Copy neutral loss of heterozygosity is more frequent in older(serous) ovarian cancer patients

Abstract

Loss of heterozygosity (LOH) is a common type of genomic alterations in ovarian cancer. Analyzing 74,415 copy neutral LOH events in 513 serous ovarian adenocarcinomas samples from the Cancer Genome Atlas, we report that the frequency of LOH events increases with age. Similar trend is observed for LOH involving chromosome 17, which is frequently implicated in ovarian cancer. The results are consistent when we analyze data from the Boston high-grade serous cancer cohort. We further show that germ line and somatic mutations in BRCA1 (in chromosome 17) and BRCA2 (in chromosome 13) loci are not necessary to establish the pattern. We also report significant age-related changes in expression patterns for several genes in the homologous recombination (HR) pathway, such as BRCA1, RAD50, RAD52, XRCC2, XRCC3, and MRE11A in these patient samples. Furthermore, we develop a metric for pathway-level imbalance, and show that increased imbalance in the HR pathway, i.e., increase in expression of some HR genes and decrease in expression of others, is common and correlates significantly with the frequency of LOH events in the patient samples. Taken together, it is highly likely that aging and deregulation of HR pathway contribute to the increased incidence of copy-neutral LOH in ovarian cancer patients.