Microsatellite Instability Predicts Clinical Outcome in Radiation-Treated Endometrioid Endometrial Cancer

Abstract

Purpose-Microsatellite instability (MSI) is the hallmark of cancer with DNA mismatch repair (MMR) deficiency and underlies 20-30% of endometrial cancer. Some in vitro studies suggest that radiation effects are modulated by the MMR system, however, little is known about the relationship between MSI and radiation response. The aim of this study was to elucidate whether MSI predicts clinical outcome in radiation treated endometrioid endometrial cancer (EEC).Methods-We have studied a consecutive series of 93 patients with EEC treated with extrafacial hysterectomy and postoperative radiotherapy. The median clinical follow up of patients was of 138 months, with a maximum of 232 months. Five quasimonomorphic mononucleotide markers (BAT-25, BAT-26, NR21, NR24 and NR27) were used for MSI classification.Results-Twenty five patients (22%) were classified as MSI. Either in the whole series and in early stages (I and II), univariate analysis showed a significant association between MSI and a poorer 10-years local disease free (LDFS), disease free (DFS), and cancer-specific survival (CSS). In multivariate analysis, MSI was excluded from de final regression model in the whole series, but in early stages, MSI provided additional significant predictive information independent of traditional prognostic and predictive factors (age, stage, grade and vascular invasion) for DFS (HR, 3.25, 95%

High frequency microsatellite instability has a prognostic value in endometrial endometrioid adenocarcinoma, but only in FIGO stage 1 cases

“…The study concluded on a negative prognostic value of MSI-H cases, but in contrast to our study all of their cases were radiation-treated [6]. MSI-L and MSI-H were found in 11% and 16% of the cancers analyzed (totalling 27%).…”

“…Another shortcoming was that the MSI markers used were less sensitive than the recently described ones assessed by the pentaplex polymerase chain reaction assay [8,9,42]. Another recent study of interest investigated early stage radiation-treated endometrioid tumors only with the same MSI markers as ours, and concluded on a negative prognostic value for MSI-H patients [6].…”

“…Increased understanding of the molecular biology in endometrial carcinogenesis has revealed several promising prognostic and predictive biomarkers, such as microsatellite instability (MSI), a characteristic finding in cancers deficient in DNA mis-match repair (MMR), seen in 9-45% of sporadic endometrial cancers (Table 1) [1,[4][5][6][7]10,12,16,17,19,25,26,28,29,32,33,42,44]. In contrast to Hereditary NonPolyposis Colorectal Cancer (HNPCC) or Lynch syndrome, which is an autosomal dominant condition involving germline MMR gene mutation, sporadic en- [15].…”

Recent findings on epigenetic gene abnormalities involved in uterine cancer

“…MMR genes may be abnormally methylated and cancer develops when MSI occurs in regions of tumor suppressor genes. Numerous microsatellites are detectable by PCR and are found in 20-40% of cases of endometrial cancer (22,(55)(56)(57). Genes involved in the MMR system include hMLH1, MutS protein homolog 2 (hMSH2) and hMSH6, and postmeiotic segregation increased 2 (hPMS2) is frequently abnormally methylated (56).…”

“…Numerous microsatellites are detectable by PCR and are found in 20-40% of cases of endometrial cancer (22,(55)(56)(57). Genes involved in the MMR system include hMLH1, MutS protein homolog 2 (hMSH2) and hMSH6, and postmeiotic segregation increased 2 (hPMS2) is frequently abnormally methylated (56). hMLH1 methylation has been found in 40.1% of cases of endometrial cancer and in 14.3% of cases of atypical endometrial hyperplasia, a precancerous endometrial lesion; therefore, abnormal methylation of hMLH1 is considered to be significantly involved in carcinogenesis (43).…”