title: The role of tandem duplicator phenotype in tumour evolution in high-grade serous ovarian cancer.
abstract: High-grade serous ovarian carcinoma (HGSOC) is characterized by genomic instability, ubiquitous TP53 loss, and frequent development of platinum resistance. Loss of homologous recombination (HR) is a mutator phenotype present in 50% of HGSOCs and confers hypersensitivity to platinum treatment. We asked which other mutator phenotypes are present in HGSOC and how they drive the emergence of platinum resistance. We performed whole-genome paired-end sequencing on a model of two HGSOC cases, each consisting of a pair of cell lines established before and after clinical resistance emerged, to describe their structural variants (SVs) and to infer their ancestral genomes as the SVs present within each pair. The first case (PEO1/PEO4), with HR deficiency, acquired translocations and small deletions through its early evolution, but a revertant BRCA2 mutation restoring HR function in the resistant lineage re-stabilized its genome and reduced platinum sensitivity. The second case (PEO14/PEO23) had 216 tandem duplications and did not show evidence of HR or mismatch repair deficiency. By comparing the cell lines to the tissues from which they originated, we showed that the tandem duplicator mutator phenotype arose early in progression in vivo and persisted throughout evolution in vivo and in vitro, which may have enabled continual evolution. From the analysis of SNP array data from 454 HGSOC cases in The Cancer Genome Atlas series, we estimate that 12.8% of cases show patterns of aberrations similar to the tandem duplicator, and this phenotype is mutually exclusive with BRCA1/2 carrier mutations.
authors.affiliation: Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge, CB2 0RE, UK.
authors.forename: Charlotte K Y
authors.initials: CK
authors.lastname: Ng
authors.forename: Susanna L
authors.initials: SL
authors.lastname: Cooke
authors.forename: Kevin
authors.initials: K
authors.lastname: Howe
authors.forename: Scott
authors.initials: S
authors.lastname: Newman
authors.forename: Jian
authors.initials: J
authors.lastname: Xian
authors.forename: Jillian
authors.initials: J
authors.lastname: Temple
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Batty
authors.forename: Jessica C M
authors.initials: JC
authors.lastname: Pole
authors.forename: Simon P
authors.initials: SP
authors.lastname: Langdon
authors.forename: Paul A W
authors.initials: PA
authors.lastname: Edwards
authors.forename: James D
authors.initials: JD
authors.lastname: Brenton
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D019313:BRCA1 Protein / Q000235:genetics; D024682:BRCA2 Protein / Q000235:genetics; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D019143:Evolution, Molecular; D005260:Female; D017353:Gene Deletion; D020440:Gene Duplication; D020022:Genetic Predisposition to Disease; D059765:Homologous Recombination; D006801:Humans; D009154:Mutation; D060787:Neoplasm Grading; D018297:Neoplasms, Cystic, Mucinous, and Serous / Q000235:genetics* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D017671:Platinum Compounds / Q000627:therapeutic use*; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D020080:Tandem Repeat Sequences; D014178:Translocation, Genetic
chemical_list: D000970:Antineoplastic Agents; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D017671:Platinum Compounds