title: Mutation of ERBB2 provides a novel alternative mechanism for the ubiquitous activation of RAS-MAPK in ovarian serous low malignant potential tumors.
abstract: Approximately, 10% to 15% of serous ovarian tumors fall into the category designated as tumors of low malignant potential (LMP). Like their invasive counterparts, LMP tumors may be associated with extraovarian disease, for example, in the peritoneal cavity and regional lymph nodes. However, unlike typical invasive carcinomas, patients generally have a favorable prognosis. The mutational profile also differs markedly from that seen in most serous carcinomas. Typically, LMP tumors are associated with KRAS and BRAF mutations. Interrogation of expression profiles in serous LMP tumors suggested overall redundancy of RAS-MAPK pathway mutations and a distinct mechanism of oncogenesis compared with high-grade ovarian carcinomas. Our findings indicate that activating mutation of the RAS-MAPK pathway in serous LMP may be present in >70% of cases compared with approximately 12.5% in serous ovarian carcinomas. In addition to mutations of KRAS (18%) and BRAF (48%) mutations, ERBB2 mutations (6%), but not EGFR, are prevalent among serous LMP tumors. Based on the expression profile signature observed throughout our serous LMP cohort, we propose that RAS-MAPK pathway activation is a requirement of serous LMP tumor development and that other activators of this pathway are yet to be defined. Importantly, as few nonsurgical options exist for treatment of recurrent LMP tumors, therapeutic targeting of this pathway may prove beneficial, especially in younger patients where maintaining fertility is important.
authors.affiliation: Peter MacCallum Cancer Centre, Victoria, Australia.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Anglesio
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Arnold
authors.forename: Joshy
authors.initials: J
authors.lastname: George
authors.forename: Anna V
authors.initials: AV
authors.lastname: Tinker
authors.forename: Richard
authors.initials: R
authors.lastname: Tothill
authors.forename: Nic
authors.initials: N
authors.lastname: Waddell
authors.forename: Lisa
authors.initials: L
authors.lastname: Simms
authors.forename: Bianca
authors.initials: B
authors.lastname: Locandro
authors.forename: Sian
authors.initials: S
authors.lastname: Fereday
authors.forename: Nadia
authors.initials: N
authors.lastname: Traficante
authors.forename: Peter
authors.initials: P
authors.lastname: Russell
authors.forename: Raghwa
authors.initials: R
authors.lastname: Sharma
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Birrer
authors.forename: Anna
authors.initials: A
authors.lastname: deFazio
authors.forename: Georgia
authors.initials: G
authors.lastname: Chenevix-Trench
authors.forename: David D L
authors.initials: DD
authors.lastname: Bowtell
mesh_terms: D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004252:DNA Mutational Analysis; D005260:Female; D020869:Gene Expression Profiling; D018773:Genes, erbB-1 / Q000235:genetics / Q000502:physiology; D018734:Genes, erbB-2; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009154:Mutation; D009361:Neoplasm Invasiveness; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D015398:Signal Transduction / Q000235:genetics; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020928:Mitogen-Activated Protein Kinases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins