Cancer genomics has shed much light on tumorigenesis, leading to improved diagnoses and treatments. The marriage of Big Data and genetics research has produced groundbreaking, epidemiologic studies of large swaths of the world's population showing the links between cancer(s) and inherited risk. This work has led to breakthroughs in our understanding of pathogenic mutations, such as in BRCA1 and BRCA2 genes—strong predictors of breast and ovarian cancer risk and possibly the strongest known predictors of aggressive prostate cancer risk. Inherited and sporadic forms of cancer often share common mutational events, with implications for diagnosis, prognosis, treatment and prevention. Our work and that of others demonstrate the significant burden of early onset ER negative breast cancer as well as high rates of pathogenic BRCA1, BRCA2 and PALB2 mutations among young women diagnosed with breast cancer. Our more recent work on the BRCA1 pseudogene identifies a novel mechanism of innate immunity driven by a host pseudogene RNA that inhibits innate immune defense mechanisms and anti-tumor responses through regulation of antiviral gene expression. Genome-Wide Association Studies (GWAS) have also identified single nucleotide polymorphisms (SNPS) associated with increased breast cancer risk, including SNP rs13074711 identified from GWAS in women of African Ancestry with breast cancer, which regulates TNFSF10/TRAIL expression in ER negative breastcancer cells. Germline genetics influence somatic mutations and the evolutionary trajectory and life history of individual cancer genomes in diverse populations. Deeper understanding of the nature of this influence will allow us to explore innovative interventions to accelerate progress in precision health care and promote health equity.

Citation Format: Olufunmilayo I. Olopade. Inherited susceptibility to cancer: From family reunions to the front line of precision healthcare [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr PL03-03.