title: Genomic classification of serous ovarian cancer with adjacent borderline differentiates RAS pathway and TP53-mutant tumors and identifies NRAS as an oncogenic driver.
abstract: OBJECTIVE
  Low-grade serous ovarian carcinomas (LGSC) are Ras pathway-mutated, TP53 wild-type, and frequently associated with borderline tumors. Patients with LGSCs respond poorly to platinum-based chemotherapy and may benefit from pathway-targeted agents. High-grade serous carcinomas (HGSC) are TP53-mutated and are thought to be rarely associated with borderline tumors. We sought to determine whether borderline histology associated with grade 2 or 3 carcinoma was an indicator of Ras mutation, and we explored the molecular relationship between coexisting invasive and borderline histologies.
  
  
  METHODS
  We reviewed >1,200 patients and identified 102 serous carcinomas with adjacent borderline regions for analyses, including candidate mutation screening, copy number, and gene expression profiling.
  
  
  RESULTS
  We found a similar frequency of low, moderate, and high-grade carcinomas with coexisting borderline histology. BRAF/KRAS alterations were common in LGSC; however, we also found recurrent NRAS mutations. Whereas borderline tumors harbored BRAF/KRAS mutations, NRAS mutations were restricted to carcinomas, representing the first example of a Ras oncogene with an obligatory association with invasive serous cancer. Coexisting borderline and invasive components showed nearly identical genomic profiles. Grade 2 cases with coexisting borderline included tumors with molecular features of LGSC, whereas others were typical of HGSC. However, all grade 3 carcinomas with coexisting borderline histology were molecularly indistinguishable from typical HGSC.
  
  
  CONCLUSIONS
  Our findings suggest that NRAS is an oncogenic driver in serous ovarian tumors. We demonstrate that borderline histology is an unreliable predictor of Ras pathway aberration and underscore an important role for molecular classification in identifying patients that may benefit from targeted agents.
authors.affiliation: Department of Gynaecological Oncology, Westmead Hospital, Sydney, New South Wales, Australia. Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, New South Wales, Australia. University of Sydney, Westmead Hospital, Sydney, New South Wales, Australia. Westmead Institute for Cancer Research, Westmead Millennium Institute, Westmead Hospital, Sydney, New South Wales, Australia.
authors.forename: Catherine
authors.initials: C
authors.lastname: Emmanuel
authors.affiliation: Department of Gynaecological Oncology, Westmead Hospital, Sydney, New South Wales, Australia. Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, New South Wales, Australia. Westmead Institute for Cancer Research, Westmead Millennium Institute, Westmead Hospital, Sydney, New South Wales, Australia.
authors.forename: Yoke-Eng
authors.initials: YE
authors.lastname: Chiew
authors.affiliation: Cancer Genomics Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors.forename: Joshy
authors.initials: J
authors.lastname: George
authors.affiliation: Cancer Genomics Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Sir Peter MacCallum Cancer Centre, Department of Oncology, University of Melbourne, Parkville, Victoria, Australia. Department of Pathology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Dariush
authors.initials: D
authors.lastname: Etemadmoghadam
authors.affiliation: Cancer Genomics Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Anglesio
authors.affiliation: University of Sydney, Westmead Hospital, Sydney, New South Wales, Australia. Pathology West ICPMR Westmead, Sydney, New South Wales, Australia. University of Western Sydney at Westmead Hospital, Westmead, New South Wales, Australia.
authors.forename: Raghwa
authors.initials: R
authors.lastname: Sharma
authors.affiliation: Department of Obstetrics, Gynaecology and Neonatology, University of Sydney, Camperdown New South Wales, Australia. Douglass Hanly Moir Pathology, Macquarie Park, New South Wales, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Russell
authors.affiliation: Department of Gynaecological Oncology, Westmead Hospital, Sydney, New South Wales, Australia. Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, New South Wales, Australia. University of Sydney, Westmead Hospital, Sydney, New South Wales, Australia. Westmead Institute for Cancer Research, Westmead Millennium Institute, Westmead Hospital, Sydney, New South Wales, Australia.
authors.forename: Catherine
authors.initials: C
authors.lastname: Kennedy
authors.affiliation: Cancer Genomics Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors.forename: Sian
authors.initials: S
authors.lastname: Fereday
authors.affiliation: Department of Gynaecological Oncology, Westmead Hospital, Sydney, New South Wales, Australia. Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, New South Wales, Australia. Westmead Institute for Cancer Research, Westmead Millennium Institute, Westmead Hospital, Sydney, New South Wales, Australia.
authors.forename: Jillian
authors.initials: J
authors.lastname: Hung
authors.affiliation: Cancer Genomics Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors.forename: Laura
authors.initials: L
authors.lastname: Galletta
authors.affiliation: Department of Gynaecological Oncology, Westmead Hospital, Sydney, New South Wales, Australia. Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, New South Wales, Australia. University of Sydney, Westmead Hospital, Sydney, New South Wales, Australia.
authors.forename: Russell
authors.initials: R
authors.lastname: Hogg
authors.affiliation: Department of Gynaecological Oncology, Westmead Hospital, Sydney, New South Wales, Australia. Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, New South Wales, Australia. University of Sydney, Westmead Hospital, Sydney, New South Wales, Australia.
authors.forename: Gerard V
authors.initials: GV
authors.lastname: Wain
authors.affiliation: Department of Gynaecological Oncology, Westmead Hospital, Sydney, New South Wales, Australia. Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, New South Wales, Australia. University of Sydney, Westmead Hospital, Sydney, New South Wales, Australia.
authors.forename: Alison
authors.initials: A
authors.lastname: Brand
authors.affiliation: University of Sydney, Westmead Hospital, Sydney, New South Wales, Australia. Westmead Institute for Cancer Research, Westmead Millennium Institute, Westmead Hospital, Sydney, New South Wales, Australia. Pathology West ICPMR Westmead, Sydney, New South Wales, Australia.
authors.forename: Rosemary
authors.initials: R
authors.lastname: Balleine
authors.affiliation: Dana-Faber Cancer Institute, Boston, Massachusetts.
authors.forename: Laura
authors.initials: L
authors.lastname: MacConaill
authors.affiliation: Dana-Faber Cancer Institute, Boston, Massachusetts.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Palescandolo
authors.affiliation: Cancer Genomics Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors.forename: Sally M
authors.initials: SM
authors.lastname: Hunter
authors.affiliation: Cancer Genomics Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Department of Pathology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Ian
authors.initials: I
authors.lastname: Campbell
authors.affiliation: Cancer Genomics Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Department of Pathology, University of Melbourne, Parkville, Victoria, Australia. School of Cancer Medicine, La Trobe University, Bundoora, Victoria, Australia.
authors.forename: Alexander
authors.initials: A
authors.lastname: Dobrovic
authors.affiliation: Cancer Genomics Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Department of Pathology, University of Melbourne, Parkville, Victoria, Australia. School of Cancer Medicine, La Trobe University, Bundoora, Victoria, Australia.
authors.forename: Stephen Q
authors.initials: SQ
authors.lastname: Wong
authors.affiliation: Cancer Genomics Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors.forename: Hongdo
authors.initials: H
authors.lastname: Do
authors.affiliation: University of Sydney, Westmead Hospital, Sydney, New South Wales, Australia. Westmead Institute for Cancer Research, Westmead Millennium Institute, Westmead Hospital, Sydney, New South Wales, Australia.
authors.forename: Christine L
authors.initials: CL
authors.lastname: Clarke
authors.affiliation: Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, New South Wales, Australia. University of Sydney, Westmead Hospital, Sydney, New South Wales, Australia. Westmead Institute for Cancer Research, Westmead Millennium Institute, Westmead Hospital, Sydney, New South Wales, Australia.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Harnett
authors.affiliation: Cancer Genomics Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Sir Peter MacCallum Cancer Centre, Department of Oncology, University of Melbourne, Parkville, Victoria, Australia. Department of Pathology, University of Melbourne, Parkville, Victoria, Australia. Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria, Australia. Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, London, United Kingdom.
authors.forename: David D L
authors.initials: DD
authors.lastname: Bowtell
authors.affiliation: Department of Gynaecological Oncology, Westmead Hospital, Sydney, New South Wales, Australia. Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, New South Wales, Australia. University of Sydney, Westmead Hospital, Sydney, New South Wales, Australia. Westmead Institute for Cancer Research, Westmead Millennium Institute, Westmead Hospital, Sydney, New South Wales, Australia. anna.defazio@sydney.edu.au.
authors.forename: Anna
authors.initials: A
authors.lastname: deFazio
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D016000:Cluster Analysis; D015331:Cohort Studies; D018284:Cystadenocarcinoma, Serous / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D056915:DNA Copy Number Variations; D005260:Female; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D055815:Young Adult; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism*
chemical_list: D011980:Receptors, Progesterone; D016159:Tumor Suppressor Protein p53; D018631:ras Proteins