Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1999 May 1;80(3-4):526–535. doi: 10.1038/sj.bjc.6690388

Chromosomal gains and losses in primary colorectal carcinomas detected by CGH and their associations with tumour DNA ploidy, genotypes and phenotypes

P M De Angelis 1, O P F Clausen 1, A Schjølberg 1, T Stokke 2
PMCID: PMC2362312  PMID: 10408863

Abstract

Comparative genomic hybridization (CGH) is used to detect amplified and/or deleted chromosomal regions in tumours by mapping their locations on normal metaphase chromosomes. Forty-five sporadic colorectal carcinomas were screened for chromosomal aberrations using direct CGH. The median number of chromosomal aberrations per tumour was 7.0 (range 0–19). Gains of 20q (67%) and losses of 18q (49%) were the most frequent aberrations. Other recurrent gains of 5p, 6p, 7, 8q, 13q, 17q, 19, X and losses of 1p, 3p, 4, 5q, 6q, 8p, 9p, 10, 15q, 17p were found in > 10% of colorectal tumours. High-level gains (ratio > 1.5) were seen only on 8q, 13q, 20 and X, and only in DNA aneuploid tumours. DNA aneuploid tumours had significantly more chromosomal aberrations (median number per tumour of 9.0) compared to diploid tumours (median of 1.0) (P < 0.0001). The median numbers of aberrations seen in DNA hyperdiploid and highly aneuploid tumours were not significantly different (8.5 and 11.0 respectively; P = 0.58). Four tumours had no detectable chromosomal aberrations and these were DNA diploid. A higher percentage of tumours from male patients showed Xq gain and 18q loss compared to tumours from female patients (P = 0.05 and 0.01 respectively). High tumour S phase fractions were associated with gain of 20q13 (P = 0.03), and low tumour apoptotic indices were associated with loss of 4q (P = 0.05). Tumours with TP53 mutations had more aberrations (median of 9.0 per tumour) compared to those without (median of 2.0) (P = 0.002), and gain of 8q23–24 and loss of 18qcen-21 were significantly associated with TP53 mutations (P = 0.04 and 0.02 respectively). Dukes' C/D stage tumours tended to have a higher number of aberrations per tumour (median of 10.0) compared to Dukes' B tumours (median of 3.0) (P = 0.06). The low number of aberrations observed in DNA diploid tumours compared to aneuploid tumours suggests that genomic instability and possible growth advantages in diploid tumours do not result from acquisition of gross chromosomal aberrations but rather from selection for other types of mutations. Our study is consistent with the idea that these two groups of tumours evolve along separate genetic pathways and that gross genomic instability is associated with TP53 gene aberrations. © 1999 Cancer Research Campaign

Keywords: colorectal tumours, direct CGH, gains, losses, oncogenes, tumour suppressor genes

Full Text

The Full Text of this article is available as a PDF (163.1 KB).

Selected References

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

  1. Aaltonen L. A., Peltomäki P., Leach F. S., Sistonen P., Pylkkänen L., Mecklin J. P., Järvinen H., Powell S. M., Jen J., Hamilton S. R. Clues to the pathogenesis of familial colorectal cancer. Science. 1993 May 7;260(5109):812–816. doi: 10.1126/science.8484121. [DOI] [PubMed] [Google Scholar]
  2. Andersen S. N., Løvig T., Breivik J., Lund E., Gaudernack G., Meling G. I., Rognum T. O. K-ras mutations and prognosis in large-bowel carcinomas. Scand J Gastroenterol. 1997 Jan;32(1):62–69. doi: 10.3109/00365529709025065. [DOI] [PubMed] [Google Scholar]
  3. Arnold N., Hagele L., Walz L., Schempp W., Pfisterer J., Bauknecht T., Kiechle M. Overrepresentation of 3q and 8q material and loss of 18q material are recurrent findings in advanced human ovarian cancer. Genes Chromosomes Cancer. 1996 May;16(1):46–54. doi: 10.1002/(SICI)1098-2264(199605)16:1<46::AID-GCC7>3.0.CO;2-3. [DOI] [PubMed] [Google Scholar]
  4. Bardi G., Sukhikh T., Pandis N., Fenger C., Kronborg O., Heim S. Karyotypic characterization of colorectal adenocarcinomas. Genes Chromosomes Cancer. 1995 Feb;12(2):97–109. doi: 10.1002/gcc.2870120204. [DOI] [PubMed] [Google Scholar]
  5. Bauer K. D., Bagwell C. B., Giaretti W., Melamed M., Zarbo R. J., Witzig T. E., Rabinovitch P. S. Consensus review of the clinical utility of DNA flow cytometry in colorectal cancer. Cytometry. 1993;14(5):486–491. doi: 10.1002/cyto.990140506. [DOI] [PubMed] [Google Scholar]
  6. Bigner S. H., Bjerkvig R., Laerum O. D., Muhlbaier L. H., Bigner D. D. DNA content and chromosomes in permanent cultured cell lines derived from malignant human gliomas. Anal Quant Cytol Histol. 1987 Oct;9(5):435–444. [PubMed] [Google Scholar]
  7. Bodmer W. F., Bailey C. J., Bodmer J., Bussey H. J., Ellis A., Gorman P., Lucibello F. C., Murday V. A., Rider S. H., Scambler P. Localization of the gene for familial adenomatous polyposis on chromosome 5. Nature. 1987 Aug 13;328(6131):614–616. doi: 10.1038/328614a0. [DOI] [PubMed] [Google Scholar]
  8. Bos J. L. ras oncogenes in human cancer: a review. Cancer Res. 1989 Sep 1;49(17):4682–4689. [PubMed] [Google Scholar]
  9. Campo E., de la Calle-Martin O., Miquel R., Palacin A., Romero M., Fabregat V., Vives J., Cardesa A., Yague J. Loss of heterozygosity of p53 gene and p53 protein expression in human colorectal carcinomas. Cancer Res. 1991 Aug 15;51(16):4436–4442. [PubMed] [Google Scholar]
  10. Cher M. L., MacGrogan D., Bookstein R., Brown J. A., Jenkins R. B., Jensen R. H. Comparative genomic hybridization, allelic imbalance, and fluorescence in situ hybridization on chromosome 8 in prostate cancer. Genes Chromosomes Cancer. 1994 Nov;11(3):153–162. doi: 10.1002/gcc.2870110304. [DOI] [PubMed] [Google Scholar]
  11. Cusick E. L., Milton J. I., Ewen S. W. The resolution of aneuploid DNA stem lines by flow cytometry: limitations imposed by the coefficient of variation and the percentage of aneuploid nuclei. Anal Cell Pathol. 1990 Apr;2(3):139–148. [PubMed] [Google Scholar]
  12. De Angelis P. M., Stokke T., Clausen O. P. NO38 expression and nucleolar counts are correlated with cellular DNA content but not with proliferation parameters in colorectal carcinomas. Mol Pathol. 1997 Aug;50(4):201–208. doi: 10.1136/mp.50.4.201. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. De Angelis P. M., Stokke T., Thorstensen L., Lothe R. A., Clausen O. P. Apoptosis and expression of Bax, Bcl-x, and Bcl-2 apoptotic regulatory proteins in colorectal carcinomas, and association with p53 genotype/phenotype. Mol Pathol. 1998 Oct;51(5):254–261. doi: 10.1136/mp.51.5.254. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. De Angelis P., Stokke T., Smedshammer L., Lothe R. A., Lehne G., Chen Y., Clausen O. P. P-glycoprotein is not expressed in a majority of colorectal carcinomas and is not regulated by mutant p53 in vivo. Br J Cancer. 1995 Aug;72(2):307–311. doi: 10.1038/bjc.1995.329. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Delattre O., Olschwang S., Law D. J., Melot T., Remvikos Y., Salmon R. J., Sastre X., Validire P., Feinberg A. P., Thomas G. Multiple genetic alterations in distal and proximal colorectal cancer. Lancet. 1989 Aug 12;2(8659):353–356. doi: 10.1016/s0140-6736(89)90537-0. [DOI] [PubMed] [Google Scholar]
  16. Eppert K., Scherer S. W., Ozcelik H., Pirone R., Hoodless P., Kim H., Tsui L. C., Bapat B., Gallinger S., Andrulis I. L. MADR2 maps to 18q21 and encodes a TGFbeta-regulated MAD-related protein that is functionally mutated in colorectal carcinoma. Cell. 1996 Aug 23;86(4):543–552. doi: 10.1016/s0092-8674(00)80128-2. [DOI] [PubMed] [Google Scholar]
  17. Fearon E. R., Hamilton S. R., Vogelstein B. Clonal analysis of human colorectal tumors. Science. 1987 Oct 9;238(4824):193–197. doi: 10.1126/science.2889267. [DOI] [PubMed] [Google Scholar]
  18. Fearon E. R., Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990 Jun 1;61(5):759–767. doi: 10.1016/0092-8674(90)90186-i. [DOI] [PubMed] [Google Scholar]
  19. Hahn S. A., Schutte M., Hoque A. T., Moskaluk C. A., da Costa L. T., Rozenblum E., Weinstein C. L., Fischer A., Yeo C. J., Hruban R. H. DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science. 1996 Jan 19;271(5247):350–353. doi: 10.1126/science.271.5247.350. [DOI] [PubMed] [Google Scholar]
  20. Heselmeyer K., Macville M., Schröck E., Blegen H., Hellström A. C., Shah K., Auer G., Ried T. Advanced-stage cervical carcinomas are defined by a recurrent pattern of chromosomal aberrations revealing high genetic instability and a consistent gain of chromosome arm 3q. Genes Chromosomes Cancer. 1997 Aug;19(4):233–240. [PubMed] [Google Scholar]
  21. Houlston R. S., Tomlinson I. P. Genetic prognostic markers in colorectal cancer. Mol Pathol. 1997 Dec;50(6):281–288. doi: 10.1136/mp.50.6.281. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Ilyas M., Tomlinson I. P. Genetic pathways in colorectal cancer. Histopathology. 1996 May;28(5):389–399. doi: 10.1046/j.1365-2559.1996.339381.x. [DOI] [PubMed] [Google Scholar]
  23. Kallioniemi A., Kallioniemi O. P., Citro G., Sauter G., DeVries S., Kerschmann R., Caroll P., Waldman F. Identification of gains and losses of DNA sequences in primary bladder cancer by comparative genomic hybridization. Genes Chromosomes Cancer. 1995 Mar;12(3):213–219. doi: 10.1002/gcc.2870120309. [DOI] [PubMed] [Google Scholar]
  24. 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]
  25. 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]
  26. Karhu R., Kähkönen M., Kuukasjärvi T., Pennanen S., Tirkkonen M., Kallioniemi O. Quality control of CGH: impact of metaphase chromosomes and the dynamic range of hybridization. Cytometry. 1997 Jul 1;28(3):198–205. doi: 10.1002/(sici)1097-0320(19970701)28:3<198::aid-cyto3>3.0.co;2-a. [DOI] [PubMed] [Google Scholar]
  27. Kikuchi-Yanoshita R., Konishi M., Ito S., Seki M., Tanaka K., Maeda Y., Iino H., Fukayama M., Koike M., Mori T. Genetic changes of both p53 alleles associated with the conversion from colorectal adenoma to early carcinoma in familial adenomatous polyposis and non-familial adenomatous polyposis patients. Cancer Res. 1992 Jul 15;52(14):3965–3971. [PubMed] [Google Scholar]
  28. Korn W. M., Oide Weghuis D. E., Suijkerbuijk R. F., Schmidt U., Otto T., du Manoir S., Geurts van Kessel A., Harstrick A., Seeber S., Becher R. Detection of chromosomal DNA gains and losses in testicular germ cell tumors by comparative genomic hybridization. Genes Chromosomes Cancer. 1996 Oct;17(2):78–87. doi: 10.1002/(SICI)1098-2264(199610)17:2<78::AID-GCC2>3.0.CO;2-Y. [DOI] [PubMed] [Google Scholar]
  29. Lothe R. A., Peltomäki P., Meling G. I., Aaltonen L. A., Nyström-Lahti M., Pylkkänen L., Heimdal K., Andersen T. I., Møller P., Rognum T. O. Genomic instability in colorectal cancer: relationship to clinicopathological variables and family history. Cancer Res. 1993 Dec 15;53(24):5849–5852. [PubMed] [Google Scholar]
  30. MacGrogan D., Pegram M., Slamon D., Bookstein R. Comparative mutational analysis of DPC4 (Smad4) in prostatic and colorectal carcinomas. Oncogene. 1997 Aug 28;15(9):1111–1114. doi: 10.1038/sj.onc.1201232. [DOI] [PubMed] [Google Scholar]
  31. Meling G. I., Lothe R. A., Børresen A. L., Graue C., Hauge S., Clausen O. P., Rognum T. O. The TP53 tumour suppressor gene in colorectal carcinomas. II. Relation to DNA ploidy pattern and clinicopathological variables. Br J Cancer. 1993 Jan;67(1):93–98. doi: 10.1038/bjc.1993.15. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Miyaki M., Konishi M., Kikuchi-Yanoshita R., Enomoto M., Igari T., Tanaka K., Muraoka M., Takahashi H., Amada Y., Fukayama M. Characteristics of somatic mutation of the adenomatous polyposis coli gene in colorectal tumors. Cancer Res. 1994 Jun 1;54(11):3011–3020. [PubMed] [Google Scholar]
  33. Miyashita T., Reed J. C. Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell. 1995 Jan 27;80(2):293–299. doi: 10.1016/0092-8674(95)90412-3. [DOI] [PubMed] [Google Scholar]
  34. Muleris M., Salmon R. J., Dutrillaux B. Cytogenetics of colorectal adenocarcinomas. Cancer Genet Cytogenet. 1990 Jun;46(2):143–156. doi: 10.1016/0165-4608(90)90100-o. [DOI] [PubMed] [Google Scholar]
  35. Nakao K., Shibusawa M., Tsunoda A., Yoshizawa H., Murakami M., Kusano M., Uesugi N., Sasaki K. Genetic changes in primary colorectal cancer by comparative genomic hybridization. Surg Today. 1998;28(5):567–569. doi: 10.1007/s005950050185. [DOI] [PubMed] [Google Scholar]
  36. Offerhaus G. J., De Feyter E. P., Cornelisse C. J., Tersmette K. W., Floyd J., Kern S. E., Vogelstein B., Hamilton S. R. The relationship of DNA aneuploidy to molecular genetic alterations in colorectal carcinoma. Gastroenterology. 1992 May;102(5):1612–1619. doi: 10.1016/0016-5085(92)91721-f. [DOI] [PubMed] [Google Scholar]
  37. Powell S. M., Zilz N., Beazer-Barclay Y., Bryan T. M., Hamilton S. R., Thibodeau S. N., Vogelstein B., Kinzler K. W. APC mutations occur early during colorectal tumorigenesis. Nature. 1992 Sep 17;359(6392):235–237. doi: 10.1038/359235a0. [DOI] [PubMed] [Google Scholar]
  38. Rampino N., Yamamoto H., Ionov Y., Li Y., Sawai H., Reed J. C., Perucho M. Somatic frameshift mutations in the BAX gene in colon cancers of the microsatellite mutator phenotype. Science. 1997 Feb 14;275(5302):967–969. doi: 10.1126/science.275.5302.967. [DOI] [PubMed] [Google Scholar]
  39. Remvikos Y., Laurent-Puig P., Salmon R. J., Frelat G., Dutrillaux B., Thomas G. Simultaneous monitoring of P53 protein and DNA content of colorectal adenocarcinomas by flow cytometry. Int J Cancer. 1990 Mar 15;45(3):450–456. doi: 10.1002/ijc.2910450313. [DOI] [PubMed] [Google Scholar]
  40. Remvikos Y., Vogt N., Muleris M., Salmon R. J., Malfoy B., Dutrillaux B. DNA-repeat instability is associated with colorectal cancers presenting minimal chromosome rearrangements. Genes Chromosomes Cancer. 1995 Apr;12(4):272–276. doi: 10.1002/gcc.2870120406. [DOI] [PubMed] [Google Scholar]
  41. Ried T., Knutzen R., Steinbeck R., Blegen H., Schröck E., Heselmeyer K., du Manoir S., Auer G. Comparative genomic hybridization reveals a specific pattern of chromosomal gains and losses during the genesis of colorectal tumors. Genes Chromosomes Cancer. 1996 Apr;15(4):234–245. doi: 10.1002/(SICI)1098-2264(199604)15:4<234::AID-GCC5>3.0.CO;2-2. [DOI] [PubMed] [Google Scholar]
  42. Rognum T. O., Lund E., Meling G. I., Langmark F. Near diploid large bowel carcinomas have better five-year survival than aneuploid ones. Cancer. 1991 Sep 1;68(5):1077–1081. doi: 10.1002/1097-0142(19910901)68:5<1077::aid-cncr2820680528>3.0.co;2-m. [DOI] [PubMed] [Google Scholar]
  43. Senger D. R. Molecular framework for angiogenesis: a complex web of interactions between extravasated plasma proteins and endothelial cell proteins induced by angiogenic cytokines. Am J Pathol. 1996 Jul;149(1):1–7. [PMC free article] [PubMed] [Google Scholar]
  44. Shackney S. E., Shankey T. V. Common patterns of genetic evolution in human solid tumors. Cytometry. 1997 Sep 1;29(1):1–27. [PubMed] [Google Scholar]
  45. Shackney S. E., Smith C. A., Miller B. W., Burholt D. R., Murtha K., Giles H. R., Ketterer D. M., Pollice A. A. Model for the genetic evolution of human solid tumors. Cancer Res. 1989 Jun 15;49(12):3344–3354. [PubMed] [Google Scholar]
  46. Solomon E., Voss R., Hall V., Bodmer W. F., Jass J. R., Jeffreys A. J., Lucibello F. C., Patel I., Rider S. H. Chromosome 5 allele loss in human colorectal carcinomas. Nature. 1987 Aug 13;328(6131):616–619. doi: 10.1038/328616a0. [DOI] [PubMed] [Google Scholar]
  47. Takagi Y., Kohmura H., Futamura M., Kida H., Tanemura H., Shimokawa K., Saji S. Somatic alterations of the DPC4 gene in human colorectal cancers in vivo. Gastroenterology. 1996 Nov;111(5):1369–1372. doi: 10.1053/gast.1996.v111.pm8898652. [DOI] [PubMed] [Google Scholar]
  48. Tanner M. M., Tirkkonen M., Kallioniemi A., Collins C., Stokke T., Karhu R., Kowbel D., Shadravan F., Hintz M., Kuo W. L. Increased copy number at 20q13 in breast cancer: defining the critical region and exclusion of candidate genes. Cancer Res. 1994 Aug 15;54(16):4257–4260. [PubMed] [Google Scholar]
  49. Thiagalingam S., Lengauer C., Leach F. S., Schutte M., Hahn S. A., Overhauser J., Willson J. K., Markowitz S., Hamilton S. R., Kern S. E. Evaluation of candidate tumour suppressor genes on chromosome 18 in colorectal cancers. Nat Genet. 1996 Jul;13(3):343–346. doi: 10.1038/ng0796-343. [DOI] [PubMed] [Google Scholar]
  50. Tirkkonen M., Tanner M., Karhu R., Kallioniemi A., Isola J., Kallioniemi O. P. Molecular cytogenetics of primary breast cancer by CGH. Genes Chromosomes Cancer. 1998 Mar;21(3):177–184. [PubMed] [Google Scholar]
  51. Tribukait B., Granberg-Ohman I., Wijkström H. Flow cytometric DNA and cytogenetic studies in human tumors: a comparison and discussion of the differences in modal values obtained by the two methods. Cytometry. 1986 Mar;7(2):194–199. doi: 10.1002/cyto.990070211. [DOI] [PubMed] [Google Scholar]
  52. Vindeløv L. L., Christensen I. J., Nissen N. I. A detergent-trypsin method for the preparation of nuclei for flow cytometric DNA analysis. Cytometry. 1983 Mar;3(5):323–327. doi: 10.1002/cyto.990030503. [DOI] [PubMed] [Google Scholar]
  53. Vogelstein B., Fearon E. R., Hamilton S. R., Kern S. E., Preisinger A. C., Leppert M., Nakamura Y., White R., Smits A. M., Bos J. L. Genetic alterations during colorectal-tumor development. N Engl J Med. 1988 Sep 1;319(9):525–532. doi: 10.1056/NEJM198809013190901. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES