Rare BAP1 variant of unknown significance (VUS) and analysis of BAP1 codon 146 genomics: Potential germline and therapeutic implications.

Abstract

10533 Background: The BAP1 gene ( B RCA1-Associated Protein) encodes a protein ubiquitin carboxyl-terminal hydrolase (BAP1), which removes ubiquitin moieties and regulates various cellular functions including DNA repair. This association has driven interest in defining if BAP1 variants confer susceptibility to PARP inhibitors (PARPi). Germline and somatic BAP1 alterations are both rare, mostly unique, often classified as VUS’s, and associated with a broad range of overlapping tumor types. Based on the identification of a BAP1 R146K VUS variant in tumor, also previously identified as germline, an analysis of BAP1 codon 146 alterations was initiated to explore potential genetic and therapeutic implications. Methods: 394,756 tumor specimens were tested using hybrid capture-based genomic profiling (Foundation Medicine) for all variant types and Tumor Mutational Burden (TMB). BAP1 codon 146 cases were analyzed for clinicogenomic features and germline results when available. Results: BAP1 codon 146 variants were identified in 23 unique patients across the following tumor types: cholangiocarcinoma (CCA) (4), mesothelioma (4), NSCLC (3), RCC (2), ocular melanoma (2), and carcinoma of unknown primary (CUP) (3); many of which overlap with known and suspected germline associated BAP1 syndromic tumor types. BAP1 R146 mutations were classified as VUS in 16 patients and 7 were likely or known pathogenic. In 20 of the 23 cases where zygosity could be determined 16 (80%) were homozygous and 4 (20%) were heterozygous. In 2 of the 3 NSCLC cases, the BAP1 variant appeared likely somatic and/or associated with a high TMB. A previously reported germline BAP1 variant in a RCC patient, R146K, occurred 5 times in our tumor database. One case which was homozygous in tumor and confirmed in germline occurred in a patient who had both breast and CCA. She also had a sibling with RCC who shared the germline BAP1 R146K variant along with multiple 1st and 2nd degree relatives with RCC, mesothelioma, melanoma, liver cancer, colon cancer, and a cancer of unknown primary. Conclusions: Codon 146 of BAP1 localizes to the UCH (ubiquitin carboxyl hydrolase) domain, which includes the BARD1 interaction region. Loss of BAP1 activity as a consequence of germline or somatic mutation likely impacts ubiquitination status and activity of downstream proteins, such as those involved in DNA repair. For patients with suspected BAP1 inactivating alterations, often seen in non-homologous recombination deficiency related tumor types, PARPi therapy may be relevant. As demonstrated here, variants identified through tumor testing may also aid in re-classification of germline VUS’s. These results support the further investigation and validation of BAP1 alterations for germline risk stratification and therapeutic strategies with either PARPi and/or other therapies specific to tumors with impaired chromatin remodeling.