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Clinical Cancer Research Vol. 9, 1808-1814, May 2003
© 2003 American Association for Cancer Research

Molecular Oncology, Markers, Clinical Correlates

Gain of Chromosome 8q23–24 Is a Predictive Marker for Lymph Node Positivity in Colorectal Cancer

B. Michael Ghadimi1, Marian Grade2, Torsten Liersch, Claus Langer, Alexander Siemer, László Füzesi and Heinz Becker

Department of General, Visceral, and Transplantation Surgery [B. M. G., M. G., T. L., C. L., H. B.], Institute of Pathology [L. F.], and Department of Medical Statistics [A. S.], University Medical Center Göttingen, 37075 Göttingen, Germany


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Purpose: The prognosis of patients with colorectal cancer is largely determined by tumor stage. In this respect, colorectal cancers with lymph node metastases indicate a worse prognosis versus lymph node-negative tumors. Accordingly, there is considerable clinical interest in understanding the genetic mechanisms underlying metastasis formation. Furthermore, sensitive and specific biomarkers are needed to predict the metastatic phenotype at the time of diagnosis.

Experimental Design: Fifty colorectal cancers with or without lymph node metastases were assessed for genomic imbalances by comparative genomic hybridization. Particular interest was focused on whether specific chromosomal alterations exist in primary tumors that might be indicative and specific for the metastatic phenotype.

Results: The analysis revealed that lymph node-positive colorectal cancers show a higher degree of chromosomal instability than lymph node-negative cancers (average number of chromosomal copy alterations, 9.8 versus 7.5). Chromosomal alterations commonly described in colorectal cancers such as gain of 20q or loss of 18q21 were not different. However, the gain of chromosomal region 8q23–24 was seen in the vast majority of lymph node-positive cancers, whereas it was rather rare in lymph node-negative carcinomas (P = 0.0016).

Conclusions: These data suggest that genes located at 8q23–24 might favor the development of lymphatic metastases in colorectal cancers. Additionally, the gain of this region could be used to predict the metastatic potential of primary colorectal cancers.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The prognosis of patients with colorectal cancer is largely determined by the tumor stage UICC.3 In this respect, both lymph node and hepatic metastases indicate advanced disease with an unfavorable prognosis. At the time of diagnosis, approximately 60% of colorectal cancers have already formed lymph node metastases, and in this respect, rectal cancers might benefit from neoadjuvant radiochemotherapy before surgical resection (1) . There is thus considerable clinical interest in understanding the genetic mechanisms underlying metastasis formation. Furthermore, sensitive and specific biomarkers are needed to predict the metastatic phenotype at the time of diagnosis. In recent years, gene-by-gene analysis has not fully succeeded in coming up with a comprehensive understanding of the mechanisms that enable individual cancers to form lymph node metastases (2) . In the field of colorectal cancer, several studies have analyzed the progression of colorectal adenomas to invasive cancers and found a stage-specific chromosomal aberration pattern indicating the sequential emergence of chromosomal gains and losses (3 , 4) . These nonrandom, tumor type-specific chromosomal alterations include gains of chromosome 1, 7p, 8q, 13, and 20. Chromosomal losses frequently map to chromosome 4, 8p, 10q, 17p, and 18q (3 , 5) . However, there is considerable scientific and clinical interest in locating tumor stage-dependent chromosomal regions to find genes that may be responsible for tumor progression and using such hot spots as predictive biomarkers for a pretherapeutic molecular staging and individual risk estimation. In this respect, considerable work has been done to study the changes that occur between primary colorectal cancer and its hepatic metastases. It has been found that gains of chromosome 6q, 7q, 8q, 13q, and 20q occur frequently in hepatic metastases and might pinpoint relevant genomic loci that are necessary for the formation of metastases (6, 7, 8, 9) . However, no detailed study has been published assessing the chromosomal profiles of colorectal cancers with the capacity for local lymphatic spread, which represent the majority of cancers.

The purpose of this study was to investigate the genomic differences in colorectal cancer progression with respect to the extent of tumor infiltration into the colonic wall and, in particular, the capacity of the individual tumor to form lymphatic metastases. We therefore screened three groups of colorectal cancers with CGH to search for chromosomal alterations that might be responsible for local tumor growth and to delineate genomic regions that might indicate the lymphatic metastatic phenotype.


   PATIENTS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patient Material.
In the present study, surgical specimens from 50 patients diagnosed with a colorectal cancer between 1998 and 2001 were analyzed. Only fresh frozen tumor samples with a tumor cell content of at least 70% were studied. The histopathological classification was based on the WHO histological typing of colorectal cancers (UICC, 1997). All tumors were adenocarcinomas. The clinical data are summarized in Table 1Citation . Three groups of tumors were analyzed to delineate the differences between small nonmetastasizing tumors (group 1, T2, N0; n = 15) versus large nonmetastasizing tumors (group 2, T3–4, N0; n = 15) versus large tumors metastasizing into the surrounding lymph nodes (group 3, T3–4, N1–2; n = 20).


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  		Table 1 Clinicopathological data of 50 patients with colorectal cancer

 
CGH.
CGH experiments and analysis were performed as described previously (10) . Briefly, CGH was performed on normal, sex-matched metaphase chromosomes prepared according to standard procedures following the criteria of du Manoir et al. (11) . Control DNA was labeled with digoxigenin-12-dUTP (Boehringer Mannheim, Mannheim, Germany) by nick translation. Tumor DNA was extracted from colorectal cancers using a commercially available DNA isolation kit from Qiagen (Hilden, Germany). Labeling of genomic tumor DNA was performed by nick translation, substituting dTTP with biotin-16-dUTP (Boehringer Mannheim). Three hundred ng of each differentially labeled genome were precipitated together with an excess (30 µg) of the Cot-1 fraction of human DNA (Life Technologies, Inc., Gaithersburg, MD). The probe DNA was resuspended in 10 µl of hybridization solution (50% formamide, 2x SSC, and 10% dextran sulfate), denatured (5 min, 75°C), and preannealed for 1 h at 37°C. The normal metaphase chromosomes were denatured separately (70% formamide and 2x SSC) for 2 min at 75°C. Hybridization took place under a coverslip for 2 days at 37°C. Posthybridization washes and immunocytochemical detection were performed as described previously (10) . Biotin-labeled tumor sequences were detected with avidin conjugated to FITC (Vector laboratories), and the digoxigenin-labeled reference DNA was developed using a mouse antidigoxin antibody, followed by a TRITC-conjugated antimouse antibody (Sigma, St. Louis, MO). The slides were counterstained with 4',6-diamidino-2-phenylindole and embedded in an antifade solution containing para-phenylenediamine (Sigma).

Gray level images were acquired for each fluorochrome using a cooled charge-coupled device camera (Sensys, Photometrics, Munich, Germany) coupled to an epifluorescence microscope (Axiovert 25; Zeiss, Jena, Germany), using sequential exposure through fluorochrome-specific filters. For automated karyotyping and analysis, a software package was used (Quips Karyotyping/CGH; Vysis). The karyograms (see Figs. 1Citation 2Citation 3Citation ) summarize the individual CGH experiments for the tumors. The lines to the left of the chromosomal ideograms indicate chromosomal losses (ratio, 0.75), and the lines to the right indicate chromosomal gains (ratio, 1.25). Amplifications are drawn as bold lines. Genomic instability was estimated as the ANCA/case (for details, see Ref. 12 ).



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  		Fig. 1. Karyogram of chromosomal gains and losses in group 1 (T2, N0).

 


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  		Fig. 2. Karyogram of chromosomal gains and losses in group 2 (T3–4, N0).

 


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  		Fig. 3. Karyogram of chromosomal gains and losses in group 3 (T3–4, N1–3).

 
Statistical Analysis.
The first part of the statistical analysis was done by pairwise comparisons of the three groups. All hypotheses were tested in a two-sided test at a level of 5%. Fisher’s exact test was used to determine the significance values. Differences with a P < 0.05 were considered statistically significant.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
CGH analysis was performed in 50 patients with colorectal cancer. These cancers could be assigned to three different groups according to the UICC classification: group 1 (pT2, N0), n = 15; group 2 (pT3–4, N0), n = 15; and group 3 (pT3–4, N1–3), n = 20 (Table 1)Citation .

Genetic Changes in Small Tumors without Lymph Node Metastases (Group 1, n = 15).
The most frequent chromosomal alterations in group 1 were gains at 20q (53%) and losses of 17p (46%), 18q (40%), and 19p (40%). In two cases, no chromosomal aberrations could be detected. The ANCA was 5.7. Amplifications localized to 8q and 20q and, in one case, to 12q15 (Fig. 1)Citation .

Genetic Changes in Large Tumors without Lymph Node Metastases (Group 2, n = 15).
In group 2, the ANCA increased to 7.5, with two tumors exhibiting no chromosomal changes, and one tumor showing 19 copy alterations. Frequent chromosomal gains mapped to 7q (46%), 13 (46%), Xq (46%), and 12p (33%). Whole chromosomal gains were found for chromosomes 7 (40%), 20 (40%), and X (40%). Losses mapped primarily to 18q (40%), Y (40%), and 8p (33%). Losses of 17p as the locus for p53 occurred in 4 of 15 cases (27%). Amplifications were located at 20q and 5q31 (Fig. 2)Citation .

Genetic Changes in Large Tumors with Lymph Node Metastases (Group 3, n = 20).
This group of locally advanced colorectal cancers showed an ANCA of 9.8, indicating a high degree of chromosomal instability. Frequent whole arm chromosomal gains mapped to 7p (45%), 8q (35%), 13 (40%), and X (35%). When only chromosomal bands 8q23–24 were studied, gains could be found in 14 of 20 studied cancers (70%). In two cancers, amplifications were found at 20q. Losses could be seen at 4q (30%), 8p (30%), 17p (35%), and 18q (60%). Detailed analysis revealed losses at 18q21-ter in 14 of 20 studied colorectal cancers (70%; Fig. 3Citation ).

Comparison of Nonmetastasizing versus Metastasizing Colorectal Cancers.
In group 3, the highest amount of chromosomal instability was found reflected by an ANCA of 9.8 versus 5.7 in group 1. The frequency of amplifications was not different in the three studied groups. Also, gains of 20q and losses of 18q21, often described as markers of advanced colorectal cancer, were not statistically different between the three groups. However, a comparison of groups 1 and group 2, which differed only in the depth of infiltration into the colonic wall, revealed an increase of gains of chromosome 7p from 7% in group 1 to 45% in group 2. Although, this difference was not statistically significant (P = 0.08), it also prevailed in group 3.

A major finding of our study was that gains of chromosome 8q23–24 occurred in the vast majority of lymph node-positive colorectal cancers (70%) versus only 7% in lymph node-negative cancers (P = 0.0016; Fig. 4Citation ).



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  		Fig. 4. Frequency of subchromosomal alterations in groups 1–3.

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In recent years, progress has been achieved in the treatment of colorectal cancer. New therapeutic regimens have been adopted including neoadjuvant radiochemotherapies for locally advanced rectal cancers (1 , 13 , 14) as well as new chemotherapeutic agents for metastasizing colon cancers (15) . Nonetheless, the metastatic potential of tumors, especially to regional lymph nodes, is the major obstacle to successful treatment for this type of malignancy. In this respect, the genetic analysis of primary colorectal cancers that have the capacity to form lymph node metastases versus cancers of the same size that do not metastasize is essential to identify the genes responsible. Furthermore, the establishment of biomarkers for molecular staging based on indicative genomic hot spots is a major goal in translational research. We therefore studied lymph node-negative versus lymph node-positive colorectal cancers with different degrees of infiltration into the colonic wall. Our CGH analysis revealed certain chromosomal changes that are common in colorectal cancers, such as gains of chromosome 7, 8q, 13q, 20q, and X. Frequent chromosomal losses mapped to 4, 17p, 18q, and Y. These chromosomal changes have been described previously and are specific for colorectal cancers (3 , 4 , 5 , 7 , 8) . However, in these publications, no detailed chromosomal analysis was made with respect to the nodal status.

In the present study, it is shown that lymph node-positive carcinomas reveal a very high degree of chromosomal instability compared with lymph node-negative tumors with the same depth of infiltration into the colonic wall. It was demonstrated that genomic gains and losses result in up-regulation or down-regulation of gene activity measured by expression profiling (16 , 17) . It can therefore be hypothesized that the metastatic phenotype requires a higher number of up-regulated oncogenes and down-regulated tumor suppressor genes. However, a study has recently been published demonstrating that chromosomal gains do not necessarily result in an up-regulation of genes located at the corresponding chromosomal loci in colorectal cancer (18) .

The major finding of the present study is the high frequency of chromosomal gains at the 8q23–24 locus almost exclusively in lymph node-positive colorectal cancers. This chromosomal gain is rarely found in lymph node-negative carcinomas.

In addition to the data in colorectal cancers, the high frequency of gains of 8q23–24 has also been demonstrated in esophageal cancers (19) . In this study, the authors conclude that gain of chromosome 8q23-ter could be used as marker to predict lymph node metastases in esophageal cancers. In our study, however, gain of 20q is also frequently found, but it does not significantly correlate with lymph node positivity. In this respect, gain of chromosome 20q seems rather to be a marker for hepatic metastases in colorectal cancers (8) .

Relevant target genes mapping to the genomic region 8q23–24 are Myc, EIF3S3, PVT 1, BV 1, and the PRL-3 gene. For instance, EIF3S3 encodes for the p40 subunit of the eukaryotic translation initiation factor 3 (20) . It has been demonstrated that amplification of EIF3S3 is a marker of tumor progression, worse prognosis, and, in particular, lymphatic metastases in prostate cancer (21) . Interphase fluorescence in situ hybridization analysis of colorectal cancers at different stages is therefore needed to determine the role of EIF3S3 in lymphatic metastases. Additionally, the PRL-3 gene has recently been demonstrated to be associated with metastasis formation in colorectal cancers and to be the possible target gene of the underlying amplification of 8q24 (22) .

In summary, the study indicates that a high degree chromosomal instability correlates with colorectal cancers metastatic to the surrounding lymph nodes. In particular, gain of the chromosomal locus 8q23–24 almost exclusively occurs in lymph node-positive cancers and might pinpoint relevant target genes located in this region. Detection of gains of 8q23–24 by using interphase DNA probes on cytological specimens or colorectal DNA chip technology in the clinical setting might predict lymph node positivity before therapy. Such molecular approaches could enhance the sensitivity and specificity of precise staging that is mandatory for individual multimodal cancer therapy.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 To whom requests for reprints should be addressed, at Department of General Surgery, Georg-August-University Göttingen, Robert-Koch-Strasse 40, D-37075 Göttingen, Germany. E-mail: mghadimi{at}surgery-goettingen.de Back

2 This manuscript is part of the doctoral thesis of M.G. Back

3 The abbreviations used are: UICC, International Union Against Cancer; CGH, comparative genomic hybridization; ANCA, average number of chromosomal copy alterations. Back

Received 7/ 9/02; revised 11/25/02; accepted 11/25/02.


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 DISCUSSION
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HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online