title: Combined image and genomic analysis of high-grade serous ovarian cancer reveals PTEN loss as a common driver event and prognostic classifier.
abstract: BACKGROUND
  TP53 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.
  
  
  RESULTS
  Automatic 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.
  
  
  CONCLUSIONS
  PTEN 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.
authors.forename: Filipe C
authors.initials: FC
authors.lastname: Martins
authors.forename: Ines de
authors.initials: Id
authors.lastname: Santiago
authors.forename: Anne
authors.initials: A
authors.lastname: Trinh
authors.forename: Jian
authors.initials: J
authors.lastname: Xian
authors.forename: Anne
authors.initials: A
authors.lastname: Guo
authors.forename: Karen
authors.initials: K
authors.lastname: Sayal
authors.forename: Mercedes
authors.initials: M
authors.lastname: Jimenez-Linan
authors.forename: Suha
authors.initials: S
authors.lastname: Deen
authors.forename: Kristy
authors.initials: K
authors.lastname: Driver
authors.forename: Marie
authors.initials: M
authors.lastname: Mack
authors.forename: Jennifer
authors.initials: J
authors.lastname: Aslop
authors.forename: Paul D
authors.initials: PD
authors.lastname: Pharoah
authors.forename: Florian
authors.initials: F
authors.lastname: Markowetz
authors.forename: James D
authors.initials: JD
authors.lastname: Brenton
mesh_terms: D000368:Aged; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018284:Cystadenocarcinoma, Serous / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D023281:Genomics / Q000379:methods*; D006801:Humans; D008875:Middle Aged; D009375:Neoplasms, Glandular and Epithelial / Q000378:metabolism* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D011379:Prognosis; D011944:Receptors, Androgen / Q000378:metabolism; D046888:Tissue Array Analysis
chemical_list: C410798:AR protein, human; D011944:Receptors, Androgen; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human