Loss of hMSH2 and hMSH6 Expression Is Frequent in Sporadic Endometrial Carcinomas with Microsatellite Instability: A Population-based Study 1 Ingunn Stefansson, Lars A. Akslen, Nicola MacDonald, Andy Ryan, Soma Das, Ian J. Jacobs, and Helga B. Salvesen 2 Department of Pathology, The Gade Institute [I. S., L. A. A., H. B. S.]; Department of Gynecology and Obstetrics, Haukeland University Hospital, N-5021 Bergen, Norway [H. B. S.]; Gynaecology Cancer Research Unit, Department of Gynaecological Oncology, St. Bartholomew’s Hospital and The Royal London Hospital School of Medicine and Dentistry, London EC1A 7BE, United Kingdom [N. M., A. R., I. J. J.]; and Department of Human Genetics, The University of Chicago, Chicago, Illinois 60637 [S. D.] ABSTRACT Microsatellite instability (MSI) seems to be important in the development of various human cancers including sporadic endometrial cancer. It has previously been shown that alterations in the mismatch repair gene hMLH1 seem to be important for the development of MSI in these tumors. The role of the other mismatch repair genes hMSH2 and hMSH6 has been less well studied, but investigations on patients with hereditary nonpolyposis colorectal cancer in- dicate that these genes also may be involved. We therefore wanted to investigate the pattern of hMSH2 and hMSH6 expression in a prospective and population-based series of endometrial carcinomas with known hMLH1 expression and MSI status. A total of 138 patients were studied, and pathological staining was seen in 19 cases (14%) for hMLH1, 26 cases (19%) for hMSH2, and 17 cases (12.3%) for hMSH6. Pathological hMLH1 expression was more frequent among tumors with high MSI (those positive for four to five of five markers), whereas pathological expression of hMSH2 and hMSH6 was more frequent among tumors with inter- mediate MSI (those positive for two to three of five mark- ers). MSI was significantly correlated with pathological ex- pression of hMLH1 (P < 0.001), hMSH2 (P  0.04), and hMSH6 (P  0.001). In the group with high MSI, 14 of 16 tumors (88%) showed pathological expression for at least one of the markers. The expression of hMLH1, hMSH2, or hMSH6 did not significantly influence survival. In conclu- sion, pathological expression of hMLH1 does not seem to account for all tumors with a MSI-positive phenotype in this population-based series of endometrial carcinomas. Our data indicate that the other mismatch repair genes hMSH2 and hMSH6 are also involved, especially in cases with inter- mediate MSI. INTRODUCTION MSI 3 is characterized by small deletions or expansions in tumor DNA, manifested as shifts in allelic electrophoretic mo- bility. Genetic instability is considered to be responsible for a rapid accumulation of somatic mutations in various tumor sup- pressor genes and oncogenes, thus playing an important role in the initiation and progression of malignant tumors (1). MSI was first detected in tumors from patients with HNPCC (2). Germ-line mutations in mismatch repair genes have been reported in these HNPCC families, and hMLH1, hMSH2, and hMSH6 account for the mismatch repair defect in a majority of the patients (3–5). Later studies have also dem- onstrated that MSI is present in about 20% of sporadic colorec- tal tumors (6). Endometrial cancer is one of the most common extracolonic tumors associated with HNPCC (7), and MSI has been reported to be present in 9 – 45% of sporadic cases (8 –18). Previous studies have indicated that loss of hMLH1 ex- pression can account for a large proportion of sporadic endo- metrial tumors (17, 19, 20). Recently, in a population-based study, we found loss of hMLH1 expression in the majority of endometrial tumors with high MSI (those positive for four to five of five markers), whereas loss of expression was less frequent in tumors with intermediate MSI (those positive for two to three of five markers; Ref. 21). Thus, pathological expression of hMLH1 does not seem to account for all tumors with a MSI-positive phenotype, indicating that other mismatch repair genes might also be involved. With this background, the aim of our study was to investigate the pattern of hMSH2 and hMSH6 expression in a prospective and population-based series of endometrial carcinomas with known hMLH1 expression and MSI status. We also wanted to study hMSH2 and hMSH6 expression in relation to clinicopathological variables, other Received 5/8/01; revised 10/11/01; accepted 10/18/01. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 Supported by Norske Kvinners Sanitetsforening, The Norwegian Can- cer Society, NIH Grant CA81652-01, St. Bartholomew’s Cancer Re- search Committee, The Blix Family Fund, Elena and Gustav B. Bull’s Legacy and Kaptein L. A. Hermansens og hustru I. Hermansens Legacy. The research has been approved by the Norwegian Data Inspectorate and the Institutional Review Board at the University of Chicago (Pro- tocol 9457). 2 To whom requests for reprints should be addressed, at Department of Gynecology and Obstetrics, Haukeland University Hospital, N-5021 Bergen, Norway. Phone: 47-55-97-42-00; Fax: 47-55-97-49-68; E-mail: helga.salvesen@haukeland.no. 3 The abbreviations used are: MSI, microsatellite instability; HNPCC, hereditary nonpolyposis colorectal cancer; FIGO, International Federa- tion of Gynecology and Obstetrics. 138 Vol. 8, 138 –143, January 2002 Clinical Cancer Research Research. on December 11, 2021. © 2002 American Association for Cancer clincancerres.aacrjournals.org Downloaded from