title: Tandem duplication of chromosomal segments is common in ovarian and breast cancer genomes.
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.
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK. david.bowtell@petermac.org
authors.forename: David J
authors.initials: DJ
authors.lastname: McBride
authors.forename: Dariush
authors.initials: D
authors.lastname: Etemadmoghadam
authors.forename: Susanna L
authors.initials: SL
authors.lastname: Cooke
authors.forename: Kathryn
authors.initials: K
authors.lastname: Alsop
authors.forename: Joshy
authors.initials: J
authors.lastname: George
authors.forename: Adam
authors.initials: A
authors.lastname: Butler
authors.forename: Juok
authors.initials: J
authors.lastname: Cho
authors.forename: Danushka
authors.initials: D
authors.lastname: Galappaththige
authors.forename: Chris
authors.initials: C
authors.lastname: Greenman
authors.forename: Karen D
authors.initials: KD
authors.lastname: Howarth
authors.forename: King W
authors.initials: KW
authors.lastname: Lau
authors.forename: Charlotte K
authors.initials: CK
authors.lastname: Ng
authors.forename: Keiran
authors.initials: K
authors.lastname: Raine
authors.forename: Jon
authors.initials: J
authors.lastname: Teague
authors.forename: David C
authors.initials: DC
authors.lastname: Wedge
authors.forename: Australian Ovarian
authors.initials: AO
authors.lastname: Cancer Study Group
authors.forename: Xavier
authors.initials: X
authors.lastname: Caubit
authors.forename: Michael R
authors.initials: MR
authors.lastname: Stratton
authors.forename: James D
authors.initials: JD
authors.lastname: Brenton
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Campbell
authors.forename: P Andrew
authors.initials: PA
authors.lastname: Futreal
authors.forename: David Dl
authors.initials: DD
authors.lastname: Bowtell
mesh_terms: D018262:Adenocarcinoma, Clear Cell / Q000235:genetics / Q000473:pathology; D019313:BRCA1 Protein / Q000235:genetics; D024682:BRCA2 Protein / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D058674:Chromosome Duplication / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics*; D005260:Female; D015321:Gene Rearrangement / Q000235:genetics; D016678:Genome / Q000235:genetics*; D006801:Humans; D009154:Mutation / Q000235:genetics; D018297:Neoplasms, Cystic, Mucinous, and Serous / Q000235:genetics / Q000473:pathology; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D020080:Tandem Repeat Sequences / Q000235:genetics*
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D004273:DNA, Neoplasm