Frequent microsatellite instability in primary esophageal carcinoma associated with extraesophageal primary carcinoma.
Patients with esophageal squamous cell carcinoma (ESCC) frequently develop other primary cancers, such as gastric cancer and head and neck cancer. Details of carcinogenesis in patients with multiple primaries that include esophageal carcinoma with other primary carcinoma (ECOPC) remain uncertain. We examined microsatellite instability (MSI) status, frameshift mutation in target genes of MSI, mismatch repair protein expression and hypermethylation of the hMLH1 promoter region in ECOPC patients to better understand the underlying carcinogenic processes. High frequency MSI (MSI-H) was found in 15 (44.1%) of 34 patients with ECOPC, but in only 6 (14.3%) of 42 patients with esophageal cancer alone (p < 0.01). Frameshift mutations in TGFbetaRII, BAX, MSH3 and MSH6 genes respectively were present in 4, 1, 2 and 2 of 34 ECOPC patients. Immunohistochemical study showed that 12 (80.0%) of 15 MSI-H tumors showed loss of expression of either hMLH1 or hMSH2. In addition, 6 of 9 tumors (66.7%) that showed reduced hMLH1 expression also had hypermethylation of the hMLH1 promoter region. Our findings suggested that carcinogenesis in ECOPC was closely associated with the MSI pathway because of mismatch repair protein deficiency.
Kubo
Naoshi
N
Department of Surgical Oncology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan.
Yashiro
Masakazu
M
Ohira
Masaichi
M
Hori
Takeshi
T
Fujiwara
Ichiro
I
Hirakawa
Kosei
K
D048868:Adaptor Proteins, Signal Transducing; D000368:Aged; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D002352:Carrier Proteins; D043171:Chromosomal Instability / Q000235:genetics*; D019175:DNA Methylation; D017931:DNA Primers; D004273:DNA, Neoplasm / Q000302:isolation & purification; D004268:DNA-Binding Proteins / Q000235:genetics; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D005819:Genetic Markers; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009363:Neoplasm Proteins / Q000235:genetics; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics; D012907:Smoking; D016019:Survival Analysis; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D017931:DNA Primers; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D005819:Genetic Markers; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein