Affiliations 

  • 1 Department of Cancer Biology and Genetics, The Ohio State University College of Medicine, Columbus, Ohio
  • 2 The City College of New York, City University of New York, New York, New York
  • 3 Cancer Research Malaysia, Subang Jaya, Selangor, Malaysia
  • 4 Division of Epidemiology, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee
  • 5 Biomedical Sciences, The Ohio State University College of Medicine, Columbus, Ohio
  • 6 Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, California
  • 7 Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California
  • 8 The Ohio State University Comprehensive Cancer Center, Columbus, Ohio
  • 9 Department of Internal Medicine, Division of Human Genetics, The Ohio State University, Columbus, Ohio
  • 10 Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, California
  • 11 Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, New York
  • 12 Department of Cancer Control and Prevention, Roswell Park Comprehensive Cancer Center, Buffalo, New York
  • 13 Slone Epidemiology Center at Boston University, Boston, Massachusetts
  • 14 City of Hope Comprehensive Cancer Center, Duarte, California
  • 15 Bioinformatics Shared Resource, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio
  • 16 Genomics Shared Resource, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio
  • 17 Department of Public Health Sciences, University of Chicago, Chicago, Illinois
  • 18 Department of Biomedical Informatics, The Ohio State University Center for Biostatistics, Columbus, Ohio
Cancer Res Commun, 2024 Jun 27;4(6):1597-1608.
PMID: 38836758 DOI: 10.1158/2767-9764.CRC-24-0026

Abstract

In breast tumors, somatic mutation frequencies in TP53 and PIK3CA vary by tumor subtype and ancestry. Emerging data suggest tumor mutation status is associated with germline variants and genetic ancestry. We aimed to identify germline variants that are associated with somatic TP53 or PIK3CA mutation status in breast tumors. A genome-wide association study was conducted in 2,850 women of European ancestry with breast cancer using TP53 and PIK3CA mutation status (positive or negative) as well as specific functional categories [e.g., TP53 gain-of-function (GOF) and loss-of-function, PIK3CA activating] as phenotypes. Germline variants showing evidence of association were selected for validation analyses and tested in multiple independent datasets. Discovery association analyses found five variants associated with TP53 mutation status with P values <1 × 10-6 and 33 variants with P values <1 × 10-5. Forty-four variants were associated with PIK3CA mutation status with P values <1 × 10-5. In validation analyses, only variants at the ESR1 locus were associated with TP53 mutation status after multiple comparisons corrections. Combined analyses in European and Malaysian populations found ESR1 locus variants rs9383938 and rs9479090 associated with the presence of TP53 mutations overall (P values 2 × 10-11 and 4.6 × 10-10, respectively). rs9383938 also showed association with TP53 GOF mutations (P value 6.1 × 10-7). rs9479090 showed suggestive evidence (P value 0.02) for association with TP53 mutation status in African ancestry populations. No other variants were significantly associated with TP53 or PIK3CA mutation status. Larger studies are needed to confirm these findings and determine if additional variants contribute to ancestry-specific differences in mutation frequency.

SIGNIFICANCE: Emerging data show ancestry-specific differences in TP53 and PIK3CA mutation frequency in breast tumors suggesting that germline variants may influence somatic mutational processes. This study identified variants near ESR1 associated with TP53 mutation status and identified additional loci with suggestive association which may provide biological insight into observed differences.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.