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Distinct evolutionary trajectories of primary high‐grade serous ovarian cancers revealed through spatial mutational profiling
Author(s) -
Bashashati Ali,
Ha Gavin,
Tone Alicia,
Ding Jiarui,
Prentice Leah M,
Roth Andrew,
Rosner Jamie,
Shumansky Karey,
Kalloger Steve,
Senz Janine,
Yang Winnie,
McConechy Melissa,
Melnyk Nataliya,
Anglesio Michael,
Luk Margaret TY,
Tse Kane,
Zeng Thomas,
Moore Richard,
Zhao Yongjun,
Marra Marco A,
Gilks Blake,
Yip Stephen,
Huntsman David G,
McAlpine Jessica N,
Shah Sohrab P
Publication year - 2013
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.4230
Subject(s) - biology , serous fluid , ovarian cancer , copy number analysis , amplicon , fallopian tube , copy number variation , somatic evolution in cancer , exome , exome sequencing , germline mutation , genetics , mutation , gene , cancer , genome , polymerase chain reaction , biochemistry , anatomy
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. © 2013 The Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.