Tandem duplication of chromosomal segments is common in ovarian and breast cancer genomes

Dariush Etemadmoghadam,Keiran Raine,David D Bowtell ,Chris Greenman,Joshy George,P Andrew Futreal ,Kathryn Alsop,Jon W Teague ,James D Brenton ,Australian Ovarian Cancer Study Group,Charlotte K.y Ng ,Karen Howarth ,Peter J Campbell ,Xavier Caubit,David C Wedge ,Juok Cho,Michael R Stratton ,King Wai Lau ,Danushka Galappaththige,Susanna L Cooke ,Adam Butler,David J Mcbride

doi:10.1002/path.4042

Abstract

The application of paired-end next generation sequencing approaches has made it possible to systematically characterize rearrangements of the cancer genome to base-pair level. Utilizing this approach, we report the first detailed analysis of ovarian cancer rearrangements, comparing high-grade serous and clear cell cancers, and these histotypes with other solid cancers. Somatic rearrangements were systematically characterized in eight high-grade serous and five clear cell ovarian cancer genomes and we report here the identification of > 600 somatic rearrangements. Recurrent rearrangements of the transcriptional regulator gene, TSHZ3, were found in three of eight serous cases. Comparison to breast, pancreatic and prostate cancer genomes revealed that a subset of ovarian cancers share a marked tandem duplication phenotype with triple-negative breast cancers. The tandem duplication phenotype was not linked to BRCA1/2 mutation, suggesting that other common mechanisms or carcinogenic exposures are operative. High-grade serous cancers arising in women with germline BRCA1 or BRCA2 mutation showed a high frequency of small chromosomal deletions. These findings indicate that BRCA1/2 germline mutation may contribute to widespread structural change and that other undefined mechanism(s), which are potentially shared with triple-negative breast cancer, promote tandem chromosomal duplications that sculpt the ovarian cancer genome. Copyright © 2012 Pathological Society of Great Britain and Ireland.

Highlights

Acquired structural genomic rearrangements are common in most solid cancers and are especially so in ovarian cancer [1]
To identify DNA rearrangements in ovarian cancer genomes, we carried out paired end sequencing of tumour DNA from 13 ovarian tumour samples
Putative structural rearrangements were identified from incorrectly mapping read pairs [18,23] and 634 confirmed somatically acquired DNA rearrangements were identified across 13 ovarian cancers, with base pair sequence level resolution of 598 individual breakpoints (94%; see Supporting information, Table S2)

Summary

Introduction

Acquired structural genomic rearrangements are common in most solid cancers and are especially so in ovarian cancer [1]. Ovarian cancer is a collective term for a number of distinctly different histotypes and tumours of varying degrees of malignancy [2]. The most common epithelial ovarian cancer histotypes include serous, clear cell, mucinous and endometrioid. High-grade serous cancers (HGSCs) are the most common, accounting for Increasingly comprehensive genomic analyses of HGSCs and clear cell cancers are providing insights into pathways of transformation and the molecular determinants of response to therapy. Our previous gene expression profiling of HGSCs identified four molecular subtypes [3], which are associated with different clinical outcomes [3,4]. A signalling pathway involving MYCN, LIN28B and LET7 is associated with one of the four subtypes [4], suggesting that specific pathway activation may drive the development and

Methods

Results

Conclusion