Mutation of ERBB2 provides a novel alternative mechanism for the ubiquitous activation of RAS-MAPK in ovarian serous low malignant potential tumors

Arnold, JM, George, J, Tinker, AV, Tothill, R, Waddell, N, Simms, L, Locandro, B, Fereday, S, Traficante, N, Birrer, MJ, Defazio, A, Chenevix-Trench, G, Bowtelll, DDL and AOCS Study Grp (2008) Mutation of ERBB2 provides a novel alternative mechanism for the ubiquitous activation of RAS-MAPK in ovarian serous low malignant potential tumors. Molecular Cancer Research, 6 11: 1678-1690. doi:10.1158/1541-7786.MCR-08-0193


Author Arnold, JM
George, J
Tinker, AV
Tothill, R
Waddell, N
Simms, L
Locandro, B
Fereday, S
Traficante, N
Birrer, MJ
Defazio, A
Chenevix-Trench, G
Bowtelll, DDL
AOCS Study Grp
Title Mutation of ERBB2 provides a novel alternative mechanism for the ubiquitous activation of RAS-MAPK in ovarian serous low malignant potential tumors
Journal name Molecular Cancer Research   Check publisher's open access policy
ISSN 1541-7786
Publication date 2008-11-01
Year available 2008
Sub-type Article (original research)
DOI 10.1158/1541-7786.MCR-08-0193
Open Access Status
Volume 6
Issue 11
Start page 1678
End page 1690
Total pages 13
Place of publication United States
Publisher American Association for Cancer Research (AACR)
Language eng
Subject C1
920102 Cancer and Related Disorders
111203 Cancer Genetics
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.
Formatted 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.
Q-Index Code C1
Q-Index Status Provisional Code
Additional Notes Author does not want UQ affiliation receorded for this publication

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Medicine Publications
 
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Created: Thu, 09 Apr 2009, 19:25:42 EST by Amanda Jones on behalf of School of Medicine