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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 mutated tumor suppressor genes is a key event in the evolution of epithelial and mesenchymal tumors1. Global patterns of LOH can be understood through allelotyping of tumors with polymorphic genetic markers2. Simple sequence length polymorphisms (SSLPs, or microsatellites) are reliable genetic markers for studying LOH3, but only a modest number of SSLPs are used in LOH studies because the genotyping procedure is rather tedious. Here, we report the use of a highly parallel approach to genotype large numbers of single-nucleotide polymorphisms (SNPs) for LOH, in which samples are genotyped for nearly 1,500 loci by performing 24 polymerase chain reactions (PCR), pooling the resulting amplification products and hybridizing the mixture to a high-density oligonucleotide array4. We characterize the results of LOH analyses on human small-cell lung cancer (SCLC) and control DNA samples by hybridization. We show that the patterns of LOH are consistent with those obtained by analysis with both SSLPs5 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.

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Figure 1: (A) Representative images of fluorescence intensities for SNP array hybridization to normal and tumor DNA samples.
Figure 2: Maps of chromosome 3 (A) and 20 (B) with estimated windows of LOH19.
Figure 3: Fraction of tumors showing allelic imbalance/LOH using either SNP (black), SSLP (striped), or CGH (gray) or gain using CGH (white) on each p (A) and q (B) arm of the chromosomes.


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We thank T. Webster, N. Nouri, N. Patil, and T. Ryder at Affymetrix, Inc., for valuable assistance with the HuSNP chip. This research was supported in part by a research contract from Bristol-Myers Squibb, Millennium Pharmaceuticals, Inc., Affymetrix (E.S.L. and T.J.H.), and grants from the Pew Foundation (M.M.), the American Lung Association (M.M.), and the National Institutes of Health (HG01806). K.L. is the recipient of a scholarship from the Swedish Institute (4478/1998). D.M.T. is the recipient of a Harvard Medical School Pathology Fellowship (5T34CA72320-03). L.W.O and C.L. were supported by the Swedish Cancer Foundation and by the Torsten and Ragnar Söderberg Foundations. T.J.H. is a recipient of a clinician-scientist award from the Medical Research Council of Canada.

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Correspondence to Eric S. Lander or Matthew Meyerson.

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Lindblad-Toh, K., Tanenbaum, D., Daly, M. et al. Loss-of-heterozygosity analysis of small-cell lung carcinomas using single-nucleotide polymorphism arrays. Nat Biotechnol 18, 1001–1005 (2000).

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