Mutation of ERBB2 Provides a Novel Alternative Mechanism for the Ubiquitous Activation of RAS-MAPK in Ovarian Serous Low Malignant Potential Tumors

被引:94
作者
Anglesio, Michael S. [1 ]
Arnold, Jeremy M. [2 ]
George, Joshy [1 ]
Tinker, Anna V. [3 ]
Tothill, Richard [1 ]
Waddell, Nic [2 ]
Simms, Lisa [2 ]
Locandro, Bianca [1 ]
Fereday, Sian [1 ]
Traficante, Nadia [1 ]
Russell, Peter [4 ]
Sharma, Raghwa [5 ]
Birrer, Michael J. [8 ]
deFazio, Anna [6 ,7 ]
Chenevix-Trench, Georgia [2 ]
Bowtelll, David D. L. [1 ]
机构
[1] Peter MacCallum Canc Ctr, Melbourne, Vic 8006, Australia
[2] Queensland Inst Med Res, Brisbane, Qld 4006, Australia
[3] British Columbia Canc Agcy, Vancouver Ctr, Dept Oncol, Vancouver, BC V5Z 4E6, Canada
[4] Univ Sydney, Dept Pathol, Royal Prince Alfred Hosp, Dept Anat Pathol, Sydney, NSW 2006, Australia
[5] Westmead Hosp, Dept Anat Pathol, Sydney, NSW, Australia
[6] Univ Sydney, Westmead Millennium Inst, Westmead Hosp, Westmead Inst Canc Res, Sydney, NSW 2006, Australia
[7] Westmead Hosp, Dept Gynaecol Oncol, Sydney, NSW, Australia
[8] NCI, Ctr Canc Res, Bethesda, MD 20892 USA
关键词
D O I
10.1158/1541-7786.MCR-08-0193
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 similar to 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. (Mol Cancer Res 2008;6(11):1678-90)
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收藏
页码:1678 / 1690
页数:13
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