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A gene signature associated with PTEN activation defines good prognosis intermediate risk prostate cancer cases

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dc.contributor.authorOng, C.W.
dc.contributor.authorMaxwell, P.
dc.contributor.authorAlvi, M.A.
dc.contributor.authorMcQuaid, S.
dc.contributor.authorWaugh, D.
dc.contributor.authorMills, I.
dc.contributor.authorSalto Tellez, M.
dc.date.issued2018
dc.description.abstractAccurate identification of intermediate risk (Gleason 3+4=7) prostate cancer patients with low risk of disease progression is an unmet challenge in treatment decision making. Here we describe a gene signature that could guide clinicians in the selection of patients with intermediate stage clinically localized prostate cancer for active surveillance. We examined six major drivers of aggressive disease - PTEN, MYC, RB1, TP53, AURKA, AR - by immunohistochemistry in a focused (N=69) cohort predominantly consisting of intermediate risk prostate cancer. Fuzzy clustering and unsupervised hierarchical clustering were utilized to determine the correlation of gene expression and methylation values with immunohistochemical expression. From the immunohistochemistry observation, we found that intermediate risk prostate cancer cases could be classified as 'complex' (differential expression of more than one driver) or 'simple' (differential expression of only one). Focussing on the 'simple' cases, expression and methylation profiling generated signatures which correlated tightly only with differential PTEN expression and not with any of the other drivers assessed by immunohistochemistry. From this, we derived a geneset of 35 genes linked to high PTEN expression. Subsequently we determined its prognostic significance in intermediate-risk cases extracted from three publicly available clinical datasets (Total N=215). Hence, this study shows that, by using immunohistochemistry as an upfront stratifier of intermediate risk prostate cancers, it is possible to identify through differential gene expression profiling a geneset with prognostic power across multiple cohorts. This strategy has not been used previously and the signature has the potential to impact on treatment decisions in patients for whom decision making is currently empirical at best.
dc.identifier.citationThe Journal of Pathology: Clinical Research, 2018; 4(2):103-113
dc.identifier.doi10.1002/cjp2.94
dc.identifier.issn2056-4538
dc.identifier.issn2056-4538
dc.identifier.urihttps://hdl.handle.net/11541.2/34024
dc.language.isoen
dc.publisherWiley-Blackwell Publishing
dc.relation.fundingMedical Research Council MR/J007641/1
dc.relation.fundingCancer Research UK
dc.relation.fundingPublic Health Agency SPI/3315/06
dc.rightsCopyright 2018 The Authors The Journal of Pathology: Clinical Research published by The Pathological Society of Great Britain and Ireland and John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)
dc.source.urihttps://doi.org/10.1002/cjp2.94
dc.subjectgene signature
dc.subjectprognostic
dc.subjectprostate cancer
dc.titleA gene signature associated with PTEN activation defines good prognosis intermediate risk prostate cancer cases
dc.typeJournal article
pubs.publication-statusPublished
ror.fileinfo12262890240001831 13262890230001831 A gene signature associated with PTEN activation defines good prognosis intermediate risk prostate cancer cases
ror.mmsid9916738431201831

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