Clinicogenomic landscape and function of PIK3CA , AKT1 , and PTEN mutations in breast cancer

Abstract Purpose To comprehensively characterize the clinical and genomic landscapes of PIK3CA, AKT1, and PTEN alterations and examine their functional implications in AKT-driven breast cancer. Experimental Design Comprehensive genomic profiling of 51,767 breast tumors was performed with FoundationOne ® CDx or FoundationOne ® . We examined the genomic landscape of PIK3CA , PTEN , and AKT1 alterations and their distribution across clinical variables of interest. Prior deep mutational scanning (DMS) data was used to functionally characterize clinical PTEN variants. Results There were 29,157 total variants across PIK3CA, AKT1, and PTEN , including pathogenic variants and VUS. The most frequently altered gene was PIK3CA (37.4% of cases), followed by PTEN (13.5%), then AKT1 (5.4%). The most common alterations in each gene were PIK3CA H1047R (35.6% of PIK3CA -altered cases), E545K (19.7%), and E542K (11.7%); AKT1 E17K (69.7%); and PTEN homozygous copy number deletion (37.3%). PIK3CA alterations were less prevalent in patients of African genetic ancestry (27.1% vs 38.6% in European genetic ancestry), while AKT1 and PTEN alterations were balanced across ancestries. PIK3CA , AKT1 , and PTEN pathogenic alterations were all mutually exclusive to each other. Using available DMS data on missense PTEN mutations, we found that 32.5% showed discordant effects on protein stability and phosphatase activity, underscoring the need for functional validation beyond predicted loss-of-function. Conclusions Here we present the landscape of PIK3CA , AKT1 , and PTEN alterations in the largest clinical cohort examined to date. The functional implications of lesser-known variants in each gene warrant further investigation by tools such as deep mutational scanning.