Effect of germline mutations on somatic alteration landscapes in BRCA-associated cancers.
Authors: Arafa Ali , Marshall Catherine Handy , Hwang Justin , Armstrong Deborah Kay , Isaacs William B. , Mauer Elizabeth , Chao Calvin Y. , Antonarakis Emmanuel S. 
Published: June 2023

10509 Background: The interaction between germline alterations in homologous recombination repair (gHRR) genes and tumoral genomic landscapes is poorly understood. We hypothesized that gHRR alterations may influence somatic mutational landscapes in BRCA-associated cancers. Methods: Using a large de-identified real-world dataset of patients undergoing matched tumor/normal next-generation DNA sequencing (Tempus xT), we compared somatic genomic landscapes of tumors arising in individuals with germline HRR mutations (g BRCA1, g BRCA2, g PALB2, g ATM, g CHEK2) versus their sporadic counterparts, across four BRCA-associated cancers (breast, ovary, pancreas, prostate). Results: In breast cancer (N = 6955; gHRR-altered 5.9%, sporadic 94.1%), somatic TP53 muts were enriched in g BRCA1 pts, and depleted in g ATM and g CHEK2 pts (all P < 0.001). ESR1 muts were depleted in g BRCA1 pts, and enriched in g ATM and g CHEK2 pts (all P < 0.05). PIK3CA muts were depleted in g BRCA1/ 2 pts, and enriched in g ATM and g CHEK2 pts (all P < 0.05). FGFR1 muts were depleted in g BRCA1/2 and g PALB2 pts, and enriched in g ATM pts (all P < 0.01). HER2 and CDH1 alterations were depleted in g BRCA1 pts (P < 0.05). In ovarian cancer (N = 4244; gHRR-altered 6.2%, sporadic 93.8%), somatic TP53 muts were enriched in g BRCA1/ 2 pts, and depleted in g ATM and g CHEK2 pts (all P < 0.05). ESR1 muts were enriched in g ATM pts (P < 0.001). PIK3CA muts were depleted in g BRCA1/ 2 pts, and enriched in g ATM pts (all P < 0.05). KRAS muts were depleted in g BRCA1/ 2 pts (P < 0.05). In pancreatic cancer (N = 5386; gHRR-altered 3.9%, sporadic 96.1%), somatic TP53 muts were enriched in g BRCA1 pts, and depleted in g ATM and g PALB2 pts (all P < 0.05). KRAS muts were enriched in g BRCA1/2 and g ATM pts (P < 0.05). Unexpectedly, ESR1 muts were enriched in g PALB2 and g CHEK2 pts (P < 0.05). In prostate cancer (N = 4378; gHRR-altered 4.5%, sporadic 95.5%), somatic TP53 muts trended higher in g BRCA1 pts, and lower in g ATM and g PALB2 pts (P = NS). TMPRSS2-ERG fusions were depleted in g BRCA1 and g BRCA2 pts (P < 0.05). FOXA1 muts were enriched in g BRCA2 pts (P < 0.05), while BRAF and CDK12 muts were enriched in g CHEK2 pts (P < 0.05 and P = 0.07). Median TMB was higher in BRCA-associated cancers with g BRCA1/2 and gPALB2 muts relative to sporadic cancers (all P < 0.05), but not in pts with g ATM or g CHEK2 muts. There were no differences in MMR mutations or MSI status. Conclusions: Across four BRCA-associated cancers, TP53 muts are enriched in BRCA1 pts and depleted in g ATM pts. In breast/ovarian cancers, PIK3CA muts are depleted in g BRCA1/ 2 pts, while ESR1 muts are enriched in g ATM pts. KRAS muts are enriched in g BRCA1/2-altered pancreas cancers, but are depleted in g BRCA1/2-altered ovarian cancers. g BRCA2-altered prostate cancers are enriched in FOXA1 muts, and depleted in ERG fusions. These data suggest that gHRR-mutated cancers have distinct genomic landscapes compared to their sporadic counterparts; this may influence therapeutic considerations.