Abstract 1747: Both somatic and germline BRCA mutations show high degree of bi-allelic loss in breast and ovarian cancers
Authors: Lai Zhongwu , Hodgson Darren , Sun James , Johnson Adrienne , Barrett Carl , Dry Jonathan 
Published: August 2019

PARP inhibitors (PARPi) are promising novel therapies for tumors harboring defects in homologous recombination (HR) DNA repair. Loss of function (LoF) mutations in the tumor suppressors BRCA1 and BRCA2, two critical components in HR pathway, are the most common cause of HR deficiency in tumors. Complete loss of BRCA1/2 function requires bi-allelic loss, and it is hypothesized to be needed for PARPi sensitivity. However, the degrees of bi-allelic loss in breast and ovarian tumors are still lacking consensus, especially when both LoF events are somatic. Recent publications shown a high percentage of germline BRCA2 lacking LOH, including TCGA’s breast and ovarian cohorts.

To better understand the loss of wild type BRCA genes, we reanalyzed raw data from TCGA using a novel pipeline to identify both germline and somatic BRCA mutations in breast and ovarian. We then applied mathematical models to determine LOH or bi-allelic loss of those mutations. Our analysis shows a higher degree of bi-allelic loss of BRCA mutations than previously reported, especially germline BRCA2 in breast cancer, which shows nearly 80%. Furthermore, somatic BRCA mutations, which account for about 1/3 of all BRCA mutations, showed a similar degree of bi-allelic loss as germline BRCA mutations. In addition, somatic and germline BRCA were shown to have comparable HRD scores, a measure of tumor genomic instability. Germline BRCA patients are typically diagnosed at younger ages in breast and ovarian cancer, whereas somatic show no difference to non-BRCA patients. In ovarian cancer, patients with somatic or germline BRCA had similar progression-free and overall survival with comparable treatment journeys, suggesting a phenotypic equivalence. Interestingly, BRCA2 tumors showed lower HRD scores than BRCA1 tumors in both breast and ovarian. In breast cancer BRCA1 mutation is significantly enriched in TNBC, but the degree of bi-allelic loss did not show any significant difference between ER+ and TNBC subtypes.

To validate our findings, we examined a much larger cohort of breast (n &gt; 5,000) and ovarian (n &gt; 2,500) cancers sequenced by Foundation Medicine, with germline/somatic and LOH status determined computationally using validated methodology. We found similar prevalence of somatic BRCA mutations and the degree of bi-allelic loss and HRD scores in both germline and somatic BRCA mutations. In addition, potential reactivating reversion mutations were discovered in both somatic and germline mutated BRCA in both breast and ovarian cancers, suggesting they are driver mutations.

In summary, large scale analysis of BRCA mutations in breast and ovarian cancers suggest that about 1/3 of BRCA mutations are somatic, and both germline and somatic BRCA mutations show high degree of bi-allelic loss and similar genomic instability and may benefit from PARPi therapies.

Citation Format: Zhongwu Lai, Darren Hodgson, James Sun, Adrienne Johnson, Carl Barrett, Jonathan Dry. Both somatic and germline BRCA mutations show high degree of bi-allelic loss in breast and ovarian cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1747.