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Genetic and clinical features of human pancreatic ductal adenocarcinomas with widespread microsatellite instability.
Cancer Res. 2001 Apr 01; 61(7):3139-44.CR

Abstract

The incidences of microsatellite instability (MSI) and underlying DNA mismatch repair (MMR) defects in pancreatic carcinogenesis have not been well established. We analyzed 100 sporadic and 3 hereditary pancreatic ductal adenocarcinomas for MSI, and high-frequency MSI (MSI-H) and low-frequency MSI (MSI-L) tumors were further analyzed for frameshift mutations of possible target genes and for promoter methylation and mutation of DNA MMR genes, including hMLH1, hMSH2, hMSH3, and hMSH6 genes. Among the 100 sporadic tumors, 13 (13%) were MSI-H, 13 (13%) were MSI-L, and 74 (74%) were microsatellite stable (MSS) tumors. All of the three hereditary tumors from hereditary nonpolyposis colorectal cancer (HNPCC) patients were MSI-H. MSI-H tumors were significantly associated with poor differentiation and the presence of wild-type K-RAS and p53 genes. Patients with MSI-H tumors had a significantly longer overall survival time than did those with MSI-L or MSS tumors (P = 0.0057). Frameshift mutations of hMSH3, hMLH3, BRCA-2, TGF-beta type II receptor, and BAX genes were detected in MSI-H tumors. Hypermethylation of the hMLH1 promoter was observed in 6 (46%) of the 13 sporadic MSI-H tumors but not in any of the 3 hereditary MSI-H tumors or 13 MSI-L tumors. All of the 3 HNPCC cases had germ-line hMLH1 mutation accompanied by loss of heterogeneity or other mutation in the tumor. Our results suggest that pancreatic carcinomas with MSI-H represent a distinctive oncogenic pathway because they exhibit peculiar clinical, pathological, and molecular characteristics. Our results also suggest the principal involvement of epigenetic or genetic inactivation of the hMLH1 gene in the pathogenesis of pancreatic carcinoma with MSI-H.

Authors+Show Affiliations

First Department of Internal Medicine, Sapporo Medical University, Japan. h-yama@sapmed.ac.jpNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

11306499

Citation

Yamamoto, H, et al. "Genetic and Clinical Features of Human Pancreatic Ductal Adenocarcinomas With Widespread Microsatellite Instability." Cancer Research, vol. 61, no. 7, 2001, pp. 3139-44.
Yamamoto H, Itoh F, Nakamura H, et al. Genetic and clinical features of human pancreatic ductal adenocarcinomas with widespread microsatellite instability. Cancer Res. 2001;61(7):3139-44.
Yamamoto, H., Itoh, F., Nakamura, H., Fukushima, H., Sasaki, S., Perucho, M., & Imai, K. (2001). Genetic and clinical features of human pancreatic ductal adenocarcinomas with widespread microsatellite instability. Cancer Research, 61(7), 3139-44.
Yamamoto H, et al. Genetic and Clinical Features of Human Pancreatic Ductal Adenocarcinomas With Widespread Microsatellite Instability. Cancer Res. 2001 Apr 1;61(7):3139-44. PubMed PMID: 11306499.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Genetic and clinical features of human pancreatic ductal adenocarcinomas with widespread microsatellite instability. AU - Yamamoto,H, AU - Itoh,F, AU - Nakamura,H, AU - Fukushima,H, AU - Sasaki,S, AU - Perucho,M, AU - Imai,K, PY - 2001/4/18/pubmed PY - 2001/5/5/medline PY - 2001/4/18/entrez SP - 3139 EP - 44 JF - Cancer research JO - Cancer Res. VL - 61 IS - 7 N2 - The incidences of microsatellite instability (MSI) and underlying DNA mismatch repair (MMR) defects in pancreatic carcinogenesis have not been well established. We analyzed 100 sporadic and 3 hereditary pancreatic ductal adenocarcinomas for MSI, and high-frequency MSI (MSI-H) and low-frequency MSI (MSI-L) tumors were further analyzed for frameshift mutations of possible target genes and for promoter methylation and mutation of DNA MMR genes, including hMLH1, hMSH2, hMSH3, and hMSH6 genes. Among the 100 sporadic tumors, 13 (13%) were MSI-H, 13 (13%) were MSI-L, and 74 (74%) were microsatellite stable (MSS) tumors. All of the three hereditary tumors from hereditary nonpolyposis colorectal cancer (HNPCC) patients were MSI-H. MSI-H tumors were significantly associated with poor differentiation and the presence of wild-type K-RAS and p53 genes. Patients with MSI-H tumors had a significantly longer overall survival time than did those with MSI-L or MSS tumors (P = 0.0057). Frameshift mutations of hMSH3, hMLH3, BRCA-2, TGF-beta type II receptor, and BAX genes were detected in MSI-H tumors. Hypermethylation of the hMLH1 promoter was observed in 6 (46%) of the 13 sporadic MSI-H tumors but not in any of the 3 hereditary MSI-H tumors or 13 MSI-L tumors. All of the 3 HNPCC cases had germ-line hMLH1 mutation accompanied by loss of heterogeneity or other mutation in the tumor. Our results suggest that pancreatic carcinomas with MSI-H represent a distinctive oncogenic pathway because they exhibit peculiar clinical, pathological, and molecular characteristics. Our results also suggest the principal involvement of epigenetic or genetic inactivation of the hMLH1 gene in the pathogenesis of pancreatic carcinoma with MSI-H. SN - 0008-5472 UR - https://www.unboundmedicine.com/medline/citation/11306499/Genetic_and_clinical_features_of_human_pancreatic_ductal_adenocarcinomas_with_widespread_microsatellite_instability_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=11306499 DB - PRIME DP - Unbound Medicine ER -