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Loss of p16INK4A Expression in Low-grade Ovarian Serous Carcinomas

Schlosshauer, Peter W. M.D.; Deligdisch, Liane M.D.; Penault-Llorca, Frédérique M.D.; Fatemi, Delaram M.D.; Qiao, Rui M.D.; Yao, Shen M.D.; Pearl, Meghan B.A.; Yang, Zhen M.Sc.; Sheng, Tao M.D., M.Sc.; Dong, Jianli M.D., Ph.D.

International Journal of Gynecological Pathology: January 2011 - Volume 30 - Issue 1 - p 22–29
doi: 10.1097/PGP.0b013e3181ed89b3

According to a tumor progression model, low-grade ovarian serous carcinomas may evolve from serous borderline tumors or micropapillary tumors. We sought to investigate the role of and associations between BRAF mutational status, extracellular signal regulated kinase activation, and p16INK4A expression in various types of ovarian serous tumors. We analyzed 29 typical ovarian serous borderline tumors, 8 micropapillary tumors, 4 low-grade invasive ovarian serous carcinomas, and 24 high-grade invasive ovarian serous carcinomas for the BRAF mutational status at codon 600; in addition, expression levels of the downstream signaling protein extracellular signal regulated kinase and the p16INK4A tumor suppressor protein were assessed by immunohistochemistry. There was a decline in p16INK4A expression from serous borderline tumors to micropapillary tumors with almost complete loss in low-grade invasive carcinomas. High-grade carcinomas had a variable p16INK4A expression pattern. We found a T1799A BRAF mutation in 12 typical serous borderline tumors (41%) and 1 micropapillary tumor (12.5%). No mutations were found in the low-grade and high-grade invasive carcinomas (0%). Among the typical borderline tumors, cases with BRAF mutations tended to have stronger p16INK4A expression compared with cases with wild-type BRAF. No other correlations were identified between the BRAF mutational status and expression levels of the analyzed proteins. Loss of p16INK4A expression may be a pathogenetic factor in the progression from serous borderline tumors to low-grade invasive carcinomas. The divergent molecular profiles support the theory that high-grade carcinomas are unrelated to serous borderline tumors or low-grade carcinomas.

Department of Pathology (P.W.S., L.D., D.F., R.Q., S.Y., M.P.), Mount Sinai School of Medicine, New York, NY

Department of Pathology (F.P.), Centre Jean Perrin, Clermont-Ferrand, France

Department of Pathology (Z.Y., T.S., J.D.), University of Texas Medical Branch, Galveston, TX

Address correspondence and reprint requests to Peter W. Schlosshauer, MD, The Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1194, New York, NY 10029. e-mail:

©2011International Society of Gynecological Pathologists