Analysis of the L-MYC gene polymorphisms and tumor prognosis in Italian and Japanese lung cancer patients

Monica Spinola1, Tomoko Nomoto2, Giacomo Manenti1, Pier Paolo Brega Massone1, Ignazio Cataldo1, Pinuccia Valagussa, Matteo Incarbone3, Toshikazu Ushijima2, Tommaso A. Dragani1

1 Istituto Nazionale Tumori, Milano, Italy

2 National Cancer Center Research Institute, Tokyo, Japan

3 Istituto Clinico Humanitas, Rozzano, Italy

Patients with tumor of the same histotype and with similar clinicopathological features show great differences in their prognosis. Variation in cancer progression may depend on either somatic alterations accumulated in the neoplastic lesions or genetic polymorphisms. Indeed, an intragenic EcoRI RFLP of the L-MYC gene significantly correlated with lung tumor prognosis in Japanese and Chinese patients. L-MYC maps in a human chromosomal region (1p34) homologous to the mouse region where the Papg1 locus that specifically affects the growth of lung tumors has been mapped. These results in humans and in an experimental disease model indicate that L-MYC itself or a nearby gene in linkage disequilibrium (LD) with it may affect tumor prognosis. We analyzed the nucleotide sequence of the coding and non-coding regions of the L-MYC gene (~ 6000 bp) in 10-14 Italian lung cancer patients. We found no polymorphisms in the coding regions, but we confirmed the EcoRI polymorphism (position 3109 of the gene) and found two additional single nucleotide polymorphisms (SNPs) in the 3'-UTR, located at position 5453 and 6130, respectively. The three SNPs were genotyped by allele specific oligonucleotide hybridization in 203 Italian adenocarcinoma patients and in 116 Japanese non-small cell lung cancer patients. In the Italian population, the EcoRI polymorphism showed a significant LD with the other two SNPs; however, the 3'-UTR polymorphisms showed no significant LD between them despite their short distance. No significant association was found between any of the three SNPs and clinical stage or survival. In the Japanese population, the allele frequency of the EcoRI SNP was similar to that of the Italian population (0.49 vs. 0.44). However, the less abundant alleles of the 3'-UTR SNPs (frequencies in the Italian population of 0.17 and 0.24, respectively) were either absent or very rare (0.009) in the Japanese population. These results showed that significant LD between intragenic SNPs may not correlate with their physical distance and that different human populations may show significantly different allele frequency in multiple SNPs located in the same gene. The differences in allele frequency and LD patterns in different populations may explain the contrasting results in the Asian and Caucasian population on the role of the L-MYC EcoRI polymorphism in lung tumor prognosis.

A poster reporting the results of the cited research, carried out through the Associazione Marta Nurizzo fellowship, was presented at the American Association for Cancer Research Meeting, hold in New Orleans, LA (USA), march 24th-28th 2001.