Skip to main content
PMC home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1994 Jun 7;91(12):5513–5517. doi: 10.1073/pnas.91.12.5513

Three tumor-suppressor regions on chromosome 11p identified by high-resolution deletion mapping in human non-small-cell lung cancer.

G Bepler 1, M A Garcia-Blanco 1
PMCID: PMC44026  PMID: 8202519

Abstract

Non-small-cell lung cancer is the leading cause of cancer death for men and women in the industrialized nations. Identification of regions for genes involved in its pathogenesis has been difficult. Data presented here show three distinct regions identified on chromosome 11p. Two regions on 11p13 distal to the Wilms tumor gene WT1 and on 11p15.5 between the markers HBB and D11S860 are described. The third region on the telomere of 11p15.5 has been previously described and is further delineated in this communication. By high-resolution mapping the size of each of these regions was estimated to be 2-3 megabases. The frequency of somatic loss of genetic information in these regions (57%, 71%, and 45%, respectively) was comparable to that seen in heritable tumors such as Wilms tumor (55%) and retinoblastoma (70%) and suggests their involvement in pathogenesis of non-small-cell lung cancer. Gene dosage analyses revealed duplication of the remaining allele in the majority of cases in the 11p13 and the proximal 11p15.5 region but rarely in the distal 11p15.5 region. In tumors with loss of heterozygosity in all three regions any combination of duplication or simple deletion was observed, suggesting that loss of heterozygosity occurs independently and perhaps at different points in time. These results provide a basis for studies directed at cloning potential tumor-suppressor genes in these regions and for assessing their biological and clinical significance in non-small-cell lung cancer.

Full text

PDF
5513

Images in this article

5514Image
on p.5514
5515Image
on p.5515
5516Image
on p.5516
5516Image
on p.5516

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ali I. U., Lidereau R., Theillet C., Callahan R. Reduction to homozygosity of genes on chromosome 11 in human breast neoplasia. Science. 1987 Oct 9;238(4824):185–188. doi: 10.1126/science.3659909. [DOI] [PubMed] [Google Scholar]
  2. Blin N., Stafford D. W. A general method for isolation of high molecular weight DNA from eukaryotes. Nucleic Acids Res. 1976 Sep;3(9):2303–2308. doi: 10.1093/nar/3.9.2303. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Boring C. C., Squires T. S., Tong T. Cancer statistics, 1993. CA Cancer J Clin. 1993 Jan-Feb;43(1):7–26. doi: 10.3322/canjclin.43.1.7. [DOI] [PubMed] [Google Scholar]
  4. Brauch H., Johnson B., Hovis J., Yano T., Gazdar A., Pettengill O. S., Graziano S., Sorenson G. D., Poiesz B. J., Minna J. Molecular analysis of the short arm of chromosome 3 in small-cell and non-small-cell carcinoma of the lung. N Engl J Med. 1987 Oct 29;317(18):1109–1113. doi: 10.1056/NEJM198710293171803. [DOI] [PubMed] [Google Scholar]
  5. Call K. M., Glaser T., Ito C. Y., Buckler A. J., Pelletier J., Haber D. A., Rose E. A., Kral A., Yeger H., Lewis W. H. Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. Cell. 1990 Feb 9;60(3):509–520. doi: 10.1016/0092-8674(90)90601-a. [DOI] [PubMed] [Google Scholar]
  6. Cavenee W. K., Dryja T. P., Phillips R. A., Benedict W. F., Godbout R., Gallie B. L., Murphree A. L., Strong L. C., White R. L. Expression of recessive alleles by chromosomal mechanisms in retinoblastoma. 1983 Oct 27-Nov 2Nature. 305(5937):779–784. doi: 10.1038/305779a0. [DOI] [PubMed] [Google Scholar]
  7. Center R., Lukeis R., Dietzsch E., Gillespie M., Garson O. M. Molecular deletion of 9p sequences in non-small cell lung cancer and malignant mesothelioma. Genes Chromosomes Cancer. 1993 May;7(1):47–53. doi: 10.1002/gcc.2870070108. [DOI] [PubMed] [Google Scholar]
  8. D'Amico D., Carbone D. P., Johnson B. E., Meltzer S. J., Minna J. D. Polymorphic sites within the MCC and APC loci reveal very frequent loss of heterozygosity in human small cell lung cancer. Cancer Res. 1992 Apr 1;52(7):1996–1999. [PubMed] [Google Scholar]
  9. Edwards A., Civitello A., Hammond H. A., Caskey C. T. DNA typing and genetic mapping with trimeric and tetrameric tandem repeats. Am J Hum Genet. 1991 Oct;49(4):746–756. [PMC free article] [PubMed] [Google Scholar]
  10. Emi M., Fujiwara Y., Nakajima T., Tsuchiya E., Tsuda H., Hirohashi S., Maeda Y., Tsuruta K., Miyaki M., Nakamura Y. Frequent loss of heterozygosity for loci on chromosome 8p in hepatocellular carcinoma, colorectal cancer, and lung cancer. Cancer Res. 1992 Oct 1;52(19):5368–5372. [PubMed] [Google Scholar]
  11. Fearon E. R., Feinberg A. P., Hamilton S. H., Vogelstein B. Loss of genes on the short arm of chromosome 11 in bladder cancer. 1985 Nov 28-Dec 4Nature. 318(6044):377–380. doi: 10.1038/318377a0. [DOI] [PubMed] [Google Scholar]
  12. Fearon E. R., Vogelstein B., Feinberg A. P. Somatic deletion and duplication of genes on chromosome 11 in Wilms' tumours. Nature. 1984 May 10;309(5964):176–178. doi: 10.1038/309176a0. [DOI] [PubMed] [Google Scholar]
  13. Feinberg A. P., Vogelstein B. "A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity". Addendum. Anal Biochem. 1984 Feb;137(1):266–267. doi: 10.1016/0003-2697(84)90381-6. [DOI] [PubMed] [Google Scholar]
  14. Hudson T. J., Engelstein M., Lee M. K., Ho E. C., Rubenfield M. J., Adams C. P., Housman D. E., Dracopoli N. C. Isolation and chromosomal assignment of 100 highly informative human simple sequence repeat polymorphisms. Genomics. 1992 Jul;13(3):622–629. doi: 10.1016/0888-7543(92)90133-d. [DOI] [PubMed] [Google Scholar]
  15. Huff V., Compton D. A., Strong L. C., Saunders G. F. A panel of restriction fragment length polymorphisms for chromosomal band 11p13. Hum Genet. 1990 Feb;84(3):253–257. doi: 10.1007/BF00200570. [DOI] [PubMed] [Google Scholar]
  16. Koi M., Johnson L. A., Kalikin L. M., Little P. F., Nakamura Y., Feinberg A. P. Tumor cell growth arrest caused by subchromosomal transferable DNA fragments from chromosome 11. Science. 1993 Apr 16;260(5106):361–364. doi: 10.1126/science.8469989. [DOI] [PubMed] [Google Scholar]
  17. Lichter J. B., Barr C. L., Kennedy J. L., Van Tol H. H., Kidd K. K., Livak K. J. A hypervariable segment in the human dopamine receptor D4 (DRD4) gene. Hum Mol Genet. 1993 Jun;2(6):767–773. doi: 10.1093/hmg/2.6.767. [DOI] [PubMed] [Google Scholar]
  18. Lichy J. H., Modi W. S., Seuanez H. N., Howley P. M. Identification of a human chromosome 11 gene which is differentially regulated in tumorigenic and nontumorigenic somatic cell hybrids of HeLa cells. Cell Growth Differ. 1992 Aug;3(8):541–548. [PubMed] [Google Scholar]
  19. Lukeis R., Irving L., Garson M., Hasthorpe S. Cytogenetics of non-small cell lung cancer: analysis of consistent non-random abnormalities. Genes Chromosomes Cancer. 1990 Jul;2(2):116–124. doi: 10.1002/gcc.2870020207. [DOI] [PubMed] [Google Scholar]
  20. McNoe L. A., Eccles M. R., Reeve A. E. Dinucleotide repeat polymorphism at the D11S860 locus. Nucleic Acids Res. 1992 Mar 11;20(5):1161–1161. doi: 10.1093/nar/20.5.1161-a. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Miyagi M., Inazawa J., Takita K., Nakamura Y. Cloning and characterization of an interstitial deletion at chromosome 11p15 in a sporadic breast cancer. Hum Mol Genet. 1992 Dec;1(9):705–708. doi: 10.1093/hmg/1.9.705. [DOI] [PubMed] [Google Scholar]
  22. 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. 1987 Oct 1;329(6138):451–454. doi: 10.1038/329451a0. [DOI] [PubMed] [Google Scholar]
  23. Ogawa O., Eccles M. R., Szeto J., McNoe L. A., Yun K., Maw M. A., Smith P. J., Reeve A. E. Relaxation of insulin-like growth factor II gene imprinting implicated in Wilms' tumour. Nature. 1993 Apr 22;362(6422):749–751. doi: 10.1038/362749a0. [DOI] [PubMed] [Google Scholar]
  24. Olopade O. I., Buchhagen D. L., Malik K., Sherman J., Nobori T., Bader S., Nau M. M., Gazdar A. F., Minna J. D., Diaz M. O. Homozygous loss of the interferon genes defines the critical region on 9p that is deleted in lung cancers. Cancer Res. 1993 May 15;53(10 Suppl):2410–2415. [PubMed] [Google Scholar]
  25. Ooi W. L., Elston R. C., Chen V. W., Bailey-Wilson J. E., Rothschild H. Increased familial risk for lung cancer. J Natl Cancer Inst. 1986 Feb;76(2):217–222. [PubMed] [Google Scholar]
  26. Radice P., Pierotti M. A., Lacerenza S., Mondini P., Radice M. T., Pilotti S., Della Porta G. Loss of heterozygosity in human germinal tumors. Cytogenet Cell Genet. 1989;52(1-2):72–76. doi: 10.1159/000132843. [DOI] [PubMed] [Google Scholar]
  27. Rainier S., Johnson L. A., Dobry C. J., Ping A. J., Grundy P. E., Feinberg A. P. Relaxation of imprinted genes in human cancer. Nature. 1993 Apr 22;362(6422):747–749. doi: 10.1038/362747a0. [DOI] [PubMed] [Google Scholar]
  28. Reeve A. E., Sih S. A., Raizis A. M., Feinberg A. P. Loss of allelic heterozygosity at a second locus on chromosome 11 in sporadic Wilms' tumor cells. Mol Cell Biol. 1989 Apr;9(4):1799–1803. doi: 10.1128/mcb.9.4.1799. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Scrable H. J., Witte D. P., Lampkin B. C., Cavenee W. K. Chromosomal localization of the human rhabdomyosarcoma locus by mitotic recombination mapping. Nature. 1987 Oct 15;329(6140):645–647. doi: 10.1038/329645a0. [DOI] [PubMed] [Google Scholar]
  30. Scrable H., Cavenee W., Ghavimi F., Lovell M., Morgan K., Sapienza C. A model for embryonal rhabdomyosarcoma tumorigenesis that involves genome imprinting. Proc Natl Acad Sci U S A. 1989 Oct;86(19):7480–7484. doi: 10.1073/pnas.86.19.7480. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Sellers T. A., Bailey-Wilson J. E., Elston R. C., Wilson A. F., Elston G. Z., Ooi W. L., Rothschild H. Evidence for mendelian inheritance in the pathogenesis of lung cancer. J Natl Cancer Inst. 1990 Aug 1;82(15):1272–1279. doi: 10.1093/jnci/82.15.1272. [DOI] [PubMed] [Google Scholar]
  32. Semenza G. L., Dowling C. E., Kazazian H. H., Jr Hinf I polymorphism 3' to the human beta-globin gene detected by the polymerase chain reaction (PCR). Nucleic Acids Res. 1989 Mar 25;17(6):2376–2376. doi: 10.1093/nar/17.6.2376. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Skinner M. A., Vollmer R., Huper G., Abbott P., Iglehart J. D. Loss of heterozygosity for genes on 11p and the clinical course of patients with lung carcinoma. Cancer Res. 1990 Apr 15;50(8):2303–2306. [PubMed] [Google Scholar]
  34. Southern E. M. Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Biol. 1975 Nov 5;98(3):503–517. doi: 10.1016/s0022-2836(75)80083-0. [DOI] [PubMed] [Google Scholar]
  35. Theillet C., Lidereau R., Escot C., Hutzell P., Brunet M., Gest J., Schlom J., Callahan R. Loss of a c-H-ras-1 allele and aggressive human primary breast carcinomas. Cancer Res. 1986 Sep;46(9):4776–4781. [PubMed] [Google Scholar]
  36. Wadey R. B., Pal N., Buckle B., Yeomans E., Pritchard J., Cowell J. K. Loss of heterozygosity in Wilms' tumour involves two distinct regions of chromosome 11. Oncogene. 1990 Jun;5(6):901–907. [PubMed] [Google Scholar]
  37. Weber J. L., Kwitek A. E., May P. E. Dinucleotide repeat polymorphisms at the D11S419 and CD3D loci. Nucleic Acids Res. 1990 Jul 11;18(13):4036–4036. doi: 10.1093/nar/18.13.4036. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Weissenbach J., Gyapay G., Dib C., Vignal A., Morissette J., Millasseau P., Vaysseix G., Lathrop M. A second-generation linkage map of the human genome. Nature. 1992 Oct 29;359(6398):794–801. doi: 10.1038/359794a0. [DOI] [PubMed] [Google Scholar]
  39. Weston A., Willey J. C., Modali R., Sugimura H., McDowell E. M., Resau J., Light B., Haugen A., Mann D. L., Trump B. F. Differential DNA sequence deletions from chromosomes 3, 11, 13, and 17 in squamous-cell carcinoma, large-cell carcinoma, and adenocarcinoma of the human lung. Proc Natl Acad Sci U S A. 1989 Jul;86(13):5099–5103. doi: 10.1073/pnas.86.13.5099. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Whang-Peng J., Knutsen T., Gazdar A., Steinberg S. M., Oie H., Linnoila I., Mulshine J., Nau M., Minna J. D. Nonrandom structural and numerical chromosome changes in non-small-cell lung cancer. Genes Chromosomes Cancer. 1991 May;3(3):168–188. doi: 10.1002/gcc.2870030303. [DOI] [PubMed] [Google Scholar]
  41. Williams J. C., Brown K. W., Mott M. G., Maitland N. J. Maternal allele loss in Wilms' tumour. Lancet. 1989 Feb 4;1(8632):283–284. doi: 10.1016/s0140-6736(89)91300-7. [DOI] [PubMed] [Google Scholar]
  42. Yokoyama S., Yamakawa K., Tsuchiya E., Murata M., Sakiyama S., Nakamura Y. Deletion mapping on the short arm of chromosome 3 in squamous cell carcinoma and adenocarcinoma of the lung. Cancer Res. 1992 Feb 15;52(4):873–877. [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES