title: Retinoblastoma pathway deregulatory mechanisms determine clinical outcome in high-grade serous ovarian carcinoma.
abstract: Alterations in the retinoblastoma pathway are frequent in ovarian/tubal high-grade serous cancers, but the mechanism of deregulation and the impact on patient outcome are poorly understood. A cohort of 334 high-grade serous carcinomas was studied by immunohistochemical analysis of RB1, p16, cyclin D1, cyclin E1, and Ki67. Additional detailed analyses including RB1 allelic deletion (n=42), mutation (n=75), methylation (n=31), and SNP array analyses (n=75) were performed on cases with clinical parameters, including age, debulking status, treatment, and clinical outcome. p16/RB1 expression results yielded three distinct clinically relevant subgroups upon multivariable analysis controlling for stage, debulking status, and treatment types: p16 homogeneous/RB1+ with the shortest progression-free survival (median 15 months (95% CI: 13-18); P=0.016) compared with the p16 heterogeneous/RB1+ subgroup (median 22 months (95% CI: 16-32)) and the p16 homogeneous/RB1- subgroup (median 20 months (95% CI: 15-24)). Patients in the p16 homo/RB1- subgroup showed a significant increase in overall survival (>60 months; P=0.013), which suggests an increase in sensitivity to cytotoxic agents. Analyses of Rb pathway mechanistic differences among these groups revealed frequent RB1 genomic alterations such as RB1 allelic loss and/or large spanning deletions (83%) in the p16 homo/RB1- subgroups, also indicating that RB1 deletions are frequent in high-grade serous carcinoma. CCNE1 gene gains/amplifications were frequent in the p16 homogeneous/RB1+ subgroup (68%) and cyclin D1 protein overexpression was predominantly characteristic of the p16 heterogeneous/RB1+ subgroup. These subcategories occur early in tumor progression and are seen with similar frequency in the cancer precursor lesion, serous tubal intra-epithelial carcinoma. Overall, this study uniquely identifies multiple non-synonymous mechanisms of retinoblastoma pathway deregulation that correlate with significantly different clinical outcomes. Furthermore, deregulations identified in precursor lesions suggest a key role of this pathway in serous tumor development. Recognition of these categories may identify patients with increased sensitivity to chemotherapy and new opportunities for novel therapeutics.
authors: 1] Campbell Family Institute for Breast Cancer Research, Toronto, ON, Canada [2] Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada [3] Princess Margaret Cancer Centre, Toronto, ON, Canada [4] Department of Pathology, University Health Network, Toronto, ON, Canada.
authors: Anca
authors: A
authors: Milea
authors: 1] Campbell Family Institute for Breast Cancer Research, Toronto, ON, Canada [2] Princess Margaret Cancer Centre, Toronto, ON, Canada [3] Department of Pathology, University Health Network, Toronto, ON, Canada.
authors: Sophia H L
authors: SH
authors: George
authors: 1] Department of Pathology, University Health Network, Toronto, ON, Canada [2] Impact Genetics, Toronto, ON, Canada.
authors: Donco
authors: D
authors: Matevski
authors: 1] Princess Margaret Cancer Centre, Toronto, ON, Canada [2] Department of Pathology, University Health Network, Toronto, ON, Canada.
authors: Haiyan
authors: H
authors: Jiang
authors: 1] Princess Margaret Cancer Centre, Toronto, ON, Canada [2] Department of Pathology, University Health Network, Toronto, ON, Canada.
authors: Mary
authors: M
authors: Madunic
authors: 1] Campbell Family Institute for Breast Cancer Research, Toronto, ON, Canada [2] Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada [3] Princess Margaret Cancer Centre, Toronto, ON, Canada [4] Department of Pathology, University Health Network, Toronto, ON, Canada.
authors: Hal K
authors: HK
authors: Berman
authors: 1] Campbell Family Institute for Breast Cancer Research, Toronto, ON, Canada [2] Princess Margaret Cancer Centre, Toronto, ON, Canada [3] Department of Pathology, University Health Network, Toronto, ON, Canada [4] Department of Medical Biophyics, University of Toronto, Toronto, ON, Canada.
authors: Mona L
authors: ML
authors: Gauthier
authors: 1] Princess Margaret Cancer Centre, Toronto, ON, Canada [2] Department of Pathology, University Health Network, Toronto, ON, Canada [3] Impact Genetics, Toronto, ON, Canada [4] Department of Medical Biophyics, University of Toronto, Toronto, ON, Canada [5] Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
authors: Brenda
authors: B
authors: Gallie
authors: 1] Campbell Family Institute for Breast Cancer Research, Toronto, ON, Canada [2] Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada [3] Princess Margaret Cancer Centre, Toronto, ON, Canada [4] Department of Pathology, University Health Network, Toronto, ON, Canada.
authors: Patricia A
authors: PA
authors: Shaw
mesh_terms: D000483:Alleles; D014408:Biomarkers, Tumor / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism; D019927:Cyclin E / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D018284:Cystadenocarcinoma, Serous / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D009154:Mutation; D015513:Oncogene Proteins / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D011379:Prognosis; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; C475820:CCNE1 protein, human; D019927:Cyclin E; D019941:Cyclin-Dependent Kinase Inhibitor p16; D015513:Oncogene Proteins; D016160:Retinoblastoma Protein; D019938:Cyclin D1