Multiple genetic alterations in small-cell lung carcinoma.

By restriction fragment length polymorphism (RFLP) analysis, it was found that loss of heterozygosity (LOH) at three different chromosomal loci, 3p, 13q, and 17p, occurs simultaneously in nearly 100% of small-cell lung carcinomas (SCLC). This was observed even in stage I tumors and an untreated tumor, and it occurred prior to NMYC amplification. The common region of LOH on chromosome 3p was 3p14-24.1, and this region was also frequently lost in carcinoma of the uterine cervix (100% at D3S2 on 3p14-21) as well as renal cell carcinoma (56% at ERBA beta on 3p22-24.1), suggesting the presence of tumor suppressor gene(s) for these cancers in this region. On chromosome 13, LOH was observed commonly in the region between 13q12 and 13q22, including the RB locus on 13q14, and normal RB protein was not detected in any of 9 SCLC cell lines by immunoprecipitation analysis. The common region of LOH on chromosome 17 was 17p13 and is the same as that in colon carcinoma and osteogenic sarcoma. Since LOH is supposed to unmask the recessive mutation of tumor suppressor gene in the remaining allele, these results may imply that at least six genetic alterations are necessary to convert a normal cell into a fully malignant cancer cell in SCLC. RFLP analysis was performed on several other types of human cancers, including carcinoma of the uterine cervix, neuroblastoma, hepatocellular carcinoma, pheochromocytoma, and stomach cancer to determine the chromosomal loci of putative tumor suppressor genes in each tumor. Chromosomal loci showing frequent LOH were different among these tumors.(ABSTRACT TRUNCATED AT 250 WORDS)