Effect of Germline Mutations on Somatic Alteration Landscapes in BRCA-Associated Cancers

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_BRCA_2-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.