MOLECULAR EPIDEMIOLOGY OF BREAST CANCERS IN NORTHERN AND SOUTHERN JAPAN - THE FREQUENCY, CLUSTERING, AND PATTERNS OF P53 GENE-MUTATIONS DIFFER AMONG THESE 2 LOW-RISK POPULATIONS

Comparison of acquired mutations in the p53 tumor suppressor gene can illuminate factors contributing to carcinogenesis among cancer cohorts . Japan has an ethnically homogeneous population with a low incidence of breast cancer. Previously we reported an unusual frequency, allelic status, and clustering of mutations in breast cancers from the northe rn part of the main Japanese island. To extend these findings, exons 2 -11 and adjacent intronic sequences were analysed in tumors of women f rom northern (Hokkaido) and southern (Tokushima) Japan. The frequency of breast cancers with p53 gene mutations in the Hokkaido group is the highest reported (81%) while that in Tokushima (28%) is similar to mo st other populations. Thirteen of the 19 mutations (68.4%) in the Hokk aido cohort were heterozygous, an unusually high frequency for p53 mut ations in any tumor type. There were three missense mutations at codon 175, a known hotspot for alterations in the p53 gene, and three misse nse mutations at codon 179, a rare site for p53 changes. In addition, the patterns of p53 gene mutation differed between the two Japanese co horts (P=0.04). The multiple differences in acquired p53 mutations sug gest unsuspected biological differences among breast cancers in northe rn and southern Japan. In addition, the high frequency of p53 mutation s in breast cancers from Hokkaido predicted a poorer prognosis for thi s population which was confirmed on examination of mortality data.