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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.

Original publication

DOI

10.1002/path.4042

Type

Journal article

Journal

The Journal of pathology

Publication Date

08/2012

Volume

227

Pages

446 - 455

Addresses

Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK. david.bowtell@petermac.org

Keywords

Humans, Adenocarcinoma, Clear Cell, Neoplasms, Cystic, Mucinous, and Serous, Breast Neoplasms, Ovarian Neoplasms, BRCA1 Protein, BRCA2 Protein, DNA, Neoplasm, Gene Rearrangement, Tandem Repeat Sequences, Mutation, Genome, Female, Chromosome Duplication