TY - JOUR
T1 - Molecular modifiers of hormone receptor action
T2 - Decreased androgen receptor expression in mismatch repair deficient endometrial endometrioid adenocarcinoma
AU - Gan, Qiong
AU - Crumley, Suzanne
AU - Broaddus, Russell R.
N1 - Funding Information:
From the Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas. Presented in part at the 106th USCAP Annual Meeting, March 4 to 10, 2017, San Antonio, TX. Supported by NIH SPORE in Uterine Cancer 3P50 CA098258 (R.R.B.). The authors declare no conflict of interest. Address correspondence and reprint requests to Russell R. Broaddus, MD, PhD, Department of Pathology, Unit 85, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030. E-mail: rbroaddus@mdanderson.org.
Publisher Copyright:
© 2017 by the International Society of Gynecological Pathologists.
PY - 2019/1/1
Y1 - 2019/1/1
N2 - Endometrial endometrioid carcinoma is related to estrogen excess and expression of estrogen and progesterone receptors. Epidemiological evidence suggests that exposure to elevated androgens, as in polycystic ovarian syndrome, increases the risk of endometrial cancer. Factors impacting androgen receptor (AR) expression are not well studied. Mismatch repair (MMR) deficiency due to MLH1 gene methylation is one of the most common molecular alterations in endometrial cancer, occurring in 15% to 20% of cases. MLH1 methylation can be associated with decreased expression of other genes, so we examined the effect of MMR status on AR expression. As NF-κB is known to induce AR, this transcription factor was also examined. Three hundred forty-four unselected endometrial carcinomas were evaluated for DNA MMR. Loss of expression of MLH1 with MLH1 methylation was defined as MMR deficient, and positive expression of MMR proteins was defined as MMR intact. A case-control cohort of 96 grade 2 endometrioid carcinomas was studied from this set (47 MMR deficient, 49 MMR intact). Cases were matched for histotype, grade, and age. AR and NF-κB immunohistochemical expression were evaluated by 2 different scoring systems (CAP/ASCO and Allred) used for estrogen receptor. Despite higher levels of NF-κB, MMR deficiency was associated with a significantly lower mean percentage of AR expression. The MMR deficient group had more variable AR expression, with more cases scoring on the lower end of the spectrum. These findings have implications for clinical trials of AR antagonists in gynecologic cancers.
AB - Endometrial endometrioid carcinoma is related to estrogen excess and expression of estrogen and progesterone receptors. Epidemiological evidence suggests that exposure to elevated androgens, as in polycystic ovarian syndrome, increases the risk of endometrial cancer. Factors impacting androgen receptor (AR) expression are not well studied. Mismatch repair (MMR) deficiency due to MLH1 gene methylation is one of the most common molecular alterations in endometrial cancer, occurring in 15% to 20% of cases. MLH1 methylation can be associated with decreased expression of other genes, so we examined the effect of MMR status on AR expression. As NF-κB is known to induce AR, this transcription factor was also examined. Three hundred forty-four unselected endometrial carcinomas were evaluated for DNA MMR. Loss of expression of MLH1 with MLH1 methylation was defined as MMR deficient, and positive expression of MMR proteins was defined as MMR intact. A case-control cohort of 96 grade 2 endometrioid carcinomas was studied from this set (47 MMR deficient, 49 MMR intact). Cases were matched for histotype, grade, and age. AR and NF-κB immunohistochemical expression were evaluated by 2 different scoring systems (CAP/ASCO and Allred) used for estrogen receptor. Despite higher levels of NF-κB, MMR deficiency was associated with a significantly lower mean percentage of AR expression. The MMR deficient group had more variable AR expression, with more cases scoring on the lower end of the spectrum. These findings have implications for clinical trials of AR antagonists in gynecologic cancers.
KW - Androgen receptor
KW - Endometrial endometrioid carcinoma
KW - Mismatch repair genes
KW - NF-κB
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U2 - 10.1097/PGP.0000000000000465
DO - 10.1097/PGP.0000000000000465
M3 - Article
C2 - 29210800
AN - SCOPUS:85058501529
VL - 38
SP - 44
EP - 51
JO - International Journal of Gynecological Pathology
JF - International Journal of Gynecological Pathology
SN - 0277-1691
IS - 1
ER -