OBJECTIVE: An increasing body of evidence has suggested that epithelial ovarian cancer (EOC) patients can broadly be divided into 2 groups on the basis of histopathologic parameters and molecular profiles. Type 1 tumors are slow-growing tumors with inherent mutations such as KRAS or BRAF mutations, whereas type 2 tumors are more rapidly growing tumors of which many contain TP53 mutations. In the present study, we performed a comprehensive study in a large Danish material to evaluate the clinical importance. MATERIALS AND METHODS: A total of 512 tissue samples were included (430 EOCs, 34 borderline, 28 benign tumors, and 20 normal ovaries). KRAS mutations (codon 12/13) and BRAF codon 600 mutations were analyzed from formalin-fixed paraffin-embedded tissue by ARMS qPCR. p53 expression was examined by immunohistochemistry. RESULTS: Of the EOC patients, 25% had histopathologically classified type 1 tumors, and of these, 44% were either KRAS or BRAF mutated. Of patients with histopathologic type 2 tumors, 66% showed p53 protein overexpression, whereas 4 (1.5%) patients contained a KRAS mutation. In a univariate survival analysis, a large difference in survival was seen between patients with type 1 and type 2 tumors. Patients with type histologic 2 tumors had significantly worse survival compared with patients with type 1 tumors (P < 10). International Federation of Gynecology and Obstetrics (FIGO) stage, tumor grade, residual tumor, and KRAS/BRAF mutation were independent predictors of overall survival in the multivariate analysis. Patients with KRAS/BRAF mutated carcinomas showed independent decreased overall survival with a hazard ratio of 2.01 (95% confidence interval, 1.13-3.57; P = 0.018). CONCLUSIONS: KRAS/BRAF mutations are with very few exceptions constrained to patients with histopathologic type 1 tumors, whereas p53 overexpression is very frequent in type 2 tumors. KRAS/BRAF mutations had independent prognostic importance. The classification presented here should have a major therapeutic implication and serve as a hallmark of future clinical trials.
OBJECTIVE: An increasing body of evidence has suggested that epithelial ovarian cancer (EOC) patients can broadly be divided into 2 groups on the basis of histopathologic parameters and molecular profiles. Type 1 tumors are slow-growing tumors with inherent mutations such as KRAS or BRAF mutations, whereas type 2 tumors are more rapidly growing tumors of which many contain TP53 mutations. In the present study, we performed a comprehensive study in a large Danish material to evaluate the clinical importance. MATERIALS AND METHODS: A total of 512 tissue samples were included (430 EOCs, 34 borderline, 28 benign tumors, and 20 normal ovaries). KRAS mutations (codon 12/13) and BRAF codon 600 mutations were analyzed from formalin-fixed paraffin-embedded tissue by ARMS qPCR. p53 expression was examined by immunohistochemistry. RESULTS: Of the EOC patients, 25% had histopathologically classified type 1 tumors, and of these, 44% were either KRAS or BRAF mutated. Of patients with histopathologic type 2 tumors, 66% showed p53 protein overexpression, whereas 4 (1.5%) patients contained a KRAS mutation. In a univariate survival analysis, a large difference in survival was seen between patients with type 1 and type 2 tumors. Patients with type histologic 2 tumors had significantly worse survival compared with patients with type 1 tumors (P < 10). International Federation of Gynecology and Obstetrics (FIGO) stage, tumor grade, residual tumor, and KRAS/BRAF mutation were independent predictors of overall survival in the multivariate analysis. Patients with KRAS/BRAF mutated carcinomas showed independent decreased overall survival with a hazard ratio of 2.01 (95% confidence interval, 1.13-3.57; P = 0.018). CONCLUSIONS:KRAS/BRAF mutations are with very few exceptions constrained to patients with histopathologic type 1 tumors, whereas p53 overexpression is very frequent in type 2 tumors. KRAS/BRAF mutations had independent prognostic importance. The classification presented here should have a major therapeutic implication and serve as a hallmark of future clinical trials.
Authors: Camilla Sköld; Tone Bjørge; Anders Ekbom; Anders Engeland; Mika Gissler; Tom Grotmol; Laura Madanat-Harjuoja; Anne Gulbech Ording; Olof Stephansson; Britton Trabert; Steinar Tretli; Rebecca Troisi; Henrik Toft Sørensen; Ingrid Glimelius Journal: Int J Cancer Date: 2018-07-10 Impact factor: 7.396
Authors: Sarah R Irvin; Elisabete Weiderpass; Frank Z Stanczyk; Louise A Brinton; Britton Trabert; Hilde Langseth; Nicolas Wentzensen Journal: Cancer Epidemiol Biomarkers Prev Date: 2020-01-13 Impact factor: 4.254
Authors: Elizabeth M Poole; Melissa A Merritt; Susan J Jordan; Hannah P Yang; Susan E Hankinson; Yikung Park; Bernard Rosner; Penelope M Webb; Daniel W Cramer; Nicolas Wentzensen; Kathryn L Terry; Shelley S Tworoger Journal: Cancer Epidemiol Biomarkers Prev Date: 2013-01-10 Impact factor: 4.254
Authors: Renée T Fortner; Elizabeth M Poole; Nicolas A Wentzensen; Britton Trabert; Emily White; Alan A Arslan; Alpa V Patel; V Wendy Setiawan; Kala Visvanathan; Elisabete Weiderpass; Hans-Olov Adami; Amanda Black; Leslie Bernstein; Louise A Brinton; Julie Buring; Tess V Clendenen; Agnès Fournier; Gary Fraser; Susan M Gapstur; Mia M Gaudet; Graham G Giles; Inger T Gram; Patricia Hartge; Judith Hoffman-Bolton; Annika Idahl; Rudolf Kaaks; Victoria A Kirsh; Synnove Knutsen; Woon-Puay Koh; James V Lacey; I-Min Lee; Eva Lundin; Melissa A Merritt; Roger L Milne; N Charlotte Onland-Moret; Ulrike Peters; Jenny N Poynter; Sabina Rinaldi; Kim Robien; Thomas Rohan; Maria-José Sánchez; Catherine Schairer; Leo J Schouten; Anne Tjonneland; Mary K Townsend; Ruth C Travis; Antonia Trichopoulou; Piet A van den Brandt; Paolo Vineis; Lynne Wilkens; Alicja Wolk; Hannah P Yang; Anne Zeleniuch-Jacquotte; Shelley S Tworoger Journal: Int J Cancer Date: 2019-01-14 Impact factor: 7.396
Authors: Nicolas Wentzensen; Elizabeth M Poole; Britton Trabert; Emily White; Alan A Arslan; Alpa V Patel; V Wendy Setiawan; Kala Visvanathan; Elisabete Weiderpass; Hans-Olov Adami; Amanda Black; Leslie Bernstein; Louise A Brinton; Julie Buring; Lesley M Butler; Saioa Chamosa; Tess V Clendenen; Laure Dossus; Renee Fortner; Susan M Gapstur; Mia M Gaudet; Inger T Gram; Patricia Hartge; Judith Hoffman-Bolton; Annika Idahl; Michael Jones; Rudolf Kaaks; Victoria Kirsh; Woon-Puay Koh; James V Lacey; I-Min Lee; Eva Lundin; Melissa A Merritt; N Charlotte Onland-Moret; Ulrike Peters; Jenny N Poynter; Sabina Rinaldi; Kim Robien; Thomas Rohan; Dale P Sandler; Catherine Schairer; Leo J Schouten; Louise K Sjöholm; Sabina Sieri; Anthony Swerdlow; Anna Tjonneland; Ruth Travis; Antonia Trichopoulou; Piet A van den Brandt; Lynne Wilkens; Alicja Wolk; Hannah P Yang; Anne Zeleniuch-Jacquotte; Shelley S Tworoger Journal: J Clin Oncol Date: 2016-06-20 Impact factor: 44.544