Global Autozygosity Is Associated with Cancer Risk, Mutational Signature and Prognosis

SIMPLE SUMMARY: Global autozygosity in the form of runs of homozygosity is associated with various diseases. Heterozygosity ratio, an alternative measure of global autozygosity, is used to assess cancer risk in this study. Our analysis shows strong and consistent associations between heterozygosity ratios and various cancer types. Further analysis reveals the heterozygosity ratio’s potential connections to mutational signatures and cancer prognosis. ABSTRACT: Global autozygosity quantifies the genome-wide levels of homozygous and heterozygous variants. It is the signature of non-random reproduction, though it can also be driven by other factors, and has been used to assess risk in various diseases. However, the association between global autozygosity and cancer risk has not been studied. From 4057 cancer subjects and 1668 healthy controls, we found strong associations between global autozygosity and risk in ten different cancer types. For example, the heterozygosity ratio was found to be significantly associated with breast invasive carcinoma in Blacks and with male skin cutaneous melanoma in Caucasians. We also discovered eleven associations between global autozygosity and mutational signatures which can explain a portion of the etiology. Furthermore, four significant associations for heterozygosity ratio were revealed in disease-specific survival analyses. This study demonstrates that global autozygosity is effective for cancer risk assessment.