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Tumor Karyotype Predicts Clinical Outcome in Colorectal Cancer Patients

From the Department of Genetics, "G. Papanikolaou" Research Center, Saint Savas Oncological Hospital, Athens, Greece; Department of Pathology, Odense University Hospital, Odense, Denmark; Department of Clinical Genetics, Lund University Hospital, Lund, Sweden; Department of Cancer Genetics, the Norwegian Radium Hospital, Oslo, Norway

Address reprint requests to Georgia Bardi, PhD, Department of Genetics, "G. Papanikolaou" Research Center, Saint Savas Oncological Hospital of Athens, 171 Alexandras Ave, Athens 115 22, Greece; e-mail: gbardi{at}hotmail.com

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
PURPOSE: To investigate the prognostic value of the overall karyotypic features and specific chromosome aberrations in colorectal cancer (CRC).

PATIENTS AND METHODS: Cytogenetic features of 150 primary CRCs investigated at the time of surgery were correlated with patient survival by univariate and multivariate analyses, using classical clinicopathologic parameters as covariates.

RESULTS: In univariate analysis, in addition to tumor grade and clinical stage, structural aberrations as well as rearrangements of chromosomes 8 and 16 were significantly correlated with shorter overall survival. Karyotypic complexity, rearrangements of chromosomes 8 and 16, and loss of chromosome 4 were significantly correlated with shorter disease-free survival. In multivariate analysis, in addition to tumor grade, the type of chromosome aberrations (structural or numerical), ploidy, and loss of chromosome 18 came across as independent prognostic factors in the group of all patients. In the subset of patients with stage I and II carcinomas, none of the clinicopathologic variables could independently predict patient survival, whereas the presence of structural chromosomal aberrations was the only independent predictor of poor prognosis. In the subset of patients with stage III carcinomas, the presence of structural changes of chromosome 8 was a stronger independent predictor of prognosis than was tumor grade.

CONCLUSION: Cytogenetic tumor features are valuable predictors of prognosis in CRC patients. The tumor karyotype should therefore be taken into account in the clinical management of patients with this disease, especially for patients having cancers of the early or intermediate stages I, II, and III.

	INTRODUCTION

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Despite the more detailed understanding of the cellular and molecular events underlying colorectal carcinogenesis obtained in recent years, the average 5-year survival rate of patients suffering from this disease remains approximately 40%.¹ It is therefore clear that the extensive new knowledge about the structure, function, and interaction of key genes in large bowel tumorigenesis has not yet brought about corresponding improvements in the clinical handling of patients, especially as regards the sporadic type, which constitutes more than 85% of all colorectal cancers (CRCs). Attempts have been made to assess genetic features of CRC that could predict prognosis in an independent manner; however, the studies^2-8 have almost always focused exclusively on gene-level alterations without taking into account the numerous coexisting genomic abnormalities at higher organizational levels, in particular numerical and structural chromosomal abnormalities, that are also likely to exert a pathogenetic influence. Hence, the extensive complexity and genetic heterogeneity that characterize the overall genomic profile of CRC have not been duly recognized.

We and others have previously reported that acquired clonal chromosome aberrations are nonrandomly associated with both initiation and progression in colorectal tumorigenesis.^9-17 The clinical usefulness, however, of these genetic tumor features in the proper management of patients with CRC, as an adjunct to, or independent of, the classical clinicopathologic parameters, has not been well investigated and documented. To assess whether the karyotypic pattern provides valuable and independent information about the prognosis of individual patients with CRC, we here describe the first attempt to evaluate simultaneously the prognostic importance of all nonrandom cytogenetic features compared with that of classical clinicopathologic parameters in 150 patients with CRC.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
Patients
During an 8-year period (1989 to 1997) successful cytogenetic analysis after short-term culture was performed on tumor samples from 150 untreated patients with primary colorectal adenocarcinomas, from two Scandinavian institutions (95 patients from Lund University Hospital, Sweden, and 55 patients from Odense University Hospital, Denmark). All tumor samples were obtained at the time of initial surgery. Patients in whom a diagnosis of hereditary nonpolyposis CRC or familial adenomatous polyposis was made were excluded from the present investigation. The mean patient age at the time of surgery and cytogenetic analysis was 69.6 years (range, 39 to 90 years); the age of 81 patients was above the mean, whereas that of the remaining 69 patients was below it. There were 67 women and 83 men. Among the 149 cases with available information about tumor site, 90 patients had colon cancer, and 59 had cancer of the rectum. The mean size, referring to the tumor largest diameter, was 5.02 cm (range, 1 to 16 cm) based on data from 141 tumors; 95 tumors were 5 cm or smaller, and 46 were larger than 5 cm. The tumors (148 in total) were histologically graded as "well" (6 tumors), "moderately" (103 tumors), or "poorly" differentiated (39 tumors). Disease staging was according to the American Joint Committee on Cancer TNM system classification based on the findings in 148 tumors at surgery: 21 cancers were stage I, 66 were stage II, 52 were stage III, and nine were stage IV. The degree of lymphocytic infiltration was assessed¹⁸ in 146 tumors and was found to be weak in 88 and marked in 58. Death from any cause and death from cancer were used as the clinical end points for overall survival (OS) and disease-free survival (DFS). At the end of the follow-up, 80 patients were dead, whereas 70 were alive. The median follow-up time of survivors was 50 months (range, 34 to 88 months). During follow-up, 46 patients developed distant metastases or a local recurrence.

Cytogenetic Data
The 150 consecutive CRC samples were processed with no changes in the investigative techniques. The original karyotypic data, on which the present study is based, have been published previously.^11,13,15-17 Thirty-five of the 150 tumors had a normal karyotype, whereas 115 showed clonal chromosome aberrations. The average number of chromosomes involved in chromosome aberrations per tumor was 6.17 (range, 1 to 30 chromosomes).

For the various correlation analyses, the cases were subdivided into various groups based on the presence or absence of clonal chromosome aberrations, the type of aberrations detected, the presence of cytogenetically related or unrelated clones, and the ploidy level of the tumor karyotype. The criteria used for all subdivisions followed the recommendations of the International System for Human Cytogenetic Nomenclature (ISCN 1995).¹⁹ The 150 cases were broken down into two main categories—tumors with a normal (n = 35) karyotype versus tumors with an abnormal (n = 115) karyotype. The latter group was subdivided depending on whether the karyotype was complex (with > 3 changes, n = 53) or simple (with 1 to 3 changes, n = 62).¹¹ The abnormal group was further subdivided depending on the presence of only numerical changes (n = 47) in the karyotype, versus structural, or numerical and structural changes (n = 68), as well as on the presence of one abnormal clone or more than one, but cytogenetically related, clone (monoclonal, n = 88) versus 2 or more unrelated abnormal clones (polyclonal, n = 27) in the tumor karyotype. Another subdivision was based on the modal chromosome number, stratifying the abnormal clones into four groups: hypodiploid (35 to 45 chromosomes, n = 33), pseudodiploid (46 chromosomes, n = 17), hyperdiploid (47 to 57 chromosomes, n = 35), and near-triploid (58 to 80 chromosomes, n = 30) tumors. The involvement of each chromosome in numerical and/or structural aberrations per tumor is given in Figure 1, in which tumors with abnormal karyotype are grouped on the basis of the karyotypic ploidy level.

View larger version (92K): [in this window] [in a new window]   Fig 1. One hundred fifteen cytogenetically abnormal colorectal cancers grouped according to ploidy level. Each row represents one tumor. (*), number of abnormal chromosomes per tumor; (#), number of tumors with aberrations of the specific chromosome.

Statistical Analyses
The distribution of the clinicopathologic and karyotypic variables was analyzed using Fisher's exact test and the ² test (Table 1). The postoperative period was measured from the date of surgery to the date of the last follow-up, or death. The probabilities of survival according to specific prognostic factors were plotted using Kaplan-Meier survival curves, and differences between groups were evaluated using the log-rank test (Tables 2 and 3). Simultaneous effects of various factors in DFS were determined by multivariate analysis using stepwise forward multiple regression (Tables 4 and 5). The data sets were entered in each model of the multivariate analysis on the basis of different categories of variables, description of the clinicopathologic features, the overall karyotypic characteristics, and the specific chromosome involvement in aberrations (Table 4), or on different patient subsets, according to the disease stage, the tumor site, and the patient's age (Table 5). Statistical analysis was performed using WinStat for Excel software (version 2002; Robert K. Fitch Software, Germany). The level of statistical significance was set at < .05.

	RESULTS

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Univariate analysis of the clinicopathologic variables and survival from surgery (Table 2) showed that tumor grade and disease stage were significantly associated with both OS and DFS. All the remaining variables (ie, age, sex, tumor size, tumor site [colon or rectum], and lymphocytic infiltration) did not show significant correlation with survival. Multivariate analysis of all clinicopathologic parameters showed that only tumor grade could predict survival independently (Table 4, model I).

The correlation between survival and the variables related to the overall karyotypic pattern (Table 3) by univariate analysis showed that patients with tumors showing structural chromosome aberrations had significantly shorter OS than those whose tumors had only numerical changes (Fig 2A). Also, patients with tumors that had complex karyotypes had significantly shorter DFS than those whose tumors had a simple karyotype (Fig 2B). All the other features describing global cytogenetic features (normal/abnormal karyotype, ploidy, mono-/polyclonality) did not give differences that were statistically significant. However, in multivariate analysis of the overall cytogenetic features (Table 4, model II), in addition to the presence of structural aberrations, ploidy also turned out to be an independent prognostic factor for survival, with patients whose tumors had aneuploid karyotypes having significantly shorter survival than those whose tumors had diploid karyotypes.

View larger version (8K): [in this window] [in a new window]   Fig 2. Overall survival in colorectal cancer with numerical (N) or structural (S) chromosome aberrations (A). Disease-free survival in colorectal cancer with simple (S) or complex (C) tumor karyotypes (B).

View larger version (21K): [in this window] [in a new window]   Fig 3. Overall survival in colorectal cancer with or without structural aberrations of chromosomes 8 (A) and 16 (B). Disease-free survival in colorectal cancer with or without structural aberrations of chromosomes 8 (C) and 16 (D) and with or without loss of chromosome 4 (E).

When subsets based on stage were examined separately (Table 5), which was possible only for stages II and III (few tumors were of stages I and IV), the presence of structural chromosome aberrations, loss of chromosome 21, and ploidy were the only independent predictors of poor prognosis in stage II patients (Table 5, model II), whereas structural changes of chromosome 8 and tumor grade could independently predict a dismal outcome in stage III patients (Table 5, model III). When cases stages I and II were pooled in the multivariate analysis, only the presence of structural chromosome rearrangements appeared as an independent predictor of poor prognosis (Table 5, model IV). Finally, when tumors of stages II and III were considered as one subset, loss of chromosome 18 and tumor grade were shown to be independent prognostic factors (Table 5, model V).

When cases were dichotomized according to tumor site (Table 5), the multivariate analysis of all variables showed that for colon cancer (Table 5, model VI), the clinical stage as well as the presence of structural aberrations of chromosomes 1 and 7 were independent poor prognostic factors. For rectal cancer (Table 5, model VII), the presence of numerical/structural chromosomal changes, ploidy, and tumor grade seemed to predict a poor prognosis in an independent manner.

	DISCUSSION

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Our results show a clear association between several karyotypic tumor features and the survival of patients with CRC after surgical treatment. The presence of structural chromosome changes and the finding of a nondiploid karyotype, in addition to low tumor grade, seemed to be independent predictors of poor survival in the group of patients as a whole (Table 4, model IV). Numerous previous studies have shown that aneuploidy, measured by flow cytometric techniques correlates with a poor prognosis in CRC patients.^21,22 However, in addition to the variation in determination of aneuploidy among different studies, that technique, in contrast to chromosome banding and karyotyping, cannot detect a pseudodiploid chromosome complement or one harboring only quantitatively minor gains or losses of genomic material (Fig 1); such tumors would be registered as normal by flow cytometry, whereas by karyotyping, they would be registered as diploid or near-diploid but abnormal. In fact, this could be the reason why the correlation analyses we present show that the very presence of chromosome rearrangements in the genome of CRC cells is a stronger independent predictor of prognosis (P = .001) than ploidy itself (P = .037; Table 4, model IV). This finding, as well as the finding that complex tumor karyotypes are associated with shorter DFS (Table 3, Fig 2B), support our early suggestion that the detection of structural chromosome rearrangements and complex tumor karyotypes can be used to assess prognosis more accurately in CRC patients.^11,13 The prognostic importance of the presence of structural chromosomal rearrangements in tumor cells increases further if one considers that, among all clinicopathologic and cytogenetic variables, this was the only one capable of predicting an unfavorable disease outcome in an independent manner in early cancers (ie, stages I and II [Table 5, model IV]).

Previous studies^2-8 have provided evidence that allelic imbalances on several chromosomes correlate with prognosis in CRC patients. We now assessed the prognostic information value of both imbalances and rearrangements of all chromosomes nonrandomly involved in alterations in CRC cells.

The most striking correlation between a specific chromosome aberration and prognosis was the effect of loss of chromosome 18. This loss was, together with tumor grade, found to be an independent predictor of short survival in the entire group of patients (Table 4, model VI; Table 5, model I). Furthermore, loss of chromosome 18 was shown to be a stronger independent predictor of prognosis (P = .0008) than tumor grade (P = .0047) in the subset of patients having cancers of the intermediate stages II and III (Table 5, model V). Although several candidate tumor suppressor genes on the long arm of chromosome 18 have been identified, including DCC, DPC4/SMAD4/MADH4, and SMAD2/MADH2, none of them is mutated in most CRC cases with 18q loss.^7,23 In addition, studies using microsatellite markers to assess allelic imbalances in CRC have shown that larger chromosomal segments were lost significantly more frequently than smaller ones in cases with 18q loss,^7,24 indicating, as we see it, that the crucial event perhaps is not at the genic but at the genomic level, and that in this case, tumor progression evolves by global genomic rearrangements or imbalances rather than by single gene mutations or losses.²⁵

The correlation of structural rearrangements of chromosome 8 with OS and DFS (Fig 3A and C) in univariate analysis, together with the emergence of this chromosomal variable in multivariate analysis as the strongest predictor of poor disease outcome in stage III patients (Table 5, model III), was also a remarkable finding. In a comparative genomic hybridization (CGH) study²⁶ of 50 CRCs with and without lymph node metastases, gain of 8q23-24 was found to be strongly associated with lymph node positivity, and therefore, it was suggested that gain of this chromosome region could be used to predict an increased metastatic potential in this disease. In another CGH study of 67 sporadic CRCs,²⁷ 8p loss was found to be an independent predictor of poor survival, whereas an allelic imbalance study of 508 CRCs⁴ showed that 8p loss was a predictor of dismal outcome in CRC patients of Astrel-Coller stage B2 or C. Although the above molecular genetic data appear to be at odds with one another, suggesting either amplification of an oncogene at 8q or loss of a tumor suppressor gene at 8p as the pathogenetically important event, they are both explained by the cytogenetic finding of an i(8q), which indeed is the most common structural aberration of chromosome 8 in advanced colorectal cancer.¹⁵ The process by which the loss of the short arm and the simultaneous gain of the long arm of chromosome 8 affects the metastatic properties of tumors at the molecular level is presently unknown, but the fact remains that the generation of an i(8q) is associated with the development of lymphatic metastases in CRC.

To our knowledge, this is the first report pointing to a correlation between the occurrence of structural rearrangements of chromosome 16 in the tumor cells and OS as well as DFS in CRC patients. Because such aberrations have been found to be bad predictors in other advanced malignancies (eg, hepatocellular malignancy²⁸ and bladder cancer²⁹) they might be general markers of tumor aggressiveness whose prognostic information value is not restricted to CRC. The association of loss of chromosome 4 with a shorter DFS agrees well with the findings in a previous study,² in which loss of heterozygosity at 4p14-16 was associated with a shorter DFS in CRC patients, and also the finding of more common genomic losses from chromosome 4 in CRC metastatic samples compared with cancers of lower stage.³⁰ Because the aforementioned aberrations seemed to predict a poor disease outcome only in univariate analysis, we suggest that their prognostic utility should be evaluated in larger studies of CRC, also using multivariate analysis.

It is well known that the clinical features of colon cancer differ from those of rectal cancer. The existence of two biologically different disease categories based on the tumor site in the large bowel was proposed more than a decade ago,³¹ and differences indicative of progression through different tumorigenic pathways have been recognized.³² Our results showed that although the survival of patients with colon and rectal cancers did not differ significantly (Table 2), the overall cytogenetic patterns of colon and rectal tumors did (Table 1), both with regard to the distribution of normal versus abnormal karyotypes (P = .015) and to the occurrence of simple versus complex chromosome aberrations (P = .004), indicating that the carcinomas arise through different genetic mechanisms in the colon and rectum. The detection of different predictors of poor survival by the multivariate analysis (Table 5, models VI and VII), for example, structural changes of chromosomes 1 and 7 in colon but not in rectal carcinomas, supports the previous assumption. The need to use different genetic markers for more accurate prognostication of patients with cancers located in different segments of the large bowel is clearly indicated.

Standard treatment for CRC includes adjuvant chemotherapy for patients with lymph-node metastases, but not for those without metastatic disease. However, 20% of the latter group eventually die from disease spreading. The identification of complex karyotypes and structural rearrangements of specific chromosomes as indicators of poor disease outcome as outlined above could assist oncologists in deciding which patients might benefit from adjuvant treatment after surgery. Possibilities that immediately present themselves, but which, we hasten to emphasize, first need to be confirmed in prospective studies and then to be tested out in appropriate trials, would be the following: CRC patients whose tumor profiles differ from the high-risk patterns mentioned above may not require adjuvant treatment even if this would otherwise be recommended on the basis of standard staging. Patients with primary carcinomas having rearrangements of chromosome 8 and/or loss of chromosome 18, even in the absence of apparent lymph node metastases, should be considered to be at high metastatic risk and therefore may be eligible for chemotherapy that would not be warranted for clinically similar patients without aberrations of chromosomes 8 or 18 in their tumor karyotypes. The use of fluorescence in situ hybridization probes specific for loci on chromosome 18 as well as for 8p and 8q could provide information sufficient to perform a preliminary risk-grouping of CRC. Loss of chromosome 18 and i(8q) formation can be detected even in interphase nuclei isolated from histological sections, whereas whole chromosome probes can be used in metaphase cells whenever fresh tumor material is available. A fluorescence in situ hybridization test as part of the routine laboratory evaluation of CRC is, in some respects, more reliable than analogous DNA tests that have already been proposed for a genetic–based prognostication systems,^7,21 because the cells are examined individually and not as a DNA mixture from normal and malignant cells. It is also much simpler than complete karyotypic analysis of a tumor sample, which requires considerable cytogenetic expertise. Besides, when the independent prognostic value of additional chromosome aberrations is definitely proven for a particular clinical subset of CRC, one might also utilize additional specific fluorescence in situ hybridization probes to assess prognosis more accurately than is possible based on only the standard histopathologic evaluation.

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
The authors indicated no potential conflicts of interest.

	NOTES

 
Authors' disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
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Submitted November 4, 2003; accepted April 1, 2004.

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