Distinct pattern of TP53 mutations in squamous cell carcinoma of the esophagus in Iran.
Extremely high rates of squamous cell carcinoma of the esophagus (SCCE) are observed in Iran, reflecting unknown, genetic and/or epidemiological risk factors. Among genetic alterations in SCCE, TP53 mutations are the most frequent, vary among populations, and may provide clues on etiological mechanisms. We have analysed mutations in TP53 (exons 5-8) in 98 SCCE from Iran by temporal temperature gel electrophoresis and direct sequencing. We found 58 mutations in 49 patients (50%), with a high prevalence of C to T transitions at CpG dinucleotides (29.3%). The TP53 mutation pattern in Iran was significantly different from that observed in SCCEs from high incidence areas of China and Western Europe (P=0.007). Moreover, the prevalence of mutations at A : T base pairs (transitions and transversions) was higher in men than in women (38.7% vs 11.1%, P=0.033). COX-2 overexpression was detected in 69% of the cases evaluated (24/35), without significant association with TP53 mutation. Accumulation of nitrotyrosine, a marker of protein damage by excess levels of nitric oxide, was observed in tumor cells in six of 18 [corrected] cases analysed. These results are consistent with the hypothesis that several factors are involved in TP53 mutagenesis in Iran. These factors include a baseline of chronic inflammatory stress, which may have a multiplicative impact on the sensitivity of esophageal cells to exogenous factors of risk.
Sepehr
A
A
Group of Molecular Carcinogenesis, International Agency for Research on Cancer (IARC), 150, cours Albert-Thomas, Lyon 69008, France.
Tanière
P
P
Martel-Planche
G
G
Zia'ee
A A
AA
Rastgar-Jazii
F
F
Yazdanbod
M
M
Etemad-Moghadam
G
G
Kamangar
F
F
Saidi
F
F
Hainaut
P
P
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002294:Carcinoma, Squamous Cell / Q000453:epidemiology / Q000209:etiology / Q000235:genetics*; D002681:China / Q000453:epidemiology; D002908:Chronic Disease; D003062:Codon / Q000235:genetics; D018389:Codon, Nonsense; D018899:CpG Islands; D051546:Cyclooxygenase 2; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics*; D004938:Esophageal Neoplasms / Q000453:epidemiology / Q000209:etiology / Q000235:genetics*; D004941:Esophagitis / Q000150:complications; D005060:Europe / Q000453:epidemiology; D005091:Exons / Q000235:genetics; D005260:Female; D016368:Frameshift Mutation; D016158:Genes, p53; D006801:Humans; D015994:Incidence; D007492:Iran / Q000453:epidemiology; D007527:Isoenzymes / Q000032:analysis; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D009154:Mutation; D009363:Neoplasm Proteins / Q000032:analysis; D009569:Nitric Oxide / Q000096:biosynthesis; D017354:Point Mutation; D011451:Prostaglandin-Endoperoxide Synthases / Q000032:analysis; D012307:Risk Factors; D017422:Sequence Analysis, DNA; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000032:analysis
D003062:Codon; D018389:Codon, Nonsense; D004273:DNA, Neoplasm; D007527:Isoenzymes; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases