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         headline:Combined image and genomic analysis of high-grade serous ovarian cancer reveals PTEN loss as a common driver event and prognostic classifier
         description: 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. 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. 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.
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            Androgen Receptor
            Bacterial Artificial Chromosome
            PTEN Expression
            Androgen Receptor Expression
            PTEN Loss
            Animal Genetics and Genomics
            Human Genetics
            Plant Genetics and Genomics
            Microbial Genetics and Genomics
            Bioinformatics
            Evolutionary Biology
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      headline:Combined image and genomic analysis of high-grade serous ovarian cancer reveals PTEN loss as a common driver event and prognostic classifier
      description: 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. 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. 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.
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         Bacterial Artificial Chromosome
         PTEN Expression
         Androgen Receptor Expression
         PTEN Loss
         Animal Genetics and Genomics
         Human Genetics
         Plant Genetics and Genomics
         Microbial Genetics and Genomics
         Bioinformatics
         Evolutionary Biology
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               type:PostalAddress
            type:Organization
      name:Anne Trinh
      affiliation:
            name:University of Cambridge, Li Ka Shing Centre, Robinson Way
            address:
               name:Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, UK
               type:PostalAddress
            type:Organization
      name:Jian Xian
      affiliation:
            name:University of Cambridge, Li Ka Shing Centre, Robinson Way
            address:
               name:Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, UK
               type:PostalAddress
            type:Organization
      name:Anne Guo
      affiliation:
            name:University of Cambridge, Li Ka Shing Centre, Robinson Way
            address:
               name:Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, UK
               type:PostalAddress
            type:Organization
      name:Karen Sayal
      affiliation:
            name:University of Cambridge, Li Ka Shing Centre, Robinson Way
            address:
               name:Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, UK
               type:PostalAddress
            type:Organization
      name:Mercedes Jimenez-Linan
      affiliation:
            name:Addenbrooke’s Hospital
            address:
               name:Department of Pathology, Addenbrooke’s Hospital, Cambridge, UK
               type:PostalAddress
            type:Organization
            name:National Institute for Health Research Cambridge Biomedical Research Centre
            address:
               name:National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK
               type:PostalAddress
            type:Organization
      name:Suha Deen
      affiliation:
            name:Nottingham University Hospital
            address:
               name:Department of Pathology, Nottingham University Hospital, Nottingham, UK
               type:PostalAddress
            type:Organization
      name:Kristy Driver
      affiliation:
            name:University of Cambridge, 2 Worts’ Causeway
            address:
               name:Strangeways Research Laboratories, University of Cambridge, 2 Worts’ Causeway, Cambridge, UK
               type:PostalAddress
            type:Organization
      name:Marie Mack
      affiliation:
            name:University of Cambridge, 2 Worts’ Causeway
            address:
               name:Strangeways Research Laboratories, University of Cambridge, 2 Worts’ Causeway, Cambridge, UK
               type:PostalAddress
            type:Organization
      name:Jennifer Aslop
      affiliation:
            name:University of Cambridge, 2 Worts’ Causeway
            address:
               name:Strangeways Research Laboratories, University of Cambridge, 2 Worts’ Causeway, Cambridge, UK
               type:PostalAddress
            type:Organization
      name:Paul D Pharoah
      affiliation:
            name:University of Cambridge, 2 Worts’ Causeway
            address:
               name:Strangeways Research Laboratories, University of Cambridge, 2 Worts’ Causeway, Cambridge, UK
               type:PostalAddress
            type:Organization
            name:University of Cambridge, Hutchison/MRC Research Centre
            address:
               name:Department of Oncology, University of Cambridge, Hutchison/MRC Research Centre, Cambridge, UK
               type:PostalAddress
            type:Organization
            name:Cambridge Experimental Cancer Medicine Centre
            address:
               name:Cambridge Experimental Cancer Medicine Centre, Cambridge, UK
               type:PostalAddress
            type:Organization
      name:Florian Markowetz
      affiliation:
            name:University of Cambridge, Li Ka Shing Centre, Robinson Way
            address:
               name:Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, UK
               type:PostalAddress
            type:Organization
      name:James D Brenton
      affiliation:
            name:University of Cambridge, Li Ka Shing Centre, Robinson Way
            address:
               name:Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, UK
               type:PostalAddress
            type:Organization
            name:National Institute for Health Research Cambridge Biomedical Research Centre
            address:
               name:National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK
               type:PostalAddress
            type:Organization
            name:University of Cambridge, Hutchison/MRC Research Centre
            address:
               name:Department of Oncology, University of Cambridge, Hutchison/MRC Research Centre, Cambridge, UK
               type:PostalAddress
            type:Organization
            name:Cambridge Experimental Cancer Medicine Centre
            address:
               name:Cambridge Experimental Cancer Medicine Centre, Cambridge, UK
               type:PostalAddress
            type:Organization
      email:[email protected]
PostalAddress:
      name:Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, UK
      name:Department of Obstetrics and Gynaecology, University of Cambridge, The Rosie Hospital, Robinson Way, Cambridge, UK
      name:Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, UK
      name:Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, UK
      name:Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, UK
      name:Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, UK
      name:Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, UK
      name:Department of Pathology, Addenbrooke’s Hospital, Cambridge, UK
      name:National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK
      name:Department of Pathology, Nottingham University Hospital, Nottingham, UK
      name:Strangeways Research Laboratories, University of Cambridge, 2 Worts’ Causeway, Cambridge, UK
      name:Strangeways Research Laboratories, University of Cambridge, 2 Worts’ Causeway, Cambridge, UK
      name:Strangeways Research Laboratories, University of Cambridge, 2 Worts’ Causeway, Cambridge, UK
      name:Strangeways Research Laboratories, University of Cambridge, 2 Worts’ Causeway, Cambridge, UK
      name:Department of Oncology, University of Cambridge, Hutchison/MRC Research Centre, Cambridge, UK
      name:Cambridge Experimental Cancer Medicine Centre, Cambridge, UK
      name:Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, UK
      name:Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, UK
      name:National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK
      name:Department of Oncology, University of Cambridge, Hutchison/MRC Research Centre, Cambridge, UK
      name:Cambridge Experimental Cancer Medicine Centre, Cambridge, UK

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