Combined image and genomic analysis of high-grade serous ovarian cancer reveals PTEN loss as a common driver event and prognostic classifier

Abstract

BackgroundTP53 and BRCA1/2 mutations are the main drivers in high-grade serous ovarian carcinoma (HGSOC). We hypothesise that combining tissue phenotypes from image analysis of tumour sections with genomic profiles could reveal other significant driver events.ResultsAutomatic estimates of stromal content combined with genomic analysis of TCGA HGSOC tumours show that stroma strongly biases estimates of PTEN expression. Tumour-specific PTEN expression was tested in two independent cohorts using tissue microarrays containing 521 cases of HGSOC. PTEN loss or downregulation occurred in 77% of the first cohort by immunofluorescence and 52% of the validation group by immunohistochemistry, and is associated with worse survival in a multivariate Cox-regression model adjusted for study site, age, stage and grade. Reanalysis of TCGA data shows that hemizygous loss of PTEN is common (36%) and expression of PTEN and expression of androgen receptor are positively associated. Low androgen receptor expression was associated with reduced survival in data from TCGA and immunohistochemical analysis of the first cohort.ConclusionPTEN loss is a common event in HGSOC and defines a subgroup with significantly worse prognosis, suggesting the rational use of drugs to target PI3K and androgen receptor pathways for HGSOC. This work shows that integrative approaches combining tissue phenotypes from images with genomic analysis can resolve confounding effects of tissue heterogeneity and should be used to identify new drivers in other cancers.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-014-0526-8) contains supplementary material, which is available to authorized users.

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“…4A). Because the IHC analysis does not take into account the confounding factor of PTEN expression in the tumor stroma, 18 we also evaluated the association of PD-L1 expression with the PTEN mutation, which may or may not lead to protein loss, and found that PTEN mutational status does not correlate with either PD-L1 expression (P ¼ 1) or PD-1+ TIL expression (P ¼ 1) (Fig. 4B) after false discovery rate correction.…”

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“…1). Structural change is an important mechanism for inactivation of tumour suppressors in HGSOC, through heterozygous and homozygous loss 16 and gene breakage 17 . Approximately 50% of HGSOCs are defective in the homologous recombination (HR) DNA repair pathway 14,18,19 .…”

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“…More recently, ARID1A somatic mutation and concurrent protein expression loss have been identified in up to 50% of endometrioid carcinomas 7. Also, the tumour suppressor PTEN is mutated and the protein lost in almost 70% of endometrioid carcinomas; IHC downregulation for PTEN is also reported in up to 52% of HGSCs due to either homozygous deletion or hemizygous loss 8. Moreover, cyclin E1 expression and CCNE1 amplification have been reported in many HGSCs, but are absent in endometrioid carcinomas 9–11…”