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. 1997;75(1):79–86. doi: 10.1038/bjc.1997.13

Small-cell lung cancer is characterized by a high incidence of deletions on chromosomes 3p, 4q, 5q, 10q, 13q and 17p.

I Petersen 1, H Langreck 1, G Wolf 1, A Schwendel 1, R Psille 1, P Vogt 1, M B Reichel 1, T Ried 1, M Dietel 1
PMCID: PMC2222682  PMID: 9000602

Abstract

The genetic mechanisms that define the malignant behaviour of small-cell lung cancer (SCLC) are poorly understood. We performed comparative genomic hybridization (CGH) on 22 autoptic SCLCs to screen the tumour genome for genomic imbalances. DNA loss of chromosome 3p was a basic alteration that occurred in all tumours. Additionally, deletions were observed on chromosome 10q in 94% of tumours and on chromosomes 4q, 5q, 13q and 17p in 86% of tumours. DNA loss was confirmed by loss of heterozygosity (LOH) analysis for chromosomes 3p, 5q and 10q. Simultaneous mutations of these six most abundant genetic changes were found in 12 cases. One single tumour carried at least five deletions. DNA under-representations were observed less frequently on chromosome 15q (55%) and chromosome 16q (45%). The prevalent imbalances were clearly indicated by the superposition of the 22 tumours to a CGH superkaryogram. In our view, the high incidence of chromosomal loss is an indication that SCLC is defined by a pattern of deletions and that the inactivation of multiple growth-inhibitory pathways contributes in particular to the aggressive phenotype of that type of tumour.

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Selected References

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

  1. Brennan J., O'Connor T., Makuch R. W., Simmons A. M., Russell E., Linnoila R. I., Phelps R. M., Gazdar A. F., Ihde D. C., Johnson B. E. myc family DNA amplification in 107 tumors and tumor cell lines from patients with small cell lung cancer treated with different combination chemotherapy regimens. Cancer Res. 1991 Mar 15;51(6):1708–1712. [PubMed] [Google Scholar]
  2. Brison O. Gene amplification and tumor progression. Biochim Biophys Acta. 1993 May 25;1155(1):25–41. doi: 10.1016/0304-419x(93)90020-d. [DOI] [PubMed] [Google Scholar]
  3. Brzoska P. M., Levin N. A., Fu K. K., Kaplan M. J., Singer M. I., Gray J. W., Christman M. F. Frequent novel DNA copy number increase in squamous cell head and neck tumors. Cancer Res. 1995 Jul 15;55(14):3055–3059. [PubMed] [Google Scholar]
  4. Buetow K. H., Murray J. C., Israel J. L., London W. T., Smith M., Kew M., Blanquet V., Brechot C., Redeker A., Govindarajah S. Loss of heterozygosity suggests tumor suppressor gene responsible for primary hepatocellular carcinoma. Proc Natl Acad Sci U S A. 1989 Nov;86(22):8852–8856. doi: 10.1073/pnas.86.22.8852. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Cottrell S., Bodmer W. F. Two MspI polymorphisms within the APC gene. Hum Mol Genet. 1992 Aug;1(5):352–352. doi: 10.1093/hmg/1.5.352-a. [DOI] [PubMed] [Google Scholar]
  6. Eagle L. R., Yin X., Brothman A. R., Williams B. J., Atkin N. B., Prochownik E. V. Mutation of the MXI1 gene in prostate cancer. Nat Genet. 1995 Mar;9(3):249–255. doi: 10.1038/ng0395-249. [DOI] [PubMed] [Google Scholar]
  7. Field J. K., Spandidos D. A., Stell P. M., Vaughan E. D., Evan G. I., Moore J. P. Elevated expression of the c-myc oncoprotein correlates with poor prognosis in head and neck squamous cell carcinoma. Oncogene. 1989 Dec;4(12):1463–1468. [PubMed] [Google Scholar]
  8. Fox W., Scadding J. G. Medical Research Council comparative trial of surgery and radiotherapy for primary treatment of small-celled or oat-celled carcinoma of bronchus. Ten-year follow-up. Lancet. 1973 Jul 14;2(7820):63–65. doi: 10.1016/s0140-6736(73)93260-1. [DOI] [PubMed] [Google Scholar]
  9. Ganly P. S., Rabbitts P. H. Polymerase chain reaction (PCR) for detection of BamHI polymorphism at the THRB gene. Nucleic Acids Res. 1991 Jul 11;19(13):3757–3757. [PMC free article] [PubMed] [Google Scholar]
  10. Ganly P. S., Rabbitts P. H. Polymerase chain reaction (PCR) for detection of MspI polymorphism at the D3S30 locus. Nucleic Acids Res. 1991 Jul 11;19(13):3757–3757. [PMC free article] [PubMed] [Google Scholar]
  11. Hibi K., Takahashi T., Yamakawa K., Ueda R., Sekido Y., Ariyoshi Y., Suyama M., Takagi H., Nakamura Y., Takahashi T. Three distinct regions involved in 3p deletion in human lung cancer. Oncogene. 1992 Mar;7(3):445–449. [PubMed] [Google Scholar]
  12. Hosoe S., Ueno K., Shigedo Y., Tachibana I., Osaki T., Kumagai T., Tanio Y., Kawase I., Nakamura Y., Kishimoto T. A frequent deletion of chromosome 5q21 in advanced small cell and non-small cell carcinoma of the lung. Cancer Res. 1994 Apr 1;54(7):1787–1790. [PubMed] [Google Scholar]
  13. Isola J. J., Kallioniemi O. P., Chu L. W., Fuqua S. A., Hilsenbeck S. G., Osborne C. K., Waldman F. M. Genetic aberrations detected by comparative genomic hybridization predict outcome in node-negative breast cancer. Am J Pathol. 1995 Oct;147(4):905–911. [PMC free article] [PubMed] [Google Scholar]
  14. Isshiki K., Elder D. E., Guerry D., Linnenbach A. J. Chromosome 10 allelic loss in malignant melanoma. Genes Chromosomes Cancer. 1993 Nov;8(3):178–184. doi: 10.1002/gcc.2870080307. [DOI] [PubMed] [Google Scholar]
  15. Johnson R. E., Brereton H. D., Kent C. H. "Total" therapy for small cell carcinoma of the lung. Ann Thorac Surg. 1978 Jun;25(6):510–515. doi: 10.1016/s0003-4975(10)63599-0. [DOI] [PubMed] [Google Scholar]
  16. Kallioniemi A., Kallioniemi O. P., Sudar D., Rutovitz D., Gray J. W., Waldman F., Pinkel D. Comparative genomic hybridization for molecular cytogenetic analysis of solid tumors. Science. 1992 Oct 30;258(5083):818–821. doi: 10.1126/science.1359641. [DOI] [PubMed] [Google Scholar]
  17. Kallioniemi O. P., Kallioniemi A., Piper J., Isola J., Waldman F. M., Gray J. W., Pinkel D. Optimizing comparative genomic hybridization for analysis of DNA sequence copy number changes in solid tumors. Genes Chromosomes Cancer. 1994 Aug;10(4):231–243. doi: 10.1002/gcc.2870100403. [DOI] [PubMed] [Google Scholar]
  18. Kelley M. J., Nakagawa K., Steinberg S. M., Mulshine J. L., Kamb A., Johnson B. E. Differential inactivation of CDKN2 and Rb protein in non-small-cell and small-cell lung cancer cell lines. J Natl Cancer Inst. 1995 May 17;87(10):756–761. doi: 10.1093/jnci/87.10.756. [DOI] [PubMed] [Google Scholar]
  19. Koorey D. J., McCaughan G. W., Trent R. J., Gallagher N. D. Dinucleotide repeat polymorphism at the D5S134 locus linked to the adenomatous polyposis coli (APC) gene. Hum Mol Genet. 1992 Nov;1(8):655–655. doi: 10.1093/hmg/1.8.655. [DOI] [PubMed] [Google Scholar]
  20. Leenstra S., Bijlsma E. K., Troost D., Oosting J., Westerveld A., Bosch D. A., Hulsebos T. J. Allele loss on chromosomes 10 and 17p and epidermal growth factor receptor gene amplification in human malignant astrocytoma related to prognosis. Br J Cancer. 1994 Oct;70(4):684–689. doi: 10.1038/bjc.1994.373. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Levin N. A., Brzoska P., Gupta N., Minna J. D., Gray J. W., Christman M. F. Identification of frequent novel genetic alterations in small cell lung carcinoma. Cancer Res. 1994 Oct 1;54(19):5086–5091. [PubMed] [Google Scholar]
  22. Li X., Lee N. K., Ye Y. W., Waber P. G., Schweitzer C., Cheng Q. C., Nisen P. D. Allelic loss at chromosomes 3p, 8p, 13q, and 17p associated with poor prognosis in head and neck cancer. J Natl Cancer Inst. 1994 Oct 19;86(20):1524–1529. doi: 10.1093/jnci/86.20.1524. [DOI] [PubMed] [Google Scholar]
  23. Miura I., Graziano S. L., Cheng J. Q., Doyle L. A., Testa J. R. Chromosome alterations in human small cell lung cancer: frequent involvement of 5q. Cancer Res. 1992 Mar 1;52(5):1322–1328. [PubMed] [Google Scholar]
  24. Miyoshi Y., Nagase H., Ando H., Horii A., Ichii S., Nakatsuru S., Aoki T., Miki Y., Mori T., Nakamura Y. Somatic mutations of the APC gene in colorectal tumors: mutation cluster region in the APC gene. Hum Mol Genet. 1992 Jul;1(4):229–233. doi: 10.1093/hmg/1.4.229. [DOI] [PubMed] [Google Scholar]
  25. Moch H., Presti J. C., Jr, Sauter G., Buchholz N., Jordan P., Mihatsch M. J., Waldman F. M. Genetic aberrations detected by comparative genomic hybridization are associated with clinical outcome in renal cell carcinoma. Cancer Res. 1996 Jan 1;56(1):27–30. [PubMed] [Google Scholar]
  26. Mori N., Yokota J., Oshimura M., Cavenee W. K., Mizoguchi H., Noguchi M., Shimosato Y., Sugimura T., Terada M. Concordant deletions of chromosome 3p and loss of heterozygosity for chromosomes 13 and 17 in small cell lung carcinoma. Cancer Res. 1989 Sep 15;49(18):5130–5135. [PubMed] [Google Scholar]
  27. Nimmo E. R., Sanders P. G., Padua R. A., Hughes D., Williamson R., Johnson K. J. The MEL gene: a new member of the RAB/YPT class of RAS-related genes. Oncogene. 1991 Aug;6(8):1347–1351. [PubMed] [Google Scholar]
  28. Ohta M., Inoue H., Cotticelli M. G., Kastury K., Baffa R., Palazzo J., Siprashvili Z., Mori M., McCue P., Druck T. The FHIT gene, spanning the chromosome 3p14.2 fragile site and renal carcinoma-associated t(3;8) breakpoint, is abnormal in digestive tract cancers. Cell. 1996 Feb 23;84(4):587–597. doi: 10.1016/s0092-8674(00)81034-x. [DOI] [PubMed] [Google Scholar]
  29. Peiffer S. L., Herzog T. J., Tribune D. J., Mutch D. G., Gersell D. J., Goodfellow P. J. Allelic loss of sequences from the long arm of chromosome 10 and replication errors in endometrial cancers. Cancer Res. 1995 May 1;55(9):1922–1926. [PubMed] [Google Scholar]
  30. Petersen I., Reichel M. B., Dietel M. Use of non-radioactive detection in SSCP, direct DNA sequencing and LOH analysis. Clin Mol Pathol. 1996 Apr;49(2):M118–M121. doi: 10.1136/mp.49.2.m118. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Polascik T. J., Cairns P., Chang W. Y., Schoenberg M. P., Sidransky D. Distinct regions of allelic loss on chromosome 4 in human primary bladder carcinoma. Cancer Res. 1995 Nov 15;55(22):5396–5399. [PubMed] [Google Scholar]
  32. Reifenberger G., Reifenberger J., Ichimura K., Collins V. P. Amplification at 12q13-14 in human malignant gliomas is frequently accompanied by loss of heterozygosity at loci proximal and distal to the amplification site. Cancer Res. 1995 Feb 15;55(4):731–734. [PubMed] [Google Scholar]
  33. Rempel S. A., Schwechheimer K., Davis R. L., Cavenee W. K., Rosenblum M. L. Loss of heterozygosity for loci on chromosome 10 is associated with morphologically malignant meningioma progression. Cancer Res. 1993 May 15;53(10 Suppl):2386–2392. [PubMed] [Google Scholar]
  34. Ried T., Baldini A., Rand T. C., Ward D. C. Simultaneous visualization of seven different DNA probes by in situ hybridization using combinatorial fluorescence and digital imaging microscopy. Proc Natl Acad Sci U S A. 1992 Feb 15;89(4):1388–1392. doi: 10.1073/pnas.89.4.1388. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Ried T., Petersen I., Holtgreve-Grez H., Speicher M. R., Schröck E., du Manoir S., Cremer T. Mapping of multiple DNA gains and losses in primary small cell lung carcinomas by comparative genomic hybridization. Cancer Res. 1994 Apr 1;54(7):1801–1806. [PubMed] [Google Scholar]
  36. Rodriguez E., Sreekantaiah C., Chaganti R. S. Genetic changes in epithelial solid neoplasia. Cancer Res. 1994 Jul 1;54(13):3398–3406. [PubMed] [Google Scholar]
  37. Sakurai A., Bell G. I., DeGroot L. J. Dinucleotide repeat polymorphism in the human thyroid hormone receptor beta gene (THRB) on chromosome 3. Nucleic Acids Res. 1991 Dec 11;19(23):6661–6661. doi: 10.1093/nar/19.23.6661. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Sameshima Y., Matsuno Y., Hirohashi S., Shimosato Y., Mizoguchi H., Sugimura T., Terada M., Yokota J. Alterations of the p53 gene are common and critical events for the maintenance of malignant phenotypes in small-cell lung carcinoma. Oncogene. 1992 Mar;7(3):451–457. [PubMed] [Google Scholar]
  39. Sato S., Nakamura Y., Tsuchiya E. Difference of allelotype between squamous cell carcinoma and adenocarcinoma of the lung. Cancer Res. 1994 Nov 1;54(21):5652–5655. [PubMed] [Google Scholar]
  40. Schreiber-Agus N., Chin L., Chen K., Torres R., Rao G., Guida P., Skoultchi A. I., DePinho R. A. An amino-terminal domain of Mxi1 mediates anti-Myc oncogenic activity and interacts with a homolog of the yeast transcriptional repressor SIN3. Cell. 1995 Mar 10;80(5):777–786. doi: 10.1016/0092-8674(95)90356-9. [DOI] [PubMed] [Google Scholar]
  41. Sekido Y., Bader S., Latif F., Gnarra J. R., Gazdar A. F., Linehan W. M., Zbar B., Lerman M. I., Minna J. D. Molecular analysis of the von Hippel-Lindau disease tumor suppressor gene in human lung cancer cell lines. Oncogene. 1994 Jun;9(6):1599–1604. [PubMed] [Google Scholar]
  42. Sekido Y., Takahashi T., Ueda R., Takahashi M., Suzuki H., Nishida K., Tsukamoto T., Hida T., Shimokata K., Zsebo K. M. Recombinant human stem cell factor mediates chemotaxis of small-cell lung cancer cell lines aberrantly expressing the c-kit protooncogene. Cancer Res. 1993 Apr 1;53(7):1709–1714. [PubMed] [Google Scholar]
  43. Sozzi G., Veronese M. L., Negrini M., Baffa R., Cotticelli M. G., Inoue H., Tornielli S., Pilotti S., De Gregorio L., Pastorino U. The FHIT gene 3p14.2 is abnormal in lung cancer. Cell. 1996 Apr 5;85(1):17–26. doi: 10.1016/s0092-8674(00)81078-8. [DOI] [PubMed] [Google Scholar]
  44. Speicher M. R., Howe C., Crotty P., du Manoir S., Costa J., Ward D. C. Comparative genomic hybridization detects novel deletions and amplifications in head and neck squamous cell carcinomas. Cancer Res. 1995 Mar 1;55(5):1010–1013. [PubMed] [Google Scholar]
  45. Takahashi T., Obata Y., Sekido Y., Hida T., Ueda R., Watanabe H., Ariyoshi Y., Sugiura T., Takahashi T. Expression and amplification of myc gene family in small cell lung cancer and its relation to biological characteristics. Cancer Res. 1989 May 15;49(10):2683–2688. [PubMed] [Google Scholar]
  46. Tsang S. X., Morris G. F., Lu M., Morris C. B. TATA-dependent repression of human immunodeficiency virus type-1 transcription by the adenovirus E1A 243R oncoprotein. Oncogene. 1996 Feb 15;12(4):819–826. [PubMed] [Google Scholar]
  47. Tsuchiya E., Nakamura Y., Weng S. Y., Nakagawa K., Tsuchiya S., Sugano H., Kitagawa T. Allelotype of non-small cell lung carcinoma--comparison between loss of heterozygosity in squamous cell carcinoma and adenocarcinoma. Cancer Res. 1992 May 1;52(9):2478–2481. [PubMed] [Google Scholar]
  48. Urano Y., Watanabe K., Lin C. C., Hino O., Tamaoki T. Interstitial chromosomal deletion within 4q11-q13 in a human hepatoma cell line. Cancer Res. 1991 Mar 1;51(5):1460–1464. [PubMed] [Google Scholar]
  49. Watkins D., Dion F., Poisson M., Delattre J. Y., Rouleau G. A. Analysis of oncogene expression in primary human gliomas: evidence for increased expression of the ros oncogene. Cancer Genet Cytogenet. 1994 Feb;72(2):130–136. doi: 10.1016/0165-4608(94)90128-7. [DOI] [PubMed] [Google Scholar]
  50. Whang-Peng J., Kao-Shan C. S., Lee E. C., Bunn P. A., Carney D. N., Gazdar A. F., Minna J. D. Specific chromosome defect associated with human small-cell lung cancer; deletion 3p(14-23). Science. 1982 Jan 8;215(4529):181–182. doi: 10.1126/science.6274023. [DOI] [PubMed] [Google Scholar]
  51. Wieland I., Böhm M. Frequent allelic deletion at a novel locus on chromosome 5 in human lung cancer. Cancer Res. 1994 Apr 1;54(7):1772–1774. [PubMed] [Google Scholar]
  52. Windle B., Draper B. W., Yin Y. X., O'Gorman S., Wahl G. M. A central role for chromosome breakage in gene amplification, deletion formation, and amplicon integration. Genes Dev. 1991 Feb;5(2):160–174. doi: 10.1101/gad.5.2.160. [DOI] [PubMed] [Google Scholar]
  53. Wodrich W., Volm M. Overexpression of oncoproteins in non-small cell lung carcinomas of smokers. Carcinogenesis. 1993 Jun;14(6):1121–1124. doi: 10.1093/carcin/14.6.1121. [DOI] [PubMed] [Google Scholar]
  54. Wong A. J., Ruppert J. M., Eggleston J., Hamilton S. R., Baylin S. B., Vogelstein B. Gene amplification of c-myc and N-myc in small cell carcinoma of the lung. Science. 1986 Jul 25;233(4762):461–464. doi: 10.1126/science.3014659. [DOI] [PubMed] [Google Scholar]
  55. Yokota J., Tsukada Y., Nakajima T., Gotoh M., Shimosato Y., Mori N., Tsunokawa Y., Sugimura T., Terada M. Loss of heterozygosity on the short arm of chromosome 3 in carcinoma of the uterine cervix. Cancer Res. 1989 Jul 1;49(13):3598–3601. [PubMed] [Google Scholar]
  56. Yokota J., Wada M., Shimosato Y., Terada M., Sugimura T. Loss of heterozygosity on chromosomes 3, 13, and 17 in small-cell carcinoma and on chromosome 3 in adenocarcinoma of the lung. Proc Natl Acad Sci U S A. 1987 Dec;84(24):9252–9256. doi: 10.1073/pnas.84.24.9252. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. el-Torky M., el-Zeky F., Hall J. C. Significant changes in the distribution of histologic types of lung cancer. A review of 4928 cases. Cancer. 1990 May 15;65(10):2361–2367. doi: 10.1002/1097-0142(19900515)65:10<2361::aid-cncr2820651034>3.0.co;2-c. [DOI] [PubMed] [Google Scholar]
  58. von Deimling A., Louis D. N., von Ammon K., Petersen I., Hoell T., Chung R. Y., Martuza R. L., Schoenfeld D. A., Yaşargil M. G., Wiestler O. D. Association of epidermal growth factor receptor gene amplification with loss of chromosome 10 in human glioblastoma multiforme. J Neurosurg. 1992 Aug;77(2):295–301. doi: 10.3171/jns.1992.77.2.0295. [DOI] [PubMed] [Google Scholar]

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