Microsatellite Instability and K-Ras Mutation Analysis in Tamoxifen-Associated High Grade Endometrial Cancer
Rebecca Buell-Gutbrod, Diane Yamada, Ana Tergas, Poluru Reddy, Loren Joseph, Katja Gwin. University of Chicago, Chicago, IL
Background: Tamoxifen (TAM), a selective estrogen receptor modulator, is widely used in breast carcinoma therapy. The effects of TAM on the endometrium have been attributed to partial agonist activity of estrogen receptors; however, TAM patients are also at increased risk for developing type II endometrial carcinomas. While the mechanism of TAM induced tumorigenesis is unknown, several genetic alterations have been identified in endometrial carcinoma. K-ras mutations result in constitutively active signal transduction pathways and are seen in up to 30% of endometrial carcinomas. Microsatellite instability (MSI), an indicator of the functionality of DNA mismatch repair, is found in up to 40% of endometrial carcinoma. We performed k-ras mutation and MSI analysis on high grade endometrial tumors, associated with a history of TAM use, and compared them to a matched control group.
Design: Tumor tissue from 13 high grade endometrial carcinomas (malignant mixed mullerian tumor (MMMT)=7, serous=5, grade III endometrioid=1) arising in patients previously treated with TAM for breast cancer (mean duration of TAM treatment 6 years, range 2-12 years), and 13 controls, matched for age, tumor type, and stage, were microdissected and genomic DNA extracted. K-ras mutation analysis was performed via melting curve analysis. MSI was evaluated using the fluorescent multiplex PCR-based MSI Analysis System with seven consensus markers.
Results: Mutation of k-ras was found in 8/13 (62%) cases with a history of antecedent TAM use. Of these, MMMTs comprised the majority with five cases (72% of TAM-MMMTs). K-ras mutation was also found in three serous carcinomas (60% TAM-serous carcinomas). No k-ras mutation was found in the endometrioid carcinoma. In the control group, k-ras mutations were seen in 5/12 (42%) cases. These included four MMMTs (57% of control-MMMTs) and one serous carcinoma (25% of control serous carcinomas). One control serous carcinoma could not be analyzed.
MSI analysis of the cases with history of TAM use revealed no MSI-H tumor and one MSI-L serous carcinoma (7.7%). In the control group, one MSI-H MMMT (7.7%) and one MSI-L serous carcinoma (7.7%) were found.
Conclusions: TAM-associated high grade endometrial carcinomas revealed more k-ras mutations than the control group. Additionally, k-ras mutations segregated with the histologic subtype and were more frequently found in MMMTs. This applied to both the TAM and control group. No significant differences in MSI were observed between the TAM-associated and the sporadic tumors.
Category: Gynecologic & Obstetrics
Monday, March 19, 2012 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 180, Monday Morning