1% vs 21.2%) In pathogenic group, nonsynonymous SNV of BRCA2 was the most common mutation, followed by BRCA1 and TP53. In wild type group, mutation in BRCA2 and TP53 were the two most common variants, followed by PIK3CA. The genomic copy number alteration was more prominent in wild type group. Discussion: In our study, the genomic variation according to germline BRCA1/2 pathogenicity was imperceptible, except for total number of SNVs per tumor sample. The patients with gBRCA1/2 VUS tended to similar to pathogenic group rather than wild type group. We will present more data from 50 patients on conference day. (This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health &Welfare, Republic of Korea (Grant number: HI17C2206).)
Citation Format: Ju Won Kim, Jung Yoon Choi, Soo Hyeon Lee, Won Jin Chang, Soo Youn Bae, Yoon Ji Choi, Seung Pil Jung, Kyu Ran Cho, Sang Won Shin, Yeul Hong Kim, Kyong Hwa Park. Breast cancer genomic landscape according to germline BRCA1/2 pathogenicity [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-03-08.