Microsatellite Instability and Epigenetic Inactivation of <i>MLH1</i> and Outcome of Patients With Endometrial Carcinomas of the Endometrioid Type

Zighelboim, Israel; Goodfellow, Paul J.; Gao, Feng; Gibb, Randall K.; Powell, Matthew A.; Rader, Janet S.; Mutch, David G.

doi:10.1200/jco.2006.08.2107

Cited by 197 publications

(154 citation statements)

References 37 publications

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“…The impact of microsatellite instability on the prognosis of women with endometrial cancer is controversial. Some studies reported that microsatellite instability is associated with a favorable prognosis, 31,32 whereas in other studies a significant worse prognosis was found. 33,34 Possible explanations for these discrepancies include cohort differences, lack of statistical power, and diversity of methodology.…”

Section: Discussionmentioning

confidence: 98%

Refining prognosis and identifying targetable pathways for high-risk endometrial cancer; a TransPORTEC initiative

et al. 2015

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This study aimed to investigate whether molecular analysis can be used to refine risk assessment, direct adjuvant therapy, and identify actionable alterations in high-risk endometrial cancer. TransPORTEC, an international consortium related to the PORTEC3 trial, was established for translational research in high-risk endometrial cancer. In this explorative study, routine molecular analyses were used to detect prognostic subgroups: p53 immunohistochemistry, microsatellite instability and POLE proofreading mutation. Furthermore, DNA was analyzed for hotspot mutations in 13 additional genes (BRAF, CDKNA2, CTNNB1, FBXW7, FGFR2, FGFR3, FOXL2, HRAS, KRAS, NRAS, PIK3CA, PPP2R1A, and PTEN) and protein expression of ER, PR, PTEN, and ARID1a was analyzed. Rates of distant metastasis, recurrence-free, and overall survival were calculated using the Kaplan-Meier method and log-rank test. In total, samples of 116 high-risk endometrial cancer patients were included: 86 endometrioid; 12 serous; and 18 clear cell. For endometrioid, serous, and clear cell cancers, 5-year recurrence-free survival rates were 68%, 27%, and 50% (P = 0.014) and distant metastasis rates 23%, 64%, and 50% (P = 0.001), respectively. Four prognostic subgroups were identified: (1) a group of p53-mutant tumors; (2) microsatellite instable tumors; (3) POLE proofreading-mutant tumors; and (4) a group with no specific molecular profile (NSMP). In group 3 (POLE-mutant; n = 14) and group 2 (microsatellite instable; n = 19) patients, no distant metastasis occurred, compared with 50% distant metastasis rate in group 1 (p53-mutant; n = 36) and 39% in group 4 (NSMP; Po 0.001). Five-year recurrence-free survival was 93% and 95% for group 3 (POLE-mutant) and group 2 (microsatellite instable) vs 42% (group 1, p53-mutant) and 52% (group 4, NSMP; Po 0.001). Targetable FBXW7 and FGFR2 mutations (6%), alterations in the PI3K-AKT pathway (60%) and hormone receptor positivity (45%) were frequently found. In conclusion, molecular analysis of high-risk endometrial cancer identifies four distinct prognostic subgroups, with potential therapeutic implications. High frequencies of targetable alterations were identified and may serve as targets for individualized treatment. Modern Pathology (2015) 28, 836-844; doi:10.1038/modpathol.2015 published online 27 February 2015 Risk classification of endometrial carcinomas is based upon a combination of clinical and histopathological factors and is used in guiding adjuvant therapy. High-risk factors are (combinations of) advanced age, high-grade, non-endometrioid histology, extensive lymphovascular space invasion, and

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Section: Discussionmentioning

confidence: 98%

Refining prognosis and identifying targetable pathways for high-risk endometrial cancer; a TransPORTEC initiative

et al. 2015

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“…In regard to hyperplasia, MLH1 promoter methylation was used as a surrogate marker for MMR status because it is known that most sporadic MMRdeficient endometrial carcinomas arise through promoter methylation (21,22), and only cases with MLH1 methylation (n = 4) were further examined for MMR protein expression and MSI. Two of 37 hyperplasia samples, one complex hyperplasia without atypia and one complex hyperplasia with atypia, had MLH1 protein loss and/or MSI (5%; data not shown).…”

Section: Resultsmentioning

confidence: 99%

Molecular Analysis of Endometrial Tumorigenesis: Importance of Complex Hyperplasia Regardless of Atypia

Nieminen

Gylling

Abdel‐Rahman

et al. 2009

Clinical Cancer Research

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Purpose: Endometrial carcinoma (EC) is common in the population and the most frequent extracolonic malignancy in hereditary nonpolyposis colorectal carcinoma (HNPCC)/Lynch syndrome. We characterized precursor lesions of endometrioid EC to identify markers of malignant transformation and tumor progression. Experimental Design: Serial specimens of normal endometrium, simple hyperplasia, complex hyperplasia without atypia, complex hyperplasia with atypia, and endometrial carcinoma obtained during a 10-year surveillance of DNA mismatch repair (MMR) gene mutation carriers (together 110 samples) were molecularly profiled and compared with a sporadic reference series of endometrial specimens taken for nonmalignant reasons (62 samples). Results: Among MMR gene mutation carriers, decreased MMR protein expression was present in 7% in normal endometrium, 40% in simple hyperplasia, 100% in complex hyperplasia without atypia, 92% in complex hyperplasia with atypia, and 100% in endometrial carcinoma. Microsatellite instability frequencies were lower (6%, 17%, 67%, 38%, and 64%, respectively). Among 24 tumor suppressor genes, the number of methylated loci increased from normal endometrium to simple hyperplasia to complex hyperplasia (complex hyperplasia without atypia/complex hyperplasia with atypia) in both Lynch syndrome and reference series. The most frequently methylated genes were CDH13, RASSF1A, and GSTP1. In MMR gene mutation carriers, MMR and methylation defects appeared up to 12 years before endometrial carcinoma. Conclusions: Molecular changes in endometrial tissue are detectable several years before endometrial carcinoma in genetically predisposed individuals. Abnormal MMR and methylation classify normal endometrium and simple hyperplasia into one category and complex hyperplasia without atypia, complex hyperplasia with atypia, and endometrial carcinoma into another, suggesting that, contrary to a traditional view, complex hyperplasia without atypia and complex hyperplasia with atypia are equally important as precursor lesions of endometrial carcinoma. (Clin Cancer Res 2009;15(18):5772-83) Endometrial carcinoma is the most common malignant tumor of the female genital organs in industrialized countries (1) and comprises 4% of all cancers in women worldwide (2). Estrogendependent tumors (type I, endometrioid endometrial carcinomas) account for 80% to 85% of cases and non-estrogendependent (type II, nonendometrioid endometrial carcinomas) account for the rest. Type I tumors occur in premenopausal and younger postmenopausal women, are typically low-grade and localized, and have a favorable outcome, whereas type II tumors occur in older postmenopausal women, are of high grade and more advanced stage, and have worse prognosis (1, 2). Type I tumors are considered to form in a background of endometrial hyperplasia. The WHO classifies endometrial hyperplasias as simple or complex, by degree of architectural abnormality, and as having or not having atypia, by cytology (3). Epidemiologic studies suggest that the ri...

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“…Frequent methylation for TIMP3 (Kang et al 2006) and CDH13 (Suehiro et al 2008) in the present study concurs with previously published results in endometrial cancer. Methylation of the MLH1 promoter is also a wellrecognized phenomenon in (sporadic) EEC (Simpkins et al 1999, Salvesen et al 2000a, Zighelboim et al 2007a,b, Esteller 2008. In consensus with our study, MLH1 was shown to be methylated in 20-30% of cases in previous studies (Salvesen et al 2000b, Zighelboim et al 2007a.…”

Section: Discussionmentioning

confidence: 99%

“…Methylation of the MLH1 promoter is also a wellrecognized phenomenon in (sporadic) EEC (Simpkins et al 1999, Salvesen et al 2000a, Zighelboim et al 2007a,b, Esteller 2008. In consensus with our study, MLH1 was shown to be methylated in 20-30% of cases in previous studies (Salvesen et al 2000b, Zighelboim et al 2007a. Methylation of MLH1 and subsequent lack of mRNA expression are thought to be an epigenetic silencing mechanism associated with MSI in sporadic endometrial cancers.…”

Section: Discussionmentioning

confidence: 99%

Methylation profiles of endometrioid and serous endometrial cancers

Seeber

Zweemer

Marchionni³

et al. 2010

Endocrine-Related Cancer

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Promoter methylation is a gene-and cancer type-specific epigenetic event that plays an important role in tumour development. As endometrioid (endometrioid endometrial carcinoma, EEC) and serous endometrial cancers (uterine papillary serous carcinoma, UPSC) exhibit different clinical, histological and molecular genetic characteristics, we hypothesized that these differences may be reflected in epigenetic phenomena as well. Identification of a panel of methylation biomarkers could be helpful in a correct histological classification of these two subtypes, which solely on the basis of morphology is not always easy. Methylation-specific multiplex ligation-dependent probe amplification was used to assess the extent of promoter methylation of different tumour suppressor genes in EEC and UPSC. Methylation results were correlated with histology and survival. The median cumulative methylation index of all genes was significantly higher in EEC (124) than in UPSC (93) (P!0.001). Promoter methylation of CDH13 and MLH1 was more frequently present in EEC, while CDKN2B and TP73 were more frequently methylated in UPSC. Almost 90% of EEC and 70% of UPSC could be predicted by CDH13 and TP73. In EEC, methylation of MLH1 was associated with a shorter disease-free survival (DFS; P!0.0001) and overall survival (OS; PZ0.005). In a multivariate model, MLH1 methylation emerged as an additional prognostic factor to stage for DFS (PZ0.002). In conclusion, promoter methylation is more common in EEC than UPSC. A panel of methylation biomarkers could be useful to distinguish between the two histological subtypes of endometrial cancer. Furthermore, methylation of MLH1 may have prognostic value in EEC.

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Microsatellite Instability and Epigenetic Inactivation of MLH1 and Outcome of Patients With Endometrial Carcinomas of the Endometrioid Type

Abstract: MSI is not associated with survival in patients with endometrioid endometrial cancer.

Cited by 197 publications

References 37 publications

Refining prognosis and identifying targetable pathways for high-risk endometrial cancer; a TransPORTEC initiative

Refining prognosis and identifying targetable pathways for high-risk endometrial cancer; a TransPORTEC initiative

Molecular Analysis of Endometrial Tumorigenesis: Importance of Complex Hyperplasia Regardless of Atypia

Methylation profiles of endometrioid and serous endometrial cancers

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