High level of chromosomal aberration in ovarian cancer genome correlates with poor clinical outcome

Abstract

Objectives: Structural aberration in chromosomes characterizes almost all human solid cancers and analysis of those alterations may reveal the history of chromosomal instability. However, the clinical significance of massive chromosomal abnormality in ovarian high-grade serous carcinoma (HGSC) remains elusive. In this study, we addressed this issue by analyzing the genomic profiles in 455 ovarian HGSCs available from The Cancer Genome Atlas (TCGA).

Methods: DNA copy number, mRNA expression, and clinical information were downloaded from the TCGA data portal. A chromosomal disruption index (CDI) was developed to summarize the extent of copy number aberrations across the entire genome. A Cox regression model was applied to identify factors associated with poor prognosis. Genes whose expression was associated with CDI were identified by a 2-stage multivariate linear regression and were used to find enriched pathways by Ingenuity Pathway Analysis.

Results: Multivariate survival analysis showed that a higher CDI was significantly associated with a worse overall survival in patients. Interestingly, the pattern of DNA copy number alterations across all the chromosomes was similar between tumors with high and low CDI, suggesting they did not arise from different mechanisms. We also observed that expression of several genes was highly correlated with the CDI, even after adjusting for local copy number variation. We found that molecular pathways involving DNA damage response and mitosis were significantly enriched in these CDI-correlated genes.

Conclusion: Our results provide a new insight into the role of chromosomal rearrangement in the development of HGSC and the promise of applying CDI in risk-stratifying HGSC patients, perhaps for different clinical managements. The genes whose expression is correlated with CDI are worthy of further study to elucidate the mechanism of chromosomal instability in HGSC.

Fig. 1

Extent of copy number alterations in HGSC samples. (A) The number of genes falling into altered regions in each sample. (B) The proportion of the genome implicated in copy number alterations by sample. (C) The distribution of chromosomal disruption index (CDI) by sample, calculated as the number of copy number altered segments of DNA.

Fig. 2

Overall survival by CDI and residual tumor. A Kaplan–Meier analysis of TCGA samples showed that among patients with residual tumor volumes less than 1 cm (solid lines), those with CDI less than the median (green line) had distinctly better outcomes than those with CDI greater than the median (blue line).

Fig. 3

Distribution of copy number events across chromosome 1. The CNV events identified along chromosome 1 concentrate in a number of hotspots. Interestingly, there was a nearly perfect co-location of CNVs obtained from HGSCs with high (black) and low CDI (gray).

Fig. 4

Ingenuity Pathway Analysis of genes whose expression correlated with CDI. Polo-like kinase, BRCA1-mediated DNA damage response and G2/M DNA damage checkpoint pathways were statistically significantly enriched with genes whose expression correlated positively with CDI.