title: Distinct evolutionary trajectories of primary high-grade serous ovarian cancers revealed through spatial mutational profiling.
abstract: High-grade serous ovarian cancer (HGSC) is characterized by poor outcome, often attributed to the emergence of treatment-resistant subclones. We sought to measure the degree of genomic diversity within primary, untreated HGSCs to examine the natural state of tumour evolution prior to therapy. We performed exome sequencing, copy number analysis, targeted amplicon deep sequencing and gene expression profiling on 31 spatially and temporally separated HGSC tumour specimens (six patients), including ovarian masses, distant metastases and fallopian tube lesions. We found widespread intratumoural variation in mutation, copy number and gene expression profiles, with key driver alterations in genes present in only a subset of samples (eg PIK3CA, CTNNB1, NF1). On average, only 51.5% of mutations were present in every sample of a given case (range 10.2-91.4%), with TP53 as the only somatic mutation consistently present in all samples. Complex segmental aneuploidies, such as whole-genome doubling, were present in a subset of samples from the same individual, with divergent copy number changes segregating independently of point mutation acquisition. Reconstruction of evolutionary histories showed one patient with mixed HGSC and endometrioid histology, with common aetiologic origin in the fallopian tube and subsequent selection of different driver mutations in the histologically distinct samples. In this patient, we observed mixed cell populations in the early fallopian tube lesion, indicating that diversity arises at early stages of tumourigenesis. Our results revealed that HGSCs exhibit highly individual evolutionary trajectories and diverse genomic tapestries prior to therapy, exposing an essential biological characteristic to inform future design of personalized therapeutic solutions and investigation of drug-resistance mechanisms.
authors.affiliation: Department of Molecular Oncology, British Columbia Cancer Agency, Vancouver, BC, Canada.
authors.forename: Ali
authors.initials: A
authors.lastname: Bashashati
authors.forename: Gavin
authors.initials: G
authors.lastname: Ha
authors.forename: Alicia
authors.initials: A
authors.lastname: Tone
authors.forename: Jiarui
authors.initials: J
authors.lastname: Ding
authors.forename: Leah M
authors.initials: LM
authors.lastname: Prentice
authors.forename: Andrew
authors.initials: A
authors.lastname: Roth
authors.forename: Jamie
authors.initials: J
authors.lastname: Rosner
authors.forename: Karey
authors.initials: K
authors.lastname: Shumansky
authors.forename: Steve
authors.initials: S
authors.lastname: Kalloger
authors.forename: Janine
authors.initials: J
authors.lastname: Senz
authors.forename: Winnie
authors.initials: W
authors.lastname: Yang
authors.forename: Melissa
authors.initials: M
authors.lastname: McConechy
authors.forename: Nataliya
authors.initials: N
authors.lastname: Melnyk
authors.forename: Michael
authors.initials: M
authors.lastname: Anglesio
authors.forename: Margaret T Y
authors.initials: MT
authors.lastname: Luk
authors.forename: Kane
authors.initials: K
authors.lastname: Tse
authors.forename: Thomas
authors.initials: T
authors.lastname: Zeng
authors.forename: Richard
authors.initials: R
authors.lastname: Moore
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Zhao
authors.forename: Marco A
authors.initials: MA
authors.lastname: Marra
authors.forename: Blake
authors.initials: B
authors.lastname: Gilks
authors.forename: Stephen
authors.initials: S
authors.lastname: Yip
authors.forename: David G
authors.initials: DG
authors.lastname: Huntsman
authors.forename: Jessica N
authors.initials: JN
authors.lastname: McAlpine
authors.forename: Sohrab P
authors.initials: SP
authors.lastname: Shah
mesh_terms: D000368:Aged; D002999:Clone Cells; D018284:Cystadenocarcinoma, Serous / Q000235:genetics* / Q000556:secondary; D004252:DNA Mutational Analysis / Q000379:methods*; D018450:Disease Progression; D004351:Drug Resistance; D005260:Female; D018628:Gene Dosage; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D060888:Real-Time Polymerase Chain Reaction
keywords: clonal evolution; high-grade serous ovarian cancer; intratumoural heterogeneity