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Comparative Study
. 2004 Jan-Feb;6(1):23-8.
doi: 10.1016/s1476-5586(04)80050-2.

Chromosomal alterations during lymphatic and liver metastasis formation of colorectal cancer

Thomas Knösel  1 , Karsten Schlüns, Ulrike Stein, Holger Schwabe, Peter Michael Schlag, Manfred Dietel, Iver Petersen
Affiliations
Comparative Study

Chromosomal alterations during lymphatic and liver metastasis formation of colorectal cancer

Thomas Knösel et al. Neoplasia. 2004 Jan-Feb.

Erratum in

  • Neoplasia. 2004 Sep-Oct;6(5):686

Abstract

Comparative genomic hybridization (CGH) was used to screen colorectal carcinomas for chromosomal aberrations that are associated with metastatic phenotype. In total, 63 tumor specimens from 40 patients were investigated, comprising 30 primary tumors, 22 systemic metastases (12 liver, 6 brain, and 4 abdominal wall metastases) and 11 lymph node tumors. Using statistical analysis and histograms to evaluate the chromosomal imbalances, overrepresentations were detected most frequently at 20q11.2-20q13.2, 7q11.1-7q12, 13q11.2-13q14, 16p12, 19p13, 9q34, and 19q13.1-19q13.2. Deletions were prominent at 18q12-18q23, 4q27-4q28, 4p14, 5q21, 1p21-1p22, 21q21, 6q16-6q21, 3p12, 8p22-8p23, 9p21, 11q22, and 14q13-14q21. Hematogenous metastases showed more alterations than lymph node tumors, particularly more deletions at 1p, 3, 4, 5q, 10q, 14, and 21q21 and gains at 1q, 7p, 12qter, 13, 16, and 22q. Comparing liver metastases with their corresponding primary tumors, particularly deletions at 2q, 5q, 8p, 9p, 10q, and 21q21 and gains at 1q, 11, 12qter, 17q12-q21, 19, and 22q were more often observed. The analysis suggested that the different pathways of tumor dissemination are reflected by a nonrandom accumulation of chromosomal alterations with specific changes being responsible for the different characteristics of the metastatic phenotype.

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Figures

Figure 1
Figure 1
(A) Summary of all genetic alterations of 63 advanced colorectal carcinomas in a histogram representation. The chromosomal imbalances are shown as incidence curves along each chromosome. Areas on the left side of the chromosome ideogram correspond to loss of genetic material; those on the right side correspond to DNA gains. The changes were determined by a statistical method. Those with 99% significance in the Student's t-test are shown in blue; the additional ones with only 95% significance are depicted in green. Pronounced DNA gains and losses, defined as regions where the ratio profile exceeded the fixed thresholds 1.5 and 0.5, are shown in red and most likely correspond to high copy amplification and multicopy deletions, respectively. Heterochromatic areas (centromeric and paracentromeric regions of chromosomes 1, 9, and 16; p arms of acrocentric chromosomes) must be excluded from the analysis. (B) Difference histogram of lymph node metastases (n = 11) versus liver metastases (n = 12). The red areas represent the percentage of changes that are present only in liver metastases, whereas the green color indicates the excess of changes of lymph node metastases. The white areas beneath the colored part of the histogram represent the percentage of changes that are present in both tumor groups. The liver metastases (hematogenous) showed more alterations than lymph nodes tumors (lymphogenous) with significant changes as indicated by the gray horizontal lines (light gray, regions with 95%; dark gray, regions with 99% significance; chi-square test) (e.g., overrepresentation at 1q22–q23 and deletions at 4p). (C) Case-by-case histogram of 10 paired samples (i.e., primary tumor and corresponding liver metastasis). Four conditions are represented: blue, percentage of chromosomal imbalances that are common in both tumors; green: those chromosomal imbalances that are additionally seen in the primary tumor; red, those that are extra present in metastases; yellow, proportion with no changes in both groups. The blue areas are dominating again, reflecting the high concordance between primary tumors and metastases. However, the metastases showed additional alterations at several regions (e.g., gains at 1q and losses at 2q, 5q31, 8p, and 21q).
Figure 2
Figure 2
Colorectal cancer progression model with typical morphological and chromosomal changes. Typical chromosomal imbalances associated with lymph node and liver metastasis formation are represented, DNA gains are shown in red; DNA losses in green. The two arrows indicate that lymphatic and hematogenous tumor spread may occur independently of each other, although there are alterations common for both dissemination pathways (e.g., deletions on 8p and 21q21). Additionally, there are characteristic morphologic features. Liver metastases typically show a kribriform solid tumor growth with pronounced apoptosis and necrosis with only little stroma, a pattern frequently detectable already in the primary tumor corresponding to a poorly differentiated carcinoma (G3, high-grade). In contrast, lymph node metastasis and nonmetastasizing primary tumors often show a predominant tubular differentiation with a strong desmoplastic stroma reaction and are thus classified as low-grade carcinomas (G1 and G2).
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