Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Technical Report
  • Published:

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

Nature Biotechnology volume 18, pages 1001–1005 (2000)Cite this article

Abstract

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

References

  1. Weinberg, R.A. Tumor suppressor genes. Science 254, 1138–1146 (1991).

    Article  CAS  Google Scholar 

  2. Vogelstein, B. et al. Allelotype of colorectal carcinomas. Science 244, 207–211 (1989).

    Article  CAS  Google Scholar 

  3. Weissenbach, J. et al. A second-generation linkage map of the human genome. Nature 359, 794–801 (1992).

    Article  CAS  Google Scholar 

  4. Wang, D.G. et al. Large-scale identification, mapping, and genotyping of single-nucleotide polymorphisms in the human genome. Science 280, 1077–1082 (1998).

    Article  CAS  Google Scholar 

  5. Stanton, S.E., Shin, S.W., Johnson, B.E. & Meyerson, M. Recurrent allelic deletions of chromosome arms 15q and 16q in human small cell lung carcinomas. Genes Chromosom. Cancer 27, 323–331 (2000).

    Article  CAS  Google Scholar 

  6. Lindblad-Toh, K. et al. Large-scale discovery and genotyping of single-nucleotide polymorphisms in the mouse. Nat. Genet. 24, 381–386 (2000).

    Article  CAS  Google Scholar 

  7. Hahn, S.A. et al. Allelotype of pancreatic adenocarcinoma using xenograft enrichment. Cancer Res. 55, 4670–4675 (1995).

    CAS  Google Scholar 

  8. Whang-Peng, J. et al. A nonrandom chromosomal abnormality, del 3p(14-23), in human small cell lung cancer (SCLC). Cancer Genet. Cytogenet. 6, 119–134 (1982).

    Article  CAS  Google Scholar 

  9. Naylor, S.L., Johnson, B.E., Minna, J.D. & Sakaguchi, A.Y. Loss of heterozygosity of chromosome 3p markers in small-cell lung cancer. Nature 329, 451–454 (1987).

    Article  CAS  Google Scholar 

  10. Johnson, B.E. et al. myc family DNA amplification in small cell lung cancer patients' tumors and corresponding cell lines. Cancer Res. 48, 5163–5166 (1988).

    CAS  PubMed  Google Scholar 

  11. Ried, T. et al. Mapping of multiple DNA gains and losses in primary small cell lung carcinomas by comparative genomic hybridization. Cancer Res. 54, 1801–1806 (1994).

    CAS  PubMed  Google Scholar 

  12. Levin, N.A., Brzoska, P.M., Warnock, M.L., Gray, J.W. & Christman, M.F. Identification of novel regions of altered DNA copy number in small cell lung tumors. Genes Chromosom. Cancer 13, 175–185 (1995).

    Article  CAS  Google Scholar 

  13. Petersen, I. et al. Small-cell lung cancer is characterized by a high incidence of deletions on chromosomes 3p, 4q, 5q, 10q, 13q and 17p. Br. J. Cancer 75, 79–86 (1997).

    Article  CAS  Google Scholar 

  14. Farnebo, F. et al. Alternative genetic pathways in parathyroid tumorigenesis. J. Clin. Endocrinol. Metab. 84, 3775–3780 (1999).

    CAS  PubMed  Google Scholar 

  15. Stanford Human Genome Center RH Server. http://www.shgc.stanford.edu/RH/index.html

  16. Walter, M., Spillett, D., Thomas, P., Weissenbach, J. & Goodfellow, P. A method for constructing radiation hybrid maps of whole genomes. Nat. Genet. 7, 22–28 (1994).

    Article  CAS  Google Scholar 

  17. RHmapper. http://www.genome.wi.mit.edu/cgi-bin/contig/rhmapper.pl

  18. Brodeur, G.M., Williams, D.L., Look, A.T., Bowman, W.P. & Kalwinsky, D.K. Near-haploid acute lymphoblastic leukemia: a unique subgroup with a poor prognosis? Blood 58, 14–19 (1981).

    CAS  PubMed  Google Scholar 

  19. SCLC-SNP-LOH site. http://www.genome.wi.mit.edu/SNP/human/LOH/

Download references

Acknowledgements

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.

Author information

Author notes

  1. Kerstin Lindblad-Toh and David M. Tanenbaum: These two authors contributed equally to this work.

Authors and Affiliations

  1. Whitehead Institute/MIT Center for Genome Research, Whitehead Institute for Biomedical Research, Cambridge, 02139, MA

    Kerstin Lindblad-Toh, Mark J. Daly, Ellen Winchester, Anuradha Villapakkam, Thomas J. Hudson & Eric S. Lander

  2. Department of Adult Oncology, Dana-Farber Cancer Institute, Boston, MA

    David M. Tanenbaum, Sasha E. Stanton, Bruce E. Johnson & Matthew Meyerson

  3. Department of Medicine, Harvard Medical School, Boston, MA

    David M. Tanenbaum & Bruce E. Johnson

  4. Department of Pathology, Harvard Medical School, Boston, MA

    David M. Tanenbaum & Matthew Meyerson

  5. Department of Molecular Medicine, CMM, Karolinska Hospital, Stockholm, S-171 76, Sweden

    Weng-Onn Lui & Catharina Larsson

  6. Montreal Genome Centre, McGill University Health Centre, Montréal, Québec

    Thomas J. Hudson

  7. Department of Biology, Massachusetts Institute of Technology, Cambridge, 02142, MA

    Eric S. Lander

Authors
  1. Kerstin Lindblad-Toh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David M. Tanenbaum
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mark J. Daly
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ellen Winchester
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Weng-Onn Lui
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Anuradha Villapakkam
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sasha E. Stanton
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Catharina Larsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Thomas J. Hudson
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Bruce E. Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Eric S. Lander
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Matthew Meyerson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Eric S. Lander or Matthew Meyerson.

Rights and permissions

Reprints and permissions

About this article

Cite this article

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). https://doi.org/10.1038/79269

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/79269

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing