Association ofESR1germline variants withTP53somatic variants in breast tumors in a genome-wide study

Abstract

ABSTRACTBackgroundIn breast tumors, somatic mutation frequencies inTP53andPIK3CAvary by tumor subtype and ancestry. HER2 positive and triple negative breast cancers (TNBC) have a higher frequency ofTP53somatic mutations than other subtypes.PIK3CAmutations are more frequently observed in hormone receptor positive tumors. Emerging data suggest tumor mutation status is associated with germline variants and genetic ancestry. We aimed to identify germline variants that are associated with somaticTP53orPIK3CAmutation status in breast tumors.MethodsA genome-wide association study was conducted using breast cancer mutation status ofTP53andPIK3CAand functional mutation categories includingTP53gain of function (GOF) and loss of function mutations andPIK3CAactivating/hotspot mutations. The discovery analysis consisted of 2850 European ancestry women from three datasets. Germline variants showing evidence of association with somatic mutations were selected for validation analyses based on predicted function, allele frequency, and proximity to known cancer genes or risk loci. Candidate variants were assessed for association with mutation status in a multi-ancestry validation study, a Malaysian study, and a study of African American/Black women with TNBC.ResultsThe discovery Germline x Mutation (GxM) association study found five variants associated with one or moreTP53phenotypes withPvalues <1×10-6, 33 variants associated with one or moreTP53phenotypes withPvalues <1×10-5, and 44 variants associated with one or morePIK3CAphenotypes withPvalues <1×10-5. In the multi-ancestry and Malaysian validation studies, germlineESR1locus variant, rs9383938, was associated with the presence ofTP53mutations overall (Pvalues 6.8×10-5and 9.8×10-8, respectively) andTP53GOF mutations (Pvalue 8.4×10-6). Multiple variants showed suggestive evidence of association withPIK3CAmutation status in the validation studies, but none were significant after correction for multiple comparisons.ConclusionsWe found evidence that germline variants were associated withTP53andPIK3CAmutation status in breast cancers. Variants near the estrogen receptor alpha gene,ESR1,were significantly associated with overallTP53mutations and GOF mutations. Larger multi-ancestry studies are needed to confirm these findings and determine if these variants contribute to ancestry-specific differences in mutation frequency.