Copy neutral loss of heterozygosity is more frequent in older 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.

Figure 1

A) Scatterplot showing the distribution of loss of heterozygosity (LOH) frequency for the patients in the TCGA cohort against their age. The trend line for regression is shown in dark grey. The p-value is shown at the top right corner. B) Frequency of LOH events affecting chr17 in patients of different age group. C) LOH frequency in patients with germ line or somatic mutations in BRCA1 or BRCA2. TCGA-13-1512 had germ line mutation in both BRCA1 and BRCA2.

Figure 2

A) Scatterplot showing the distribution of loss of heterozygosity (LOH) frequency for the patients in the Boston HGSC cohort against their age. The trend line for regression is shown in dark grey. The p-value is shown at the top right corner. B) Boxplot showing the age of the patients who had chr17 LOH against those who did not.

Figure 3

Change in expression level of the key homologous recombination pathway genes in young (30–49 years, light grey), intermediate (50–69 years, dark grey) and older (70–99 years, black) patients. Those with adjusted p-value <0.05 are shown with asterisk, and the wedges show the direction of increase in expression.

Figure 4

3D scatter plot showing joint distribution of the frequency of loss of heterozygosity (LOH) events per sample with the pathway imbalance score and age at diagnosis of the patients. The regression plane (LOH ~ pathway imbalance score + Age) is shown in light grey. In the 3D plot, darker points are further away compared to those with a lighter shade.