Abstract
Genomic instability and copy number alterations in cancer are generally associated with poor prognosis; however, recent studies have suggested that extreme levels of genomic aberrations may be beneficial for the survival outcome for patients with specific tumour types. We investigated the extent of genomic instability in predominantly high-grade serous ovarian cancers (SOC) using two independent datasets, generated in Norway (n = 74) and Australia (n = 70), respectively. Genomic instability was quantified by the Total Aberration Index (TAI), a measure of the abundance and genomic size of copy number changes in a tumour. In the Norwegian cohort, patients with TAI above the median revealed significantly prolonged overall survival (p<0.001) and progression-free survival (p<0.05). In the Australian cohort, patients with above median TAI showed prolonged overall survival (p<0.05) and moderately, but not significantly, prolonged progression-free survival. Results were confirmed by univariate and multivariate Cox regression analyses with TAI as a continuous variable. Our results provide further evidence supporting an association between high level of genomic instability and prolonged survival of high-grade SOC patients, possibly as disturbed genome integrity may lead to increased sensitivity to chemotherapeutic agents.
Highlights
Serous ovarian cancers (SOC) are highly aggressive but often chemosensitive tumours, characterised by substantial morphological heterogeneity, frequent genomic aberrations, and genomic instability
Based on highthroughput DNA copy number data, we investigated the relationship between survival and the degree of genomic instability within two independent datasets of predominantly high-grade serous ovarian cancers (SOC) patients
Frequency of aberrations The analysis of copy number data in serous ovarian cancers revealed that the aberrations in the Norwegian and Australian cohorts were broadly concordant (Figure 2 and Figure 3), with the most frequent gains occurring on chromosome arms 1q, 3q, 8q, and 20q, and the most frequent losses occurring on chromosome arms 4q, 5q, 6 p, 8 p, 13, 16q, 18q, and the whole of the X chromosome (Figure 2)
Summary
Serous ovarian cancers (SOC) are highly aggressive but often chemosensitive tumours, characterised by substantial morphological heterogeneity, frequent genomic aberrations, and genomic instability (see reviews by [1,2,3]). Clinical and pathological classification methods, including tumour grade and the extent of surgical debulking, still fail to fully predict disease progression and patient outcome. Previous studies have identified genomic regions of frequent copy number change and mapped potential driver genes in high grade serous, clear cell, and mucinous ovarian tumours [13,14,15,16]. Amplified genes, including RAB25 and CCNE1, have been associated with clinical parameters including histology, stage of the disease, outcome, or therapy response [17,18,19,20,21,22]. There has been some progress, prediction of clinical outcome for patients with SOC remains imprecise and challenging
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