Loss-of-heterozygosity analysis of small-cell lung carcinomas using single-nucleotide polymorphism arrays

Human cancers arise by a combination of discrete mutations and chromosomal alterations. Loss of heterozygosity (LOH) of chromosomal regions bearing mu tated tumor suppressor genes is a key event in the evolution of epithelial and mesenchymal tumors'. Global patterns of LOH can be understood through a llelotyping of tumors with polymorphic genetic markers(2), Simple sequence length polymorphisms (SSLPs, or microsatellites) are reliable genetic marke rs for studying LOH3, but only a modest number of SSLPs are used in LOH stu dies because the genotyping procedure is rather tedious. Here, we report th e use of a highly parallel approach to genotype large numbers of single-nuc leotide polymorphisms (SNPs) for LOH, in which samples are genotyped for ne arly 1,500 loci by performing 24 polymerase chain reactions (PCR), Fooling the resulting amplification products and hybridizing the mixture to a high- density oligonucleotide array(4). We characterize the results of LOH analys es on human small-cell lung cancer (SCLC) and control DNA samples by hybrid ization. We show that the patterns of LOH are consistent with those obtaine d by analysis with both SSLPs(5) and comparative genomic hybridization (CGH ), whereas amplifications rarely are detected by the SNP array. The results validate the use of SNP array hybridization for tumor studies.