Germline BRCA2, ATM and CHEK2 alterations shape somatic mutation landscapes in prostate cancer.

Abstract

148 Background: Prostate cancer (PCa) is a highly heritable malignancy. Germline mutations in homologous recombination repair (HRR) genes, especially in in ATM, BRCA2 and CHEK2, are common in men with PCa, but how these influence somatic mutations is unknown. Characterizing the somatic landscape of tumors from germline HRR-altered PCa patients may provide insights into further therapeutic strategies and identify individuals most likely to benefit from existing therapies. Methods: We retrospectively identified 118 men with germline HRR-altered PCa from Johns Hopkins with available somatic mutation data (g ATM, n = 30; g BRCA2, n = 58; g CHEK2, n = 30). In these patients, somatic NGS analysis were done primarily using prostatic (rather than metastatic) tissues. The proportion of patients in each group with somatic biallelic inactivation was determined. We then compared the somatic mutation landscapes of the 3 groups, focusing on key PCa-relevant genes including AR, TMPRSS2-ERG, PTEN, TP53, BRCA2, ATM, CDK12, APC, FOXA1, AKT1, PIK3CA, and KDM6A among others. Somatic mutation data from primary prostate cancer specimens (n = 3965) found in pooled studies (n = 23) from cBioPortal were included as a reference standard for comparison. Results: Biallelic somatic inactivation was detected in 59% (34/58) of g BRCA2-altered, 47% (14/30) of g ATM-altered, and 0% (0/30) of g CHEK2-altered patients. In all 118 germline HRR-altered individuals, the most common somatic mutations were in BRCA2 (31%), FOXA1 (26%), TMPRSS2-ERG (20%), TP53 (16%), PTEN (15%), and ATM (15%). g BRCA2-altered patients had a higher prevalence of somatic mutations in AR (9% vs 3% in cBioPortal, P < 0.05) and FOXA1 (29% vs 13% in cBioPortal, P > 0.05), suggesting a greater dependency on AR signaling, but a lower prevalence of TMPRSS2-ERG fusions (17% vs 33% in cBioPortal, P < 0.05). g ATM-altered patients had a strikingly low prevalence of somatic TP53 mutations (3% vs 25% in cBioPortal, P < 0.01), indicating mutual exclusivity between these genes. g CHEK2-altered patients had a higher prevalence of somatic CDK12 mutations (10% vs 0% in gATM/gBRCA2 patients, P < 0.05), implying an interaction between CHEK2 and CDK12. No differences were seen between the three groups with respect to alterations in the PI3K/PTEN pathway, WNT pathway, or chromatin-related genes. Conclusions: Biallelic inactivation was frequently observed in PCa patients harboring g ATM and g BRCA2 mutations, but not in those with g CHEK2 mutations. g BRCA2-altered patients were enriched for somatic AR (and FOXA1) mutations and were depleted for TMPRSS2-ERG fusions. g ATM-altered patients were depleted for somatic TP53 mutations, while g CHEK2-altered patients were enriched for somatic CDK12 mutations. Thus, germline mutations appear to impose selective pressures that influence somatic mutation landscapes in PCa.