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

Authors Ali Arafa, Catherine Handy Marshall, Justin Hwang, Deborah Kay Armstrong, William B. Isaacs, Elizabeth Mauer, Calvin Y. Chao, Emmanuel S. Antonarakis

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 (gBRCA1, gBRCA2, gPALB2, gATM, gCHEK2) 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 gBRCA1 pts, and depleted in gATM and gCHEK2 pts (all P < 0.001). ESR1 muts were depleted in gBRCA1 pts, and enriched in gATM and gCHEK2 pts (all P < 0.05). PIK3CA muts were depleted in gBRCA1/2 pts, and enriched in gATM and gCHEK2 pts (all P < 0.05). FGFR1 muts were depleted in gBRCA1/2 and gPALB2 pts, and enriched in gATM pts (all P < 0.01). HER2 and CDH1 alterations were depleted in gBRCA1 pts (P < 0.05). In ovarian cancer (N = 4244; gHRR-altered 6.2%, sporadic 93.8%), somatic TP53 muts were enriched in gBRCA1/2 pts, and depleted in gATM and gCHEK2 pts (all P < 0.05). ESR1 muts were enriched in gATM pts (P < 0.001). PIK3CA muts were depleted in gBRCA1/2 pts, and enriched in gATM pts (all P < 0.05). KRAS muts were depleted in gBRCA1/2 pts (P < 0.05). In pancreatic cancer (N = 5386; gHRR-altered 3.9%, sporadic 96.1%), somatic TP53 muts were enriched in gBRCA1 pts, and depleted in gATM and gPALB2 pts (all P < 0.05). KRAS muts were enriched in gBRCA1/2 and gATM pts (P < 0.05). Unexpectedly, ESR1 muts were enriched in gPALB2 and gCHEK2 pts (P < 0.05). In prostate cancer (N = 4378; gHRR-altered 4.5%, sporadic 95.5%), somatic TP53 muts trended higher in gBRCA1 pts, and lower in gATM and gPALB2 pts (P = NS). TMPRSS2-ERG fusions were depleted in gBRCA1 and gBRCA2 pts (P < 0.05). FOXA1 muts were enriched in gBRCA2 pts (P < 0.05), while BRAF and CDK12 muts were enriched in gCHEK2 pts (P < 0.05 and P = 0.07). Median TMB was higher in BRCA-associated cancers with gBRCA1/2 and gPALB2 muts relative to sporadic cancers (all P < 0.05), but not in pts with gATM or gCHEK2 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 gATM pts. In breast/ovarian cancers, PIK3CA muts are depleted in gBRCA1/2 pts, while ESR1 muts are enriched in gATM pts. KRAS muts are enriched in gBRCA1/2-altered pancreas cancers, but are depleted in gBRCA1/2-altered ovarian cancers. gBRCA2-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.