TY - JOUR
T1 - Microsatellite instability, MLH1 promoter methylation, and loss of mismatch repair in endometrial cancer and concomitant atypical hyperplasia
AU - Horowitz, N.
AU - Pinto, K.
AU - Mutch, D. G.
AU - Herzog, T. J.
AU - Rader, J. S.
AU - Gibb, R.
AU - Bocker-Edmonston, T.
AU - Goodfellow, P. J.
N1 - Funding Information:
This work was supported by CA71754 (P.J.G.) and P30 CA91842 to the Alvin J. Siteman Cancer Center at Washington University. We thank Dr. Mark Watson, Siteman Cancer Center Tumor Procurement Core, for his assistance with laser capture microdissection, and Drs. Richard Fishel and Juan P. Palazzo, Kimmel Cancer Center, Thomas Jefferson University, for their help with immunohistochemistry. We also thank Tonia Thompson for typing this manuscript and Christina Menke for helping with the MSI analyses.
PY - 2002
Y1 - 2002
N2 - Objective. MLH1 methylation is associated with the microsatel-lite instability (MSI) phenotype in endometrial cancer and atypical endometrial hyperplasia, a premalignant precursor to carcinoma. The observation that methylation is also seen in atypical endometrial hyperplasia without MSI suggests that methylation is an early event in endometrial tumorigenesis. Our objective was to determine if methylation is always present in MSI-positive atypical hyperplasia concomitant with MSI-positive, methylation-positive carcinoma. Methods. We used laser capture microdissection to study MLH1 methylation and MSI in a large series of endometrial cancer cases that had previously been shown to have methylation and the MSI-high (MSI-H) phenotype. We resampled areas of carcinoma from 27 patients along with 51 foci of concomitant atypical endometrial hyperplasia. Results. Consistent with previous reports, we saw MLH1 methylation in areas of atypical endometrial hyperplasia that did not show MSI. In addition, we noted that 18% of the MSI-H atypical endometrial hyperplasia DNAs lacked methylation of critical cytosines in the MLH1 promoter. Immunohistochemistry studies showed that these MSI-H unmethylated foci of atypical endometrial hyperplasia failed to express MLH1, as did regions of simple hyperplasia. Conclusion. Methylation of the MLH1 promoter is an early event in endometrial tumorigenesis. Given that not all MSI-positive tissues had methylation at cytosines 3229 and 3231, it appears that methylation may not be required for MLH1 silencing and loss of mismatch repair.
AB - Objective. MLH1 methylation is associated with the microsatel-lite instability (MSI) phenotype in endometrial cancer and atypical endometrial hyperplasia, a premalignant precursor to carcinoma. The observation that methylation is also seen in atypical endometrial hyperplasia without MSI suggests that methylation is an early event in endometrial tumorigenesis. Our objective was to determine if methylation is always present in MSI-positive atypical hyperplasia concomitant with MSI-positive, methylation-positive carcinoma. Methods. We used laser capture microdissection to study MLH1 methylation and MSI in a large series of endometrial cancer cases that had previously been shown to have methylation and the MSI-high (MSI-H) phenotype. We resampled areas of carcinoma from 27 patients along with 51 foci of concomitant atypical endometrial hyperplasia. Results. Consistent with previous reports, we saw MLH1 methylation in areas of atypical endometrial hyperplasia that did not show MSI. In addition, we noted that 18% of the MSI-H atypical endometrial hyperplasia DNAs lacked methylation of critical cytosines in the MLH1 promoter. Immunohistochemistry studies showed that these MSI-H unmethylated foci of atypical endometrial hyperplasia failed to express MLH1, as did regions of simple hyperplasia. Conclusion. Methylation of the MLH1 promoter is an early event in endometrial tumorigenesis. Given that not all MSI-positive tissues had methylation at cytosines 3229 and 3231, it appears that methylation may not be required for MLH1 silencing and loss of mismatch repair.
KW - Atypical endometrial hyperplasia
KW - Endometrial carcinoma
KW - MLH1 methylation
KW - Microsatellite instability
UR - http://www.scopus.com/inward/record.url?scp=0036311084&partnerID=8YFLogxK
U2 - 10.1006/gyno.2002.6724
DO - 10.1006/gyno.2002.6724
M3 - Article
C2 - 12079302
AN - SCOPUS:0036311084
SN - 0090-8258
VL - 86
SP - 62
EP - 68
JO - Gynecologic oncology
JF - Gynecologic oncology
IS - 1
ER -