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Genetic Analysis of Human Esophageal Tumors from Two High Incidence Geographic Areas: Frequent p53 Base Substitutions and Absence of ras Mutations

Laboratory of Human Carcinogenesis, National Cancer Institute, NIH, Bethesda, Maryland 20892 [M. C. H., J. A. W., R. A. M., C. C. H.]; Center of Digestive Diseases CEIED, Hospital de Clinicas "Dr. Manuel Quintela," Montevideo, Uruguay [L. P., M. B.]; Centre Beclesse, 14021 Caen, France [A. M. M.]; and International Agency for Research on Cancer, 69372 Lyon, France [R. M.]

Esophageal squamous cell carcinoma (ESC) samples from patients residing in Uruguay and in Normandy, France, where alcoholic beverages and tobacco smoke are major risk factors, were analyzed for point mutations in the p53 tumor suppressor gene. Among 34 tumors (15 from Normandy and 19 from Uruguay) 15 point mutations in the p53 gene that result in amino acid substitutions or chain termination were identified by polymerase chain reaction amplification of exons 5–8 and direct DNA sequencing.

Base substitutions in ESC from these high-incidence areas are dispersed over the midregion of the p53 gene. There are differences between ESC and other types of gastrointestinal cancer in the nature of frequent base substitutions. CpG to TpG transitions were far less prevalent in these ESC than in colorectal tumors, whereas G to T transversions, rarely found in colon cancers, were found in one-fourth of the ESC samples. Base substitutions at A:T pairs constitute an important fraction of ESC p53 mutations, in contrast to mutation patterns in most other types of solid tumors. In contrast to the frequent mutation of the p53 gene in these samples, no mutations in the H-, K-, or N-ras genes were found in 16 tumors from Uruguay by direct sequencing of exons in which transforming mutations are known to occur. A previous study on ras mutations in ESC from France was also negative (M. C. Hollstein et al., Cancer Res., 48: 5119–5123, 1988). The role of distinct etiological factors in generating these differences and the potential for linking patient exposure histories with patterns of p53 mutations in high risk populations are considered.

¹ Present address: IARC, 150 Cours Albert Thomas, 69372 Lyon, France.

² To whom requests for reprints should be addressed, at Laboratory of Human Carcinogenesis, National Cancer Institute, NIH, Building 37, Room 2C05, Bethesda, MD 20892.

Received 5/ 8/91. Accepted 6/11/91.

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