title: Isolated Loss of PMS2 Immunohistochemical Expression is Frequently Caused by Heterogenous MLH1 Promoter Hypermethylation in Lynch Syndrome Screening for Endometrial Cancer Patients.
abstract: Lynch syndrome (LS) is an autosomal-dominant inherited disorder mainly caused by a germline mutation in the DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) and is associated with increased risk for various cancers, particularly colorectal cancer and endometrial cancer (EC). Women with LS account for 2% to 6% of EC patients; it is clinically important to identify LS in such individuals for predicting and/or preventing additional LS-associated cancers. PMS2 germline mutation (PMS2-LS) is the rarest contribution to LS etiology among the 4 LS-associated MMR germline mutations, and its detection is complicated. Therefore, prudent screening for PMS2-LS is important as it leads to an efficient LS identification strategy. Immunohistochemistry is recommended as a screening method for LS in EC. Isolated loss of PMS2 (IL-PMS2) expression is caused not only by PMS2-LS but also by MLH1 germline mutation or MLH1 promoter hypermethylation (MLH-PHM). This study aimed to determine the association between MLH1-PHM and IL-PMS2 to avoid inappropriate genetic analysis. We performed MLH1 methylation analysis and MLH1/PMS2 germline mutation testing on the IL-PMS2 cases. By performing MMR-immunohistochemistry on 360 unselected ECs, we could select 8 (2.2%) cases as IL-PMS2. Heterogenous MLH1 staining and MLH1-PHM were detected in 4 of 8 (50%) IL-PMS2 tumors. Of the 5 IL-PMS2 patients who underwent genetic analysis, 1 had PMS2 germline mutation with normal MLH1 expression (without MLH1-PHM), and no MLH1 germline mutation was detected. We suggest that MLH1 promoter methylation analysis for IL-PMS2 EC should be performed to exclude sporadic cases before further PMS2 genetic testing.
authors: *Department of Obstetrics and Gynecology, Akita University Graduate School of Medicine †Department of Obstetrics and Gynecology, Noshiro Kosei Medical Center, Akita, Japan.
authors: Aya
authors: A
authors: Kato
authors: Naoki
authors: N
authors: Sato
authors: Tae
authors: T
authors: Sugawara
authors: Kazue
authors: K
authors: Takahashi
authors: Masahiko
authors: M
authors: Kito
authors: Kenichi
authors: K
authors: Makino
authors: Toshiharu
authors: T
authors: Sato
authors: Dai
authors: D
authors: Shimizu
authors: Hiromistu
authors: H
authors: Shirasawa
authors: Hiroshi
authors: H
authors: Miura
authors: Wataru
authors: W
authors: Sato
authors: Yukiyo
authors: Y
authors: Kumazawa
authors: Akira
authors: A
authors: Sato
authors: Jin
authors: J
authors: Kumagai
authors: Yukihiro
authors: Y
authors: Terada
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000175:diagnosis* / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics; D055088:Early Detection of Cancer; D016889:Endometrial Neoplasms / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005820:Genetic Testing / Q000379:methods; D006801:Humans; D007150:Immunohistochemistry; D000070976:Mismatch Repair Endonuclease PMS2 / Q000032:analysis / Q000096:biosynthesis*; D000070957:MutL Protein Homolog 1 / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; C501486:MLH1 protein, human; C094934:PMS2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1