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Molecular Oncology, Markers, Clinical Correlates |
Departments of Internal Medicine [S-W. C.], Microbiology [K. J. L., Y-A. B., M-G. R.], and Clinical Pathology [K-O. M., M-S. K., K-M. K.], College of Medicine, The Catholic University of Korea, Seoul 137-701, Korea
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Experimental Design: The concerted and individual effects of various chromosomal losses on survival were comparatively analyzed using a reference panel of 40 microsatellite markers in eight cancer-related chromosomes, 3p, 4p, 5q, 8p, 9p, 13q, 17p, and 18q.
Results: Of the 168 colorectal cancers tested, 29 (17%) with high-frequency MSI were associated with good survival (P < 0.05). The extent of LOH detected in 139 (83%) cases without MSI was classified as low level involving three or fewer arms (35%), moderate level involving four arms (22%), or high level involving five or more arms (43%). High-level loss correlated with earlier onset, lymphatic invasion, and rectal location, whereas low-level loss was more common in proximal colon and stages I and II (P < 0.05). The survival curve and multivariate analysis identified high- and low-level chromosomal loss as the most significant predictor of poor and good survival, respectively (log-rank test, P < 0.0001), in patients with stage II (hazard ratio, 6.27; 95% confidence interval, 1.99–19.7; P = 0.0017) and those with stage III (hazard ratio, 10.89; 95% confidence interval, 2.54–46.77; P = 0.0013). Moderate chromosomal loss showed dual prognostic values associated with favorable stage II and unfavorable stage III. Single chromosomal losses tended to play a role as a part of the concerted chromosomal function.
Conclusion: The classification of colorectal cancer based on chromosomal loss and MSI provides a prognostic index that reflects tumor pathobiology.
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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80%) and MSI (approximately 20%; Ref. 1
). Highly polymorphic, simple-repeat nucleotide sequences dispersed throughout the genome (also called microsatellite sequence) are useful for detecting unilateral chromosomal losses that give rise to differing extents of LOH (2
, 3)
and MSI, which leads to the widespread insertion and deletion of simple-repeat sequences (4, 5, 6, 7)
. Chromosomal loss is implicated as a predictor of poor survival in colorectal cancer (8, 9, 10, 11, 12, 13, 14)
, whereas MSI is associated with improved survival (6
, 7
, 15
, 16)
. Therefore, colorectal cancers are likely to be classified into two genotypes, i.e., those showing chromosomal loss and those showing MSI, both of which are determined by microsatellite markers. The standardization of the criteria used for characterizing microsatellite alteration is crucial for valid microsatellite genotyping. Worldwide efforts for standard criteria for MSI (17) have resulted in a reference panel of microsatellite markers that are likely to be clinically applicable for the diagnosis and treatment of colorectal cancer (18 , 19) . Meanwhile, a cautious attitude toward the criteria of chromosomal losses is advised because of the coexistence of different chromosomal losses in individual colorectal cancers. Single chromosomal losses may only represent sensitive indirect markers of a multifactorial set of chromosomal changes, which for example may be responsible for tumor aggressiveness (11 , 12) . Alternately, the net level of chromosomal losses estimated by whole-genome analysis may include some LOH that has no biological effects on tumor growth but which coincidentally occur during tumor progression and thus merely reflects the accumulation of genetic alterations during advanced tumor stages (11 , 12) . From this perspective, it is notable that in gastric cancers, a high and a low level of chromosomal loss, measured in cancer-related chromosomal arms including 5q, 9p, 13q, 17p, and 18q, were found to correlate with high and low risk of cancer-related deaths, respectively (20) . These findings on the level of chromosomal loss suggest that a set of microsatellite markers, selected from a subset of chromosomal arms, may plausibly represent the concerted effect of multiple cancer-specific chromosomal losses.
We analyzed 168 colorectal cancers for both chromosomal loss and MSI using 40 microsatellite markers selected from eight chromosomes, i.e., 3p (21) , 4p (8) , 5q (22) , 8p (9 , 10) , 9p (23) , 13q (24) , 17p (11, 12, 13) , and 18q (11 , 14) , all of which are known to contain candidate tumor suppressor genes or to function as prognostic factors. The five markers used per chromosome provided a high informative rate (97%) for the LOH status on every chromosomal arm tested and made it possible to measure the amount of chromosomal losses accurately in addition to MSI. The classification of microsatellite alterations based on the level of chromosomal loss and MSI was found to plausibly reflect the pathobiological characteristics of colorectal cancer, thus suggesting a means for the genetic staging of colorectal cancer.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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None of the patients tested received preoperative radiation and/or chemotherapy. The Moetrel regimen (27 , 28) consisting of i.v. bolus 5-fluorouracil and oral levamisole was administered as a standard therapy based on the physician’s judgment in each case. Follow-up data were retrieved from medical records and confirmed by direct interviews with the patients’ physicians. Cancer-related deaths were identified by the presence of prior metastases of colorectal cancer during the survival analysis. Data from patients that died from other causes were censored at the time of death. At the end of the study period (June 2001), 67 patients had died as a result of their cancers, and 10 patients had died of other causes. At the time of analysis, the median follow-up time for all patients was 53 months, ranging from 6 to 126 months.
Microdissection and DNA Amplification.
Serial 7-µm-thick sections from paraffin-embedded primary tissues were stained with H&E, and a tumor cell-rich area representative of the histological features was chosen by microscopic examination. Normal cells, such as stromal cells and lymphocytes, in the tumor portion on uncover-slipped slides were manually scraped off using a surgical scalpel under stereomicroscopic guidance (Fig. 1)
. The size of the remaining tumor portion ranged from 5 to 7 mm in diameter. Each microdissected tissue was microscopically reexamined if the tumor cell content was >70%. In each case, 50–100 microdissected cells were digested with 1 µl of Tween 20-proteinase K lysis buffer. The admixture of microdissected cells and lysis buffer was then incubated overnight at 37°C and used as template DNA for PCR analysis after proteinase K heat inactivation for 5 min. Because of the variable qualities of DNA extracted from formalin-fixed, paraffin-embedded tissue, the amounts of tumor DNA and normal DNA for PCR analysis were adjusted by visually inspecting the band intensities of serially diluted template DNAs.
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-32P]dCTP 10 µCi/ml). Of the PCR products, 2 µl were diluted with 5 µl of formamide-dye loading buffer, heated at 80°C for 3 min, and electrophoresed on 6% polyacrylamide gel containing 7 M urea. The radioisotope-labeled microsatellite sequences were visualized by denaturing gel electrophoresis. Repeated exposures of each autoradiograph were performed to obtain an optimal range of allelic band intensities for densitometric analysis.
Microsatellite Markers.
Microsatellite repetitive sequences were superimposed on erroneous products because of slippage of the repeat units, resulting in a stutter or satellite extra-ladder bands (29)
. In preliminary experiments to establish the PCR conditions for reproducible allelic bands, some microsatellite markers have equivocally produced allelic signals in repeated PCRs, which might result in false-positive or -negative LOH. We selected dinucleotide repeat markers ranging from 80 to 210 bp, in which two alleles reproduced stable allelic ratios. Five microsatellite markers per chromosomal arm were used to increase the number of heterozygous markers and to span the entire length of the arm. A total of 40 microsatellite markers covered the eight chromosomal arms, 3p, 4p, 5q, 8p, 9p, 13q, 17p, and 18q (Table 1)
.
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. If novel allelic bands that were not observed in normal DNA were found in the corresponding tumor DNA, they were interpreted as MSI (Fig. 2A
, D5S519). Sometimes, it was not possible to distinguish between MSI and LOH, especially in cases with intimately close heterozygous allelic bands. A signal reduction in one of two alleles might result not only from allelic loss (Fig. 2A
, D9S270) but also from allelic shift attributable to comigration with an adjacent allele (Fig. 2A
, D5S346). Thus, MSI was evaluated only in homozygous markers, which were free of allelic loss noise (Table 1
and Fig. 2B
).
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). The LOH of tumor DNA was scored as relative allelic ratio, which was calculated by dividing the tumor allelic ratio by the normal allelic ratio. A peak area including both main and shadow bands was measured to determine a single allelic intensity (Fig. 3A
, D8S1734). In cases with two alleles in close proximity where shadow bands from both alleles comigrated, overlapping peaks were subtracted from the allelic intensity measurements (Fig. 3A
, D9S199). When two intimate allelic bands differed in size by only one repeat unit, allele band intensities were difficult to measure because of excessive overlap (Fig. 3A
, D8S552). To determine individual allelic intensities, two alleles differing in size by more than one repeat unit (
4 bp in the dinucleotide marker) were used as informative heterozygous cases for the LOH analysis. (Table 1
and Fig. 3B
). On the basis of the distribution of relative allelic ratios among 20 patients, as determined using the 40 microsatellite markers, we decided upon a 1.55-fold value as a cutoff point because this provided the best discrimination between wild-type heterozygosity and LOH (Fig. 3C)
. This cutoff point was applied to some cases with borderline LOH, but the majority of cases with an LOH of >2.0-fold were determined visually.
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2 test and the Mantel-Haenszel 2 test. The postoperative period was measured from the date of surgery to the date of the last follow-up or death. The probabilities of disease-specific survival according to specific prognostic factors were plotted using Kaplan-Meier survival curves, and differences between groups were evaluated using the log-rank test. Simultaneous prognostic effects of various factors were determined by multivariate analysis using Cox’s proportional hazards models. Statistical analysis was performed using SAS software (version 6.12; SAS Institute, Cary, NC). The level of statistical significance was set at <0.05. |
RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. The remaining 139 cases included 135 cases without altered allelic length and 4 cases with altered allelic length in one or two homozygous markers and were defined as negative for high-frequency MSI.
LOH was determined according to the criteria for the allelic ratio of tumor DNA relative to that of normal DNA (Fig. 3)
. One hundred and thirty-five (97%) of the 139 colorectal cancers lacking high-frequency MSI were informative for LOH on every chromosomal arm. The remaining four cases (3%) were not informative of heterozygosity on chromosome 3p (1 case), 8p (1 case), and 13q (2 cases) for every marker tested and were excluded from the chromosomal loss analysis. In total, 530 chromosomal losses were found in the 135 colorectal cancers, the majority of which (493 losses, 93%) demonstrated LOH in all informative heterozygous markers on the same chromosome. Accordingly, microsatellite markers on the same chromosomal arm showed LOHs with similar frequencies (Table 1)
, suggesting that the majority of chromosomal losses involved the whole or a large portion of the chromosomal arm.
Chromosomal arms containing at least one LOH were found frequently in 8p, 17p, and 18q and less frequently in 3p, 4p, 5q, 9p, and 13q (Table 2)
. A large fraction (65%) of the 135 colorectal cancers that were informative for LOH on all chromosomal arms examined had three levels of chromosomal loss involving two, four, or five arms, whereas involvement of one, three, six, seven, and eight chromosomal arms was relatively infrequent (32%). The remaining 4 cases (3%) had no chromosomal losses as detected using the reference marker set (Table 2)
. The increased extents of chromosomal losses were frequently related to 8p, 17p, and 18q losses and relatively less frequently related to 3p, 4p, 5q, 9p, and 13q losses. Consequently, multiple concordant losses preferentially involved 8p, 17p, and 18q or combinations of these.
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showed that growth pattern, venous invasion, and rectal location were significantly associated with cancer-related deaths (P < 0.05).
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). Colorectal cancers with MSI correlated positively with an expanding growth pattern, poor differentiation, proximal colonic location, and good survival versus cases without MSI (P < 0.05; Table 5
).
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). Colorectal cancer patients burdened with high-level chromosomal losses were associated with earlier onset, lymphatic invasion, distal colonic and rectal location, and higher tumor stages than those with low-level loss, which were associated with proximal colonic location and early tumor stages (P < 0.05). Good and poor survivals were also closely correlated with low- and high-level losses, respectively, at stages II and III (P = 0.001). Colorectal cancer patients with four chromosomal losses were indicative of a low-risk subgroup in stage II (survival rate, 70%) and a high-risk subgroup in stage III (survival rate, 20%).
Prognostic Implications of MSI and Three Levels of Chromosomal Loss.
Kaplan-Meier survival curves and log-rank analysis demonstrated that cases with low-level loss or MSI were associated with good survival, and that cases with high-level loss were associated with poor survival, in both stage II (Fig. 4A)
and stage III (Fig. 4B)
colorectal cancers (P < 0.0001). Colorectal cancers with moderate-level losses demonstrated dual survival curves, i.e., diseases with favorable stage II (Fig. 4A)
and unfavorable stage III (Fig. 4B)
. Furthermore, the survival curves of colorectal cancers with 8p, 17p, or 18q loss tended to split into two disease categories of good and poor survival, depending on the level of chromosomal loss (Fig. 4)
.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. Cox’s proportional hazards model analysis, including both the level of chromosomal loss and single chromosomal losses, showed that the level of chromosomal losses, and not single chromosomal losses, was an independent factor (Table 6
, models 1 and 3). When the effect of the level of chromosomal loss was removed from the categorical variables, single chromosomal losses were found to be independent factors (Table 6
, models 2 and 4). These findings indicate that 8p, 17p, and 18q losses, all of which have been previously reported as molecular predictors (9, 10, 11, 12, 13, 14)
, play a role within the context of multiple chromosomal losses, but that they are not independent factors. Given that frequent chromosomal losses on 8p, 17p, and 18q were concurrently present against a genetic background of moderate- and high-level losses (Table 2)
, these chromosomal losses appear to be poor prognostic factors attributable to the high background level of chromosomal loss. In Cox’s proportional hazards model analysis, which included all clinicopathological and chromosomal variables, the level of chromosomal loss was the most significant determinant for the prognosis of either colorectal cancer stage II or stage III (Table 6
, models 5 and 6). Thus, the classification of colorectal cancer based on LOH and MSI may have clinical utility.
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. Some reports found more frequent LOH in rectal cancer than in colonic cancer, suggesting that the different genetic background may be responsible for a different clinical course (11
, 12)
. We found that a single chromosomal loss on 8p, 17p, or 18q and moderate- and high-level chromosomal loss were significantly associated with lymphatic invasion, a higher tumor stage, and a distal colonic and rectal location, whereas low-level losses were more frequent in the proximal colon (Tables 4
and 5
). When considering that the level of chromosomal losses functions as the predominant genetic background of colorectal malignancy, the concerted effect of chromosomal loss may account for the tissue type-specific clinical outcome. In agreement with previous findings (7
, 15
, 16)
, the MSI genotype was preferentially observed in the proximal colon but rarely in the rectum (Table 5)
. These results suggest that both chromosomal loss and MSI contribute to tumor invasion and metastasis in a tissue-dependent manner.
The concerted effects of chromosomal loss are likely to have an influence at the early stage of colorectal cancer. In a previous multifocal study on gastric cancers (32)
, we documented that different tumor areas shared the same multiple chromosomal losses, suggesting that multiple losses occur simultaneously, rather than gradually. In the present study, the age of onset of colorectal cancer with high-level loss was significantly lower than that of colorectal cancer with low-level loss. Thus, multiple chromosomal losses are likely to facilitate tumor progression in the early disease stage, leading to early disease onset, and tumors with low-level chromosome losses seem to remain in the early stage for a long period, leading to late onset. Interestingly, the loss of chromosome 4p was significantly associated with the early onset of colorectal cancer. The individual effect of 4p loss on early-onset disease is unlikely to be the result of tumor aggressiveness, because 4p loss was not found to correlate with cancer-related death (Table 4)
. On the other hand, 5q loss involving the APC tumor suppressor gene, which is known as a tumor initiator (33)
, was relatively less frequent and less associated with cancer-related death than 8p, 17p, and 18q losses. It is likely that 5q loss occurs at an initial stage in a subset of colorectal cancer, and that plays a role within the context of other multiple chromosomal losses but not as an independent factor of tumor progression. Our data on chromosomal loss imply that in general, cancer-related chromosomes tended to be concurrently involved not only during the early stage of tumor progression but also during tumor initiation.
LOH on other chromosomal arms has been reported to be less frequent than that on the eight chromosomal arms examined in this study (8, 9, 10, 11, 12, 13, 14)
. 3p and 4p losses, which were found to be relatively less frequent in the present study, were mainly observed in cases with more than four chromosomal losses, whereas these were infrequent in cases burdened with low-level losses (Table 2)
. Therefore, we believe that the use of more microsatellite markers in the present study marginally changed the low-level loss scores and increased the high-level loss scores. The range of moderate-level loss scores, involving four chromosomal arms, may have been broadened by including additional markers on the other chromosomes. In the present study, moderate-level loss was associated with dual prognostic values and distal colonic cancer (14 of 30 cases, Table 5
). Distal colonic cancers with moderate-level loss frequently manifested malignant diseases with nodal involvement (6 cases, 42%) and liver metastases (4 cases, 29%), whereas proximal colonic cancers with moderate-level loss were uncommon (4 of 30 cases) and remained at an early stage II (3 cases, 75%; statistical data are not shown because of the small sample size). These unique phenotypic features of moderate-level loss imply the presence of a tissue type-dependent genotype but not of mixed populations with low- and high-level chromosomal losses. On the other hand, 4 (3%) of 135 cases without LOH on the chromosomal arms examined in the present study were thought to have LOH on other chromosomal arms, because the clinical courses of the 4 cases were favorable. For this reason, we classified colorectal cancers without LOH as members of the low-level group.
As shown in Figs. 2
and 3
, the criteria used to determine the intensity ratio of the overlapping allelic bands (LOH) and the altered allelic length of homozygous marker (MSI) have advantages in terms of the validity of microsatellite typing. The cutoff values for a minimum of borderline cases between the wild-type and the imbalanced allelic ratios or high- and low-frequency MSI were determined on the basis of an altered or intact allele distribution among reference patients. On the other hand, DNA impurity of tumor tissue is inevitable because of stromal cell contamination or the genetic heterogeneity of tumor cell populations, which has also been proposed to lead to a wide range of LOH, including borderline or incomplete LOH (32
, 34)
. Because of DNA polyploidy, tumor cells usually contain more DNA or chromosomes than normal cells; the proportion of tumor DNA in a microdissected tissue site is thus higher than expected on the basis of tumor cell purity. Tumor DNA obtained by manual microdissection appears to be sufficiently pure to represent the allelic status of genomic tumor DNA. Consequently, it is likely that in the present study, a variety of microsatellite alterations were categorized into four genotypes, i.e., three levels of chromosomal loss and MSI. The level of chromosomal loss and MSI determined by a reference set of microsatellite markers may be applied in combination to the genetic staging of colorectal cancer. A series of tumor-related genetic elements appear to be dispersed in high density throughout the cancer-related chromosomes, because a decrease in the amount of tumor-related genetic elements may facilitate tumor invasion and metastases.
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FOOTNOTES |
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1 This study was supported by Ministry of Health and Welfare Grant HMP-99-M-03-0001, Ministry of Education Grants 1998-021-F00177 and 1998-001-F00031, and Korea Science and Engineering Foundation Grant 971-0710-090-2. 
2 To whom request for reprints should be addressed, at Department of Microbiology, College of Medicine, The Catholic University of Korea, 505 Banpo-dong, Socho-gu, Seoul 137-701, Korea. Phone: 82-2-590-1215; Fax: 82-2-596-8969; E-mail: rhyumung{at}cmc.cuk.ac.kr
3 The abbreviations used are: LOH, loss of heterozygosity; MSI, microsatellite instability; TNM, Tumor-Node-Metastasis.
Received 1/22/02; revised 4/ 4/02; accepted 4/12/02.
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