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Decoding transcriptomic intra‐tumour heterogeneity to guide personalised medicine in ovarian cancer
Author(s) -
Tan Tuan Zea,
Heong Valerie,
Ye Jieru,
Lim Diana,
Low Jeffrey,
Choolani Mahesh,
Scott Clare,
Tan David Shao Peng,
Huang Ruby YunJu
Publication year - 2019
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.5191
Subject(s) - transcriptome , ovarian cancer , oncology , pathological , tumour heterogeneity , metastasis , biology , overall survival , cancer , medicine , genetic heterogeneity , bioinformatics , computational biology , cancer research , phenotype , gene , genetics , gene expression
The evaluation of intra‐tumour heterogeneity (ITH) from a transcriptomic point of view is limited. Single‐cell cancer studies reveal significant genomic and transcriptomic ITH within a tumour and it is no longer adequate to employ single‐subtype assignment as this does not acknowledge the ITH that exists. Molecular assessment of subtype heterogeneity (MASH) was developed to comprehensively report on the composition of all transcriptomic subtypes within a tumour lesion. Using MASH on 3431 ovarian cancer samples, correlation and association analyses with survival, metastasis and clinical outcomes were performed to assess the impact of subtype composition as a surrogate for ITH. The association was validated on two independent cohorts. We identified that 30% of ovarian tumours consist of two or more subtypes. When biological features of the subtype constituents were examined, we identified significant impact on clinical outcomes with the presence of poor prognostic subtypes (Mes or Stem‐A). Poorer outcomes correlated with having higher degrees of poor prognostic subtype populations within the tumour. Subtype prediction in several independent datasets reflected a similar prognostic trend. In addition, paired analysis of primary and recurrent/metastatic tumours demonstrated Mes and/or Stem‐A subtypes predominated in recurrent and metastatic tumours regardless of the original primary subtype. Given the biological and prognostic value in delineating individual subtypes within a tumour, a clinically applicable MASH assay using NanoString ® technology was developed as a classification tool to comprehensively describe constituents of molecular subtypes. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.