Gastroenterology

Gastroenterology

Volume 123, Issue 4, October 2002, Pages 1109-1119
Gastroenterology

Basic–Alimentary Tract
Colorectal adenoma to carcinoma progression follows multiple pathways of chromosomal instability,☆☆

https://doi.org/10.1053/gast.2002.36051Get rights and content

Abstract

Background & Aims: Current models of colorectal adenoma to carcinoma progression do not fully reflect the genetic heterogeneity and complexity of the disease. The aim of the present study was to identify genetic changes discriminating adenomas that have progressed to carcinoma from adenomas that have not progressed, and to refine the current genetic models of colorectal adenoma to carcinoma progression, based on a genome-wide analysis of chromosomal aberrations. Methods: Sixty-six nonprogressed colorectal adenomas, 46 progressed adenomas (malignant polyps), and 36 colorectal carcinomas were screened for chromosomal aberrations by comparative genomic hybridization, and for mutations in the adenomatous polyposis coli (APC) and K-ras gene. Data analysis focused on cancer-associated genetic changes in adenomas. Results: Accumulation of losses in 8p21-pter, 15q11-q21, 17p12-13, and 18q12-21, and gains in 8q23-qter, 13q14-31, and 20q13 were strongly associated with adenoma-to-carcinoma progression, independent of the degree of dysplasia. Hierarchic cluster analysis demonstrated the presence of 3 distinct subgroups of adenomas, characterized by unique combinations of genetic aberrations in the adenomas (17p loss and K-ras mutation, 8q and 13q gain, and 18q loss and 20q gain, respectively). Conclusions: The presence of 2 or more of the aforementioned 7 chromosomal changes was associated with progressed colorectal adenomas and colorectal cancer. In addition, evidence was found that these chromosomal abnormalities occurred in specific combinations of a few abnormalities rather than as a mere accumulation of events, indicating the existence of multiple independent chromosomal instability pathways of colorectal cancer progression.

GASTROENTEROLOGY 2002;123:1109-1119

Section snippets

Tumor material

A total of 194 tumor samples were studied, consisting of 66 nonprogressed adenomas (i.e., simple adenomas without invasion), 46 progressed adenomas (in which a focus of carcinoma already is present, also referred to as malignant polyps), of which both the adenoma part and the carcinoma part were analyzed separately; and 36 simple carcinomas. The samples were obtained from 93 patients, 41 female and 52 male. The mean age was 67 years (range, 40–91). Thirty patients had multiple tumors: 5 had

Comparative genomic hybridization results in relation to adenoma-carcinoma progression

Nineteen nonprogressed adenomas did not show any chromosomal abnormality. The remaining 47 nonprogressed adenoma cases showed few chromosomal aberrations (on average, 4.6). These aberrations showed a rather random distribution over the chromosomes, although there were more losses than gains (ratio of loss to gain, 2:7). The average number of chromosomal aberrations in the 46 progressed adenomas was 10.5, significantly higher than in the nonprogressed adenomas (P = 0.000) and similar to the

Discussion

Current genetic models of colorectal adenoma-carcinoma progression do not reflect the complexity of the disease. We compared genomewide chromosomal aberrations in nonprogressed adenomas to adenomas proven capable of progression toward malignancy. The present data, obtained from a cross-sectional study of a total of 194 tumor samples, revealed that gains at 8q23-qter, 13q14-31, and 20q13 and losses at 8p21-pter, 15q11-q21, 17p12-13, and 18q12-21 were strongly associated with advanced lesions,

References (29)

  • SE Kern et al.

    Allelic loss in colorectal carcinoma

    JAMA

    (1989)
  • P Jernvall et al.

    Loss of heterozygosity at 18q21 is indicative of recurrence and therefore poor prognosis in a subset of colorectal cancers

    Br J Cancer

    (1999)
  • B Vogelstein et al.

    Genetic alterations during colorectal tumour development

    N Engl J Med

    (1988)
  • T Ried et al.

    Comparative genomic hybridization reveals a specific pattern of chromosomal gains and losses during the genesis of colorectal tumors

    Genes Chromosomes Cancer

    (1996)
  • Cited by (0)

    Address requests for reprints to: Gerrit Meijer, M.D., Ph.D., Department of Pathology, VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam, the Netherlands. e-mail: [email protected]; fax: (31) 20-444-2964.

    ☆☆

    Supported by the Dutch Cancer Society grants KWF97-1455 and ZONMW 28-1687, and Miur Oncology grant N.02.00273.ST97 (to W.G.).

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