Is gastric cancer part of the tumour spectrum of hereditary non-polyposis colorectal cancer? A molecular genetic study

Gylling, Annette; Abdel‐Rahman, Wael M.; Juhola, Martti; Nuorva, Kyösti; Hautala, Emmi; Järvinen, Heikki; Mecklin∥, Jukka–Pekka; Aarnio, Markku; Peltomäki, Païvi

doi:10.1136/gut.2006.114876

Cited by 90 publications

(71 citation statements)

References 61 publications

(44 reference statements)

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“…Dig stands for HhaI digested sample and Lig for undigested sample. Based on previous cell line experiments (Gylling et al 2007, Joensuu et al 2008, we considered a promoter to show methylation if the methylation dosage ratio was R0.15, which corresponds to 15% of DNA methylated. All cases were analysed in duplicate, using the mean methylation percentage of the two runs in the statistical analysis.…”

Section: Methylation-specific Multiplex Ligation-dependent Probe Amplmentioning

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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Section: Methylation-specific Multiplex Ligation-dependent Probe Amplmentioning

confidence: 99%

Methylation profiles of endometrioid and serous endometrial cancers

Seeber

Zweemer

Marchionni³

et al. 2010

Endocrine-Related Cancer

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“…Methylation dosage ratios were calculated as described (18). A dosage ratio of 0.15 (corresponding to 15% of methylated DNA), which has given the best discrimination between normal and tumor DNA in our earlier studies (18)(19)(20), was regarded to indicate promoter methylation. Statistical analysis.…”

Section: Translational Relevancementioning

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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“…Because of the relatively high incidence of gastric cancer in the general population, the true association of gastric cancer and Lynch syndrome is, however, controversial (35). Nevertheless, approximately 15-20% of gastric cancers are MSI.…”

Section: Discussionmentioning

confidence: 99%

Gastric cancer and concomitant renal cancer: A systematic immunohistochemical and molecular analysis

Betge

Pollheimer²,

Schlemmer³

et al. 2011

Oncol Rep

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Abstract. The frequency of gastric cancer in patients with renal cell carcinoma (RCC) is exceptionally high in our region suggesting a common molecular basis. Our study aimed to characterize tumors and to analyze possible underlying molecular features in 12 patients with gastric cancer and concomitant RCC. We performed an immunohistochemical analysis including p53 protein expression, proliferative activity (MIB-1), mismatch repair status (hMLH1, hMSH2, hMSH6, PMS2) and E-cadherin expression in gastric cancers, which were additionally analyzed for Epstein-Barr-Encoded-RNA (EBER) by in situ hybridization. Microsatellite instability was analyzed with a PCR multiplex system and capillary electrophoresis. KRAS mutations in codons 12 and 13 were tested by pyrosequencing. All patients had clear cell RCCs, 10 of which were well differentiated and diagnosed in an early stage, while the gastric cancers of these patients were generally poorly or undifferentiated and diagnosed in an advanced stage. Gastric cancers showed reduced E-cadherin staining in 10 out of 12 cases. Two gastric cancers demonstrated loss of hMLH1 and PMS2, which was confirmed by molecular analysis showing a high degree of microsatellite instability. All RCCs were microsatellite stable. KRAS mutation was detected in one of the two instable gastric cancers, while none of the RCCs had KRAS mutations. Another gastric cancer was positive for EBV. In conclusion, a coherent cause for gastric cancer and concomitant RCC, such as Lynch syndrome, a prominent role of KRAS mutation or EBV infection, was not found in our series. Other factors leading to a higher susceptibility for cancer must be explored to explain why individuals with RCC have a higher risk of developing gastric cancer in our region.

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Is gastric cancer part of the tumour spectrum of hereditary non-polyposis colorectal cancer? A molecular genetic study

Cited by 90 publications

References 61 publications

Methylation profiles of endometrioid and serous endometrial cancers

Methylation profiles of endometrioid and serous endometrial cancers

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

Gastric cancer and concomitant renal cancer: A systematic immunohistochemical and molecular analysis

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