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

Limin Jiang,Fei Guo,Huining Kang,Jijun Tang,Scott Ness,David C Samuels,Shuguan Leng,Fei Ye,Yan Guo

doi:10.3390/cancers12123646

Abstract

Simple SummaryGlobal 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. 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.

Highlights

The human genome is comprised of approximately three billion base pairs
The Heterozygosity Ratio (HR) was traditionally computed as the ratio between the number of heterozygous SNPs divided by the number of non-reference homozygous SNPs, which we define as HRNonRef
HRNonRef and HRMinor were computed for all The Cancer Genome Atlas (TCGA) SNP and International Genome Sample Resources (IGSR) SNP datasets

Summary

Introduction

The human genome is comprised of approximately three billion base pairs. Single NucleotidePolymorphisms (SNPs) can affect various disease risks as shown by numerous genome-wide association studies (GWAS). The human genome is comprised of approximately three billion base pairs. Polymorphisms (SNPs) can affect various disease risks as shown by numerous genome-wide association studies (GWAS). According to the GWAS catalog (May 2020), 4424 unique SNPs have been found to influence cancer risk with p < 10−5 significance. While an SNP describes the allelic information at a single genomic position, global heterozygosity and homozygosity describe the genome-wide zygosity level. Heterozygosity describes the possession of two different alleles of an SNP, and homozygosity describes the possession of the same allele at a genomic position.

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