DNA copy number profiling reveals extensive genomic loss in hereditary BRCA1 and BRCA2 ovarian carcinomas

Abstract

Background: Few studies have attempted to characterise genomic changes occurring in hereditary epithelial ovarian carcinomas (EOCs) and inconsistent results have been obtained. Given the relevance of DNA copy number alterations in ovarian oncogenesis and growing clinical implications of the BRCA-gene status, we aimed to characterise the genomic profiles of hereditary and sporadic ovarian tumours.

Methods: High-resolution array Comparative Genomic Hybridisation profiling of 53 familial (21 BRCA1, 6 BRCA2 and 26 non-BRCA1/2) and 15 sporadic tumours in combination with supervised and unsupervised analysis was used to define common and/or specific copy number features.

Results: Unsupervised hierarchical clustering did not stratify tumours according to their familial or sporadic condition or to their BRCA1/2 mutation status. Common recurrent changes, spanning genes potentially fundamental for ovarian carcinogenesis, regardless of BRCA mutations, and several candidate subtype-specific events were defined. Despite similarities, greater contribution of losses was revealed to be a hallmark of BRCA1 and BRCA2 tumours.

Conclusion: Somatic alterations occurring in the development of familial EOCs do not differ substantially from the ones occurring in sporadic carcinomas. However, some specific features like extensive genomic loss observed in BRCA1/2 tumours may be of clinical relevance helping to identify BRCA-related patients likely to respond to PARP inhibitors.

Figure 1

(A) Frequency plots of copy number gains (in green) and losses (in red) defined in all carcinomas and subgroups. The proportion of tumours with gained/lost regions is plotted on the y axis versus genomic location on the x axis. Common recurrently altered regions across all four subgroups or present in >55% of the whole series are marked with black arrows on the general plot (for all series), while group-specific regions identified for sporadic, BRCA1 and BRCAX tumours are identified on the corresponding plots with blue arrows. Simplified chromosomal locations are given next to the arrows (using the same colour code). (B) Dendrograms derived from unsupervised hierarchical clustering based on copy number alterations of epithelial ovarian carcinomas (n=68) (left panel) and a subgroup of type II carcinomas (n=31) (right panel) with colour labels defining the familial or sporadic condition of the tumour as well as the BRCA gene mutation status of the sample.

Figure 2

Average number (A–D) and length (E–H) of copy number alterations in different groups of ovarian carcinomas (A, C, E, D) and a subgroup of type II carcinomas (B, D, F, H). Significant differences in number and length of alterations between (A, B, E, F) and within (C, D, G, H) tumour groups are indicated with *(P<0.05) or **(P<0.01). Error bars represent 95% Confidence Intervals. ^aSubgroup of type II carcinomas as defined in Materials and methods.