© 1999 by Oxford University Press
Journal of the National Cancer Institute, Vol. 91, No. 15, 1295-1303,
August 4, 1999
© 1999 Oxford University Press
Microsatellite Instability and 8p Allelic Imbalance in Stage B2 and C Colorectal Cancers
Affiliations of authors: K. C. Halling, A. J. French, L. J. Burgart, L. Moon-Tasson, S. N. Thibodeau (Departments of Laboratory Medicine and Pathology), S. K. McDonnell, D. J. Schaid, B. J. Peterson, M. R. Mahoney, D. J. Sargent (Health Sciences Research, Section of Biostatistics), T. E. Witzig (Internal Medicine, Division of Hematology), Mayo Foundation, Rochester, MN; M. J. O'Connell, G. H. Farr, Jr., R. M. Goldberg, North Central Cancer Treatment Group, Rochester.
Correspondence to: Stephen N. Thibodeau, Ph.D., Laboratory Genetics/HI 970, Mayo Clinic, 200 First St., SW, Rochester, MN 55905 (e-mail: sthibodeau{at}mayo.edu).
 |
ABSTRACT |
|---|
 Top Abstract IntroductionPatients and MethodsResultsDiscussionNotesReferences |
|---|
BACKGROUND: Microsatellite instability (MSI) and allelic imbalance involving chromosome arms 5q, 8p, 17p, and 18q are genetic alterations commonly found in colorectal cancer. We investigated whether the presence or absence of these genetic alterations would allow stratification of patients with Astler-Coller stage B2 or C colorectal cancer into favorable and unfavorable prognostic groups. METHODS: Tumors from 508 patients were evaluated for MSI and allelic imbalance by use of 11 microsatellite markers located on chromosome arms 5q, 8p, 15q, 17p, and 18q. Genetic alterations involving each of these markers were examined for associations with survival and disease recurrence. All P values are two-sided. RESULTS: In univariate analyses, high MSI (MSI-H), i.e., MSI at 30% or more of the loci examined, was associated with improved survival (P = .02) and time to recurrence (P = .01). The group of patients whose tumors exhibited allelic imbalance at chromosome 8p had decreased survival (P = .02) and time to recurrence (P = .004). No statistically significant associations with survival or time to recurrence were observed for markers on chromosome arms 5q, 15q, 17p, or 18q. In multivariate analyses, MSI-H was an independent predictor of improved survival (hazard ratio [HR] = 0.51; 95% confidence interval [CI] = 0.31-0.82; P = .006) and time to recurrence (HR = 0.42; 95% CI = 0.24-0.74; P = .003), and 8p allelic imbalance was an independent predictor of decreased survival (HR = 1.89; 95% CI = 1.25-2.83; P = .002) and time to recurrence (HR = 2.07; 95% CI = 1.32-3.25; P = .002). CONCLUSIONS: Patients whose tumors exhibited MSI-H had a favorable prognosis, whereas those with 8p allelic imbalance had a poor prognosis; both alterations served as independent prognostic factors. To our knowledge, this is the first report of an association between 8p allelic imbalance and survival in patients with colorectal cancer.
|
INTRODUCTION |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionNotesReferences |
|---|
There are approximately 130 000 new cases of and 57 000 deaths from colorectal cancer annually in the United States (1). Early detection and improved surgical and medical therapies have led to modest improvements in the cure rates among these patients. An assessment of prognosis, based on features of the resected tumor, is useful information for the triage of patients into groups who may benefit from adjuvant therapy. Currently, staging is the most accurate predictor of prognosis. Patients with stage A disease and most patients with stage B1 disease usually are treated with surgery alone because of the 90% 5-year survival rates following surgical resection. Patients with stage D (metastatic) disease generally have incurable tumors and most often receive palliative therapy. Patients with stage C colon cancer and patients with stage B2 or C rectal cancer generally receive some form of adjuvant therapy (2,3). Whether adjuvant therapy benefits patients with stage B2 colon cancer, however, remains controversial (4,5). In addition, 30%-40% of patients with stage C cancer relapse despite adjuvant therapy. In the era before effective adjuvant therapy was identified, only 40% of patients with stage C disease were alive at 5 years from the time of diagnosis.
Identification of additional tumor characteristics to supplement standard clinical and pathologic staging could potentially subdivide both patients with stage B2 disease and patients with stage C disease into those at highest and lowest risk of relapse following surgery for colon or rectal cancer. This would facilitate better selection of high-risk patients (i.e., those who would benefit most from adjuvant therapy) and of low-risk patients (i.e., those with a lower likelihood of a treatment benefit, who instead would potentially benefit from avoiding the toxicity, expense, inconvenience, and risk of adjuvant therapy).
Substantial progress has been made in understanding the molecular events associated with malignant transformation. This process involves the stepwise accumulation of multiple genetic alterations including the activation of proto-oncogenes and the inactivation of tumor suppressor genes (6,7). Furthermore, colorectal cancer has been shown to arise through at least two distinct genetic pathways: one involving chromosomal instability and the other involving microsatellite instability (MSI) (8-10). Tumors characterized by chromosomal instability demonstrate a high frequency of allelic imbalance, the most common involved chromosomal arms being 5q, 8p, 17p, and 18q (7). The finding that tumor behavior is a reflection of these genetic events has stimulated numerous investigations into the possibility that specific genetic alterations may relate to prognosis. In colorectal cancer, initial studies suggested that MSI was associated with an improved prognosis (11,12), while allelic imbalance at certain loci, in particular 17p and 18q, appeared to be associated with a worse prognosis (13-15). Despite these observations, the clinical utility of such markers remains uncertain, largely because of the small numbers of patients on whom most reports have been based, and there remains a need for additional studies. To further define the clinical utility of molecular genetic alterations, we analyzed 508 patients with stage B2 or C colorectal cancer for MSI and allelic imbalance on chromosomal arms 5q, 8p, 15q, 17p, and 18q and tested these genetic alterations for associations with survival and time to disease recurrence.
|
PATIENTS AND METHODS |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionNotesReferences |
|---|
Patients
This retrospective study examined tumors from 508 of 2887 patients enrolled in one of seven
different adjuvant chemotherapy protocols (3,16-21) of the North Central
Cancer Treatment Group (NCCTG). NCCTG is a multidisciplinary cancer clinical trials
organization comprised primarily of community clinics. Patient demographics are shown in
Table 1.
Five of the protocols treated colon cancer patients, and two
protocols enrolled only rectal cancer patients. The 508 tumors that were analyzed for molecular
genetic alterations were obtained in the following way: A letter requesting paraffin-embedded
normal and tumor tissues for the 2887 patients was sent to the affiliated NCCTG institution
where each patient was treated. From this request, paraffin-embedded tissue for 976 of the 2887
patients was submitted. DNA for polymerase chain reaction (PCR) analysis could be obtained
from the paraffin-embedded normal and tumor tissues from 615 of these 976 patients. The
molecular genetics results for 107 of the 615 patients were excluded from statistical analyses
because fewer than five of the 11 markers could be amplified by PCR, leaving 508 patients
suitable for statistical analyses. Common reasons for rejecting submitted blocks were inadequate
tumor cell percentage (i.e., <60% tumor), absence of paired normal or tumor tissue, no
primary tumor available, or a diagnosis of inflammatory bowel disease.
|
For the 508 patients, the median follow-up among the 266 patients alive as of their last follow-up was 8.4 years (range, 4.9-17.0 years). Tumors were staged according to the Astler-Coller modified Dukes' classification (22). Tumor grading was performed as described by Dukes and colleagues (23,24).
Microsatellite Analysis
Tumors were analyzed for MSI and allelic imbalance at 11 dinucleotide microsatellite markers on chromosomes 5q, 8p, 15q, 17p, and 18q as previously described (25). Markers included D5S346 and D5S107, localized near the APC gene on 5q; D8S254, located near a putative tumor suppressor gene on 8p; ACTC on 15q; D17S261 and TP53 on 17p at or near the P53 locus; and D18S34, D18S49, D18S35, D18S61, and D18S58, all localized on 18q both proximal and distal to the DCC gene. DNA extraction of paraffin-embedded normal and tumor tissues was performed as previously described (25,26). The tumors analyzed were composed of at least 60% tumor cells and had a minimum of five markers that successfully amplified for both normal DNA and tumor DNA. The median number of markers that gave a PCR product for both normal DNA and tumor DNA was nine (range, five to 11).
For MSI, tumors were classified into three groups: 1) microsatellite stable (MSS) with no
MSI at any of the loci examined, 2) low instability (MSI-L, <30% of the loci
demonstrating MSI), or 3) high instability (MSI-H, 
30% demonstrating MSI). The
use of 30% as a breakpoint was based on previous work (25) that
showed the following: (a) a bimodal distribution of tumors with one group of tumors
exhibiting
MSI at less than 30% of the loci and the other group of tumors exhibiting MSI at
30% or more of the loci and (b) distinct clinicopathologic differences between
tumors
having MSI at 30% or more of loci examined when compared with tumors with MSI at
fewer than 30% of the loci examined.
Allelic imbalance was assessed by quantitation of the intensities of the upper and lower alleles in normal and tumor tissues with a phosphorimager using Image Quant software (Molecular Dynamics, Sunnyvale, CA). Tumors were classified as positive for allelic imbalance when the PCR assay for the control normal tissue showed heterozygosity of the microsatellite marker and the relative intensity of the two alleles in the tumor DNA differed from the relative intensity in the normal DNA by a factor of at least 1.5 (27).
Statistical Analysis
Survival was defined as the interval from surgery until the date of death from any cause. Time to recurrence was defined as the interval from surgery until the date of documented tumor recurrence. Time to recurrence was censored at time of death for patients dying of causes other than metastatic colon cancer. Follow-up for disease recurrence was according to protocol for 8 years from randomization and discretionary thereafter. For this analysis, all patients were censored for time to recurrence at 8 years. For the purpose of statistical analysis, the colon cancer treatments were grouped into three categories: 1) effective 5-fluorouracil (5-FU)-based therapy (5-FU plus levamisole [Lev], 5-FU plus leucovorin [LV], or 5-FU plus LV plus Lev), 2) therapies proven to have no clinical utility (Lev alone, 5-FU administered by portal vein infusion, or interferon gamma), and 3) untreated controls. The rectal cancer treatments were also broken down into three groups: 1) radiation therapy alone, 2) radiation therapy plus bolus 5-FU, and 3) radiation therapy and infusional 5-FU.
Distributions of survival times were compared with the use of the logrank test; survival distribution curves were estimated by the method of Kaplan and Meier (28). Multivariate analyses were performed with the use of the Cox proportional hazards model (29). All logrank tests and Cox models were stratified according to the treatment protocol to which the patient was randomly assigned. The patient's Dukes' stage, adjuvant treatment received, sex, and tumor grade were included as covariates in the multivariate Cox regressions. The assumption of proportional hazards was validated by graphical methods, and covariates that failed this assumption were included in the Cox proportional hazards model as stratification factors. All P values presented are two-sided, and a P value of less than .05 was considered statistically significant. Formal adjustment for multiple comparisons was not used, since the chromosomal loci studied were protocol specified on the basis of earlier studies implicating these specific loci in colorectal tumorigenesis (13,14,30). Statistical analyses were performed with the use of SAS software (SAS Institute, Inc., Cary, NC) (31).
|
RESULTS |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionNotesReferences |
|---|
Patient and tumor characteristics of the patients with usable blocks were compared with those with unusable blocks. These results are shown in Table 1
. Patients with usable blocks were more likely to have
Dukes' stage B2 disease and to have been randomly assigned to a
control regimen than patients whose blocks were not used. Although
these imbalances were statistically significant, because of the large
number of patients involved, they were not judged sufficient to declare
that the patient population studied was misrepresentative of the
overall colon and rectal cancer patient population. Of the 508 tumors, 335 (66%) exhibited MSS (i.e., no evidence of MSI), 97 (19%) exhibited MSI-L, and 76 (15%) exhibited MSI-H. In addition to lower stage, proximal site, female sex, and diploid or near-diploid DNA content (25), we also found the MSI-H phenotype to be strongly associated with high tumor grade (P = .001).
The frequency of allelic imbalance observed at individual loci and on the chromosomal arms for which more than one marker was assessed was as follows: D5S107, 98 (47%) of 210; D5S346, 170 (55%) of 310; 5q, 202 (57%) of 357; D8S254, 123 (54%) of 226; ACTC, 120 (42%) of 283; D17S261, 77 (65%) of 119; TP53, 221 (76%) of 292; 17p, 237 (74%) of 321; D18S49, 143 (66%) of 218; D18S34, 174 (74%) of 236; D18S35, 157 (76%) of 207; D18S58, 92 (80%) of 115; D18S61, 118 (72%) of 164; and 18q, 304 (79%) of 386. The presence of MSI at a microsatellite marker makes interpretation for allelic imbalance potentially inaccurate. Loci may falsely appear to have allelic imbalance when one of the two alleles in the tumor shows a greater degree of instability. Conversely, tumors may be falsely classified as lacking allelic imbalance if an unstable allele in the tumor comigrates with the imbalanced allele. For the purpose of data analysis, therefore, loci with MSI were considered noninformative for allelic imbalance. Furthermore, all loci, even those without obvious instability, were considered noninformative for allelic imbalance in MSI-H tumors. The frequency of allelic imbalance shown above reflects these considerations.
Univariate analyses for associations with survival and time to recurrence were performed for
a number of variables, including tumor stage and grade, site, sex, DNA ploidy, MSI, and allelic
imbalance (Table 2). As expected, statistically significant associations
were observed for stage and grade. The Kaplan-Meier plots for survival by stage and grade are
shown in Fig. 1.
|
|
Of the molecular markers, MSI status and 8p allelic imbalance demonstrated the strongest associations with survival. Patients with MSI-H tumors had a statistically significantly better survival (P = .02) and time to recurrence (P = .01) than patients with MSS tumors (Table 2;
Fig. 2, A). There was
no statistically significant difference in survival (P = .23) or time to recurrence (P = .49) for patients with MSI-L and MSS tumors. The MSI-H phenotype was
present in 26% and 14% of the stage B2 or C tumors, respectively. Patients with
stage C tumors that exhibited MSI-H had statistically significantly better survival (P
= .02) and time to recurrence (P = .01) than patients with MSS stage C
tumors (Fig. 2, B). The survival rate for patients with MSI-H stage C
tumors was similar to that for patients with stage B2 tumors (with or without MSI). MSI status
did not have any effect on survival for the patients with stage B2 tumors. Patients with MSI-H
high-grade (i.e., grade 3 or 4) tumors had statistically significantly better survival (P
= .001) and time to recurrence (P<.001) than patients with MSS high-grade
tumors (Fig. 2, C). The survival and time to recurrence for patients with
MSI-H high-grade tumors were similar to those for patients with low-grade tumors (with or
without MSI). For the low-grade (i.e., grade 1 or 2) tumors, MSI status had a borderline
statistically significant association with time to recurrence (P = .05) but not with
survival (P = .11). Multivariate analysis adjusting for tumor stage, protocol,
treatment, tumor grade, and sex revealed that MSI-H was independently associated with
improved survival and time to recurrence. DNA ploidy data were not available for 58% of
the patients and thus were not adjusted for in multivariate analyses. The hazard ratio (HR) for
MSI-H relative to MSS was 0.51 (95% confidence interval [CI] =
0.31-0.82; P = .006) for survival and 0.42 (95% CI = 0.24-0.74; P = .003) for time to recurrence (Table 3).
|
|
For the allelic imbalance studies, no statistically significant associations with survival or time to recurrence were observed for markers on chromosomal arms 5q, 15q, 17p, and 18q (Table 2
). However, 8p allelic imbalance was associated with a statistically
significant worse survival (P = .02) and time to recurrence (P =
.004) (Table 2; Fig. 3, A). Of the patients with
stage B2 or C disease, 53% and 55%, respectively, exhibited 8p allelic imbalance.
Patients with Astler-Coller stage C disease with 8p allelic imbalance had statistically
significantly worse survival (P = .004) and time to recurrence (P
= .002) than patients with stage C disease without 8p allelic imbalance (Fig. 3, B). The 8p allelic imbalance status was not associated with survival (P
= .82) or time to recurrence (P = .39) in patients with stage B2 disease
(Fig. 3, B). Patients with low-grade (grade 1 or 2) tumors with 8p allelic
imbalance had statistically significantly worse survival (P = .04) and time to
recurrence (P = .04) than patients with low-grade tumors without 8p allelic
imbalance. Patients with high-grade (grade 3 or 4) tumors with 8p allelic imbalance had
statistically significantly worse time to recurrence (P = .04) but not survival (P = .27) compared with patients with high-grade tumors without 8p allelic
imbalance. Multivariate analysis adjusting for tumor stage, protocol, treatment, tumor grade, and
sex revealed that 8p allelic imbalance was independently associated with decreased survival and
time to recurrence, with HRs of 1.89 (95% CI =1.25-2.83; P =
.002) and 2.07 (95% CI =1.32-3.25; P = .002), respectively (Table
3).
|
In several previous studies (13-15,32-34) that evaluated the prognostic significance of allelic imbalance, patients with MSI-H tumors were included, for a variety of reasons, with those lacking allelic imbalance in the statistical analyses. In some of these studies, tumors with the MSI-H phenotype were inadvertently included with the allelic imbalance-negative tumors because the technique used to assess allelic imbalance (Southern blot rather than microsatellite analysis) did not allow for the identification of tumor MSI (13,14,32-34). More recent studies (15,35-37), however, have utilized microsatellite analysis as the principal method to assess allelic imbalance. One of these studies (15) intentionally grouped MSI-H tumors with the allelic imbalance-negative group for the purpose of statistical analyses because 1) allelic imbalance is difficult to assess in the presence of MSI and 2) MSI-H tumors, when analyzed by Southern blot analysis, demonstrate a very low frequency of allelic imbalance (11,15). To facilitate comparisons with earlier work by other authors, we re-analyzed our data for the relationship between allelic imbalance and survival, but this time we assumed that the MSI-H tumors did not have allelic imbalance and included these tumors in the allelic imbalance-negative group for that marker. When the analyses were performed in this manner, statistically significant associations between genetic abnormalities and survival were evident (Table 4
). Survival and time to recurrence were statistically significantly associated with
allelic imbalance on 8p (P = .001 and P<.001, respectively), 17p (P = .02 and P = .003, respectively), and 18q (P
= .02 and P = .007, respectively). The survival curves for patients with
MSI-H tumors are included in Figs. 3 and 4
(survival curves for patients according to 8p, 17p, and 18q allelic imbalance status) to illustrate
how the inclusion of MSI-H patients with the allelic imbalance-negative patients strengthens the
apparent, and possibly misleading, prognostic significance of 17p and 18q allelic imbalance.
|
|
Analyses were performed to determine the impact that MSI-H and 8p allelic imbalance have on survival and time to recurrence in patients receiving no treatment (n = 143). As with the entire dataset, the untreated group of patients also showed that 8p allelic imbalance was statistically significantly associated with decreased survival (P = .04) and time to recurrence (P = .02). The trend for untreated patients with MSI-H was similar to that for the overall group. In contrast, untreated patients with MSI-H did not show statistically significant associations with survival (P = .07) or time to recurrence (P = .25). However, the number of patients in these comparisons was small, and statistical power was therefore low (e.g., there were only four events for the MSI group).
Additional analyses were also conducted to determine whether MSI-H or 8p allelic imbalance identifies which patients may benefit the most from adjuvant chemotherapy. The survival and time to recurrence of patients treated with effective therapy were compared with those of patients treated with ineffective therapy or given no treatment within each of the following subgroups: MSS, MSI-L, MSI-H, 8p allelic imbalance, and no 8p allelic imbalance. No statistically significant benefit from adjuvant treatment was observed in any of the subgroups. However, these treatment comparisons have low power for the magnitude of benefit known to be conferred by adjuvant treatment. Hence, there is no evidence from this study that MSI or 8p allelic imbalance status is predictive of a benefit or a lack of a benefit of adjuvant therapy.
|
DISCUSSION |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionNotesReferences |
|---|
Results from this study confirm and extend earlier observations that certain genetic alterations can serve as prognostic markers in patients with colorectal cancer. Of any of the markers studied, 8p allelic imbalance exhibited the most striking association with survival. Patients with 8p allelic imbalance had statistically significantly worse survival and time to recurrence than patients without 8p allelic imbalance (Fig. 3
). This was true for both univariate analyses
(P = .02 and P = .004, respectively) and multivariate
analyses (P = .002 and P = .002, respectively). In
addition to tumor stage, tumor grade, and sex, the multivariate
analyses were also adjusted for treatment and stratified on protocol.
Among the patients with stage C disease, 8p allelic imbalance status
divided the patients into better and worse prognostic groups (Fig. 3).
Because of no apparent differences, this division was not possible with
patients with stage B2 disease. To our knowledge, this is the first
report of an association between 8p allelic imbalance and survival in
patients with colorectal cancer. A previous study (38) has
noted an association between 8p allelic imbalance and advanced stage of
colorectal cancer, and another study (39) has noted an
association between 8p allelic imbalance and tumor microinvasiveness.
Microinvasion has been found to be a prognostic indicator in colorectal
carcinoma that is independent of stage (40,41). An association
between 8p allelic imbalance and poor survival has also been observed
for patients with head and neck cancer (42) and for patients
with prostate cancer (43). Although 8p allelic imbalance is a frequently observed genetic abnormality in colorectal and other cancers (27,30,38,42,44,45), a candidate tumor suppressor gene has not yet been identified. More detailed mapping studies in colorectal and other cancers suggest that there may be up to three tumor suppressor genes on 8p (38,46-51). One of the three tumor suppressor gene loci maps to 8p22, the site of the marker used in our study (38).
The 8p allelic imbalance appears to be a relatively late event in colorectal tumorigenesis, since it is identified more frequently in colorectal cancers than in colorectal adenomas (52) and more frequently in metastatic than in primary tumors (53). This observation suggests that 8p allelic imbalance is associated with tumor progression. The strong effect that 8p allelic imbalance has on prognosis may be due, in part, to its "late" occurrence in the development of colorectal cancer. Genetic alterations that occur early in the evolution of a tumor, such as alterations in APC, would be expected to have less of an influence on prognosis. This is the most likely explanation for the lack of an association between 5q allelic imbalance and survival in this study. Of significance, allelic imbalance on chromosome arm 5q has consistently failed to show any associations with survival in other studies (13,14,34,54).
Contrasting with the unfavorable prognosis associated with 8p allelic imbalance is the
favorable prognosis associated with the MSI-H phenotype. Patients with tumors exhibiting
MSI-H had a significantly better survival (P = .02) and time to recurrence (P = .01) than patients with MSS tumors. Furthermore, the MSI-H phenotype
identified a subset of patients with stage C or high-grade tumors who had a more favorable
prognosis (Fig. 2, B and C).
Several smaller studies (11,12,55-57) have demonstrated a survival advantage for patients with sporadic colorectal cancer demonstrating MSI. Patients with hereditary nonpolyposis colon cancer with colorectal cancer have also been reported to have a better prognosis (58,59). Of interest, the MSI-H phenotype observed in the majority of tumors from patients with hereditary nonpolyposis colon cancer is a consequence of germline mutations in one of several DNA mismatch repair genes, primarily hMSH2 or hMLH1 (60,61). The MSI-H phenotype observed in sporadic colorectal cancer, however, now appears to be largely due to hypermethylation of the hMLH1 promoter (62-65). The MSI-H phenotype, therefore, appears to be associated with a good prognosis, irrespective of the mechanism giving rise to it.
A previous report (25) on the same group of patients included in this study showed that MSI-H (but not MSI-L or MSS) was associated with lower disease stage, female sex, proximal location, and diploidy. Our study also revealed an association between the MSI-H phenotype and high tumor grade. Nonetheless, MSI-H was a statistically significant prognostic factor for survival and time to recurrence after adjustment was made for stage, grade, site, protocol, treatment, and sex.
Our results show that 5q, 15q, 17p, and 18q allelic imbalances do not exhibit statistically
significant associations with survival or time to recurrence. Several studies (13-15,34-36) have shown associations between 17p or 18q allelic imbalance and
decreased survival in patients with colorectal cancer, whereas other studies (13,32-34,37,66,67) have not. One of these studies (34)
showed a decreased survival for 18q allelic imbalance but not for 17p allelic imbalance. A
possible explanation for the varying reports regarding the prognostic significance of 17p and 18q
allelic imbalance is the manner in which allelic imbalance is scored in tumors with the MSI-H
phenotype. In one study (15) that found a significant association between
18q allelic imbalance and poor survival, markers from the MSI-H patients were assumed to lack
allelic imbalance and thus included with the 18q allelic imbalance-negative group. Because
Southern blot analyses (11,15) have shown that MSI-H tumors show a
very low frequency of allelic imbalance, we re-analyzed our data for associations between allelic
imbalance (on each chromosomal arm) and survival, but we included tumors with a MSI-H
phenotype in the allelic imbalance-negative group (Table 4). When
analyzed in this manner, 17p and 18q allelic imbalances then exhibited statistically significant
associations with decreased survival (P = .02 and P = .02,
respectively) and time to recurrence (P = .003 and P = .007,
respectively) (Table 4). It is apparent from Fig. 4
that the mixed group of MSI-H patients and patients whose tumors lack allelic imbalance have a
better survival and time to recurrence than patients whose tumors lack allelic imbalance alone.
Future prognostic studies should be careful to identify and to separate for subset analysis the
group of patients with MSI-H tumors.
The use of different 18q markers by various investigators may provide another explanation for the differing findings regarding the prognostic importance of 18q allelic imbalance. Several potential tumor suppressor genes have been mapped to 18q21. These genes include DCC, Smad4 (DPC4), and Smad 2 (68-70). Boland and co-workers (37) found no association between allelic imbalance and survival when they used five markers that were very close to the DCC gene. On the other hand, Martínez-López et al. (36) found an association between poor survival and allelic imbalance with an 18q marker proximal to DCC but not with a marker distal to DCC at 18q23. Our studies demonstrated a lack of an association across all of the markers tested.
At least two studies (13,14) have found that 17p allelic imbalance is associated with an adverse prognosis in colorectal cancer. Three other studies (32-34), however, have not found this association. The 17p allelic imbalance (at or near the P53 locus) is strongly associated with the presence of a point mutation on the remaining P53 allele (71,72) and is frequently accompanied by overexpression of the mutant p53 protein (73,74). Many studies [reviewed by Smith and Goh (75)] have examined the relationship between p53 overexpression and prognosis and between p53 mutation and prognosis. Studies of p53 overexpression have reached varied conclusions. A number of studies have found that p53 overexpression is associated with poor prognosis, but other studies have not [reviewed in (75)]. Several studies (76-78) have found that a P53 point mutation is strongly associated with an adverse prognosis and an independent prognosticator in multivariate analyses. With regard to this study, it is important to realize that 17p allelic imbalance does not necessarily imply the presence of a P53 mutation and that, while P53 mutations may negatively affect prognosis, 17p allelic imbalance may not (78).
The statistical analyses performed in this study involved multiple comparisons. We have not adjusted for multiple comparisons (Bonferroni correction) because the analyses performed were for a preselected and limited set of genetic loci that are implicated in colorectal tumorigenesis (13,14,30). The chromosomal regions 5q, 8p, 17p, or 18q examined in this study are sites of known or putative tumor suppressor genes. Chromosomal arm 15q was included in this study as a control, since a previous study (30) had not implicated this region in colorectal tumorigenesis. Hence, the analyses that were performed were protocol specified.
A secondary aim of this study was to identify patients who may be more likely to benefit from adjuvant chemotherapy. The survival and time to recurrence distributions of patients receiving effective 5-FU-based therapy were compared with those of patients receiving ineffective treatment or control (no therapy) in subgroups defined by MSI and 8p allelic imbalance status. Overall, a statistically significant benefit from adjuvant treatment was not observed for any of the subgroups examined. These results should be interpreted with caution, however, since these treatment comparisons had low power for the magnitude of benefit known to be conferred by adjuvant treatment. Because patients in this study received a variety of treatments over an extended period of time (13 years), this may not be the ideal setting for testing a marker's ability to predict a treatment effect. A better setting for such an analysis, for example, would be a single, large phase III randomized clinical trial, such as Cancer and Acute Leukemia Group B study C9581, testing the efficacy of 17-1A monoclonal antibody versus control in patients with Dukes' stage B2 colon cancer.
To our knowledge, this is the largest study to date exploring the role that allelic imbalance and MSI play in prognosis of colorectal cancer patients. Key attributes of this patient population include mature follow-up, protocolized prospective follow-up, and large sample size. The most significant findings of this study are confirmation that the MSI-H phenotype defines a good prognostic group and the novel finding that 8p allelic imbalance status defines a poor prognostic group. However, MSI or 8p allelic imbalance did not predict which patients would benefit the most from adjuvant therapy. Identification of the putative tumor suppressor gene on 8p may lead to an understanding of the biologic basis of the adverse prognosis associated with 8p allelic imbalance. Similarly, additional studies may elucidate the mechanism by which MSI-H leads to improved prognosis.
|
NOTES |
|---|
Editor's note: S. N. Thibodeau holds a patent on the use of microsatellite instability measurements for clinical purposes.
Supported by Public Health Service grants CA60117 and CA25224 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services.
|
REFERENCES |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionNotesReferences |
|---|
1 Parker SL, Tong T, Bolden S, Wingo PA. Cancer statistics, 1997 [published erratum appears in CA Cancer J Clin 1997;47:68]. CA Cancer J Clin 1997;47:5-27.[Web of Science][Medline]cancerlit;97149268
2 Vaughn DJ, Haller DG. Adjuvant therapy for colorectal cancer: past accomplishments, future directions. Cancer Invest 1997;15:435-47.[Web of Science][Medline]cancerlit;97462383
3
O'Connell MJ, Martenson JA, Wieand HS, Krook JE,
Macdonald JS, Haller DG, et al. Improving adjuvant therapy for rectal cancer by combining
protracted-infusion fluorouracil with radiation therapy after curative surgery. N Engl J
Med 1994;331:502-7.
4
Manounas EP, Rockette H, Jones J, Wieand HS, Wickerham DL,
Fisher B, et al. Comparative efficacy of adjuvant chemotherapy in patients with Dukes' B
versus Dukes' C colon cancer: results from four NSABP adjuvant studies (C-01, C-02,
C-03, C-04). J Clin Oncol 1999;17:1349-55.
5
Impact B2 Investigators. Efficacy of adjuvant fluorouracil and
folinic acid in B2 colon cancer. J Clin Oncol 1998;17:1356-63.
6 Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell 1990;61:759-67.[CrossRef][Web of Science][Medline]cancerlit;90263101
7 Fearon ER. Molecular genetics of colorectal cancer. Ann N Y Acad Sci 1995;768:101-10.[Web of Science][Medline]cancerlit;96098071
8 Lengauer C, Kinzler KW, Vogelstein B. Genetic instability in colorectal cancers. Nature 1997;386:623-7.[CrossRef][Medline]cancerlit;97256539
9 Dutrillaux B. Pathways of chromosome alteration in human epithelial cancers. Adv Cancer Res 1995;67:59-82.[Web of Science][Medline]cancerlit;96126124
10 Sweezy MA, Fishel R. Multiple pathways leading to genomic instability and tumorigenesis. Ann N Y Acad Sci 1994;726:165-77.[CrossRef][Web of Science][Medline]cancerlit;94379621
11
Thibodeau SN, Bren G, Schaid D. Microsatellite instability in
cancer of the proximal colon. Science 1993;260:816-9.
12
Lothe RA, Peltomaki P, Meling GI, Aaltonen LA,
Nystrom-Lahti M, Pylkkanen L, et al. Genomic instability in colorectal cancer: relationship to
clinicopathological variables and family history. Cancer Res 1993;53:5849-52.
13 Laurent-Puig P, Olschwang S, Delattre O, Remvikos Y, Asselain B, Melot T, et al. Survival and acquired genetic alterations in colorectal cancer. Gastroenterology 1992;102:1136-41.[Web of Science][Medline]cancerlit;92201549
14
Kern SE, Fearon ER, Tersmette KW, Enterline JP, Leppert M,
Nakamura Y, et al. Clinical and pathological associations with allelic loss in colorectal
carcinoma [corrected] [published erratum appears in JAMA
1989;262:1952]. JAMA 1989;261:3099-103.
15
Jen J, Kim H, Piantadosi S, Liu ZF, Levitt RC, Sistonen P, et al.
Allelic loss of chromosome 18q and prognosis in colorectal cancer. N Engl J Med 1994;331:213-21.
16 Laurie JA, Moertel CG, Fleming TR, Wieand HS, Leigh JE, Rubin J, et al. Surgical adjuvant therapy of large-bowel carcinoma: an evaluation of levamisole and the combination of levamisole and fluorouracil. The North Central Cancer Treatment Group and the Mayo Clinic. J Clin Oncol 1989;7:1447-56.[Abstract]cancerlit;89381769
17
Beart RW Jr, Moertel CG, Wieand HS, Leigh JE, Windschitl
HE, van Heerden JA, et al. Adjuvant therapy for resectable colorectal carcinoma with
fluorouracil administered by portal vein infusion. A study of the Mayo Clinic and the North
Central Cancer Treatment Group. Arch Surg 1990;125:897-901.
18 Krook JE, Moertel CG, Gunderson LL, Wieand HS, Collins RT, Beart RW, et al. Effective surgical adjuvant chemotherapy for high-risk rectal carcinoma. N Engl J Med 1991;324:709-15.[Abstract]cancerlit;91148651
19
Moertel CG, Fleming TR, Macdonald JS, Haller DG, Laurie JA,
Tangen CM, et al. Fluorouracil plus levamisole as effective adjuvant therapy after resection of
stage III colon carcinoma: a final report. Ann Intern Med 1995;122:321-6.
20
Wiesenfeld M, O'Connell MJ, Wieand HS, Gonchoroff
NJ, Donohue JH, Fitzgibbons RJ Jr, et al. Controlled clinical trial of interferon-
as
postoperative surgical adjuvant therapy for colon cancer. J Clin Oncol 1995;13:2324-9.
21
O'Connell MJ, Laurie JA, Kahn M, Fitzgibbons RJ Jr,
Erlichman C, Shepherd L, et al. Prospectively randomized trial of postoperative adjuvant
chemotherapy in patients with high-risk colon cancer. J Clin Oncol 1998;16:295-300.
22 Astler VB, Coller J. The prognostic significance of direct extension of carcinoma of the colon and rectum. Ann Surg 1954;139:846-51.[Web of Science][Medline]
23 Dukes CE. Histological grading of rectal cancer. Proc Royal Soc Med 1937;30:371-6.
24 Jass JR, Atkin WS, Cuzick J, Bussey HJ, Morson BC, Northover JM, et al. The grading of rectal cancer: historical perspectives and a multivariate analysis of 447 cases. Histopathology 1986;10:437-59.[Web of Science][Medline]cancerlit;86249125
25
Thibodeau SN, French AJ, Cunningham JM, Tester D, Burgart
LJ, Roche PC, et al. Microsatellite instability in colorectal cancer: different mutator phenotypes
and the principal involvement of hMLH1. Cancer Res 1998;58:1713-8.
26
Moslein G, Tester DJ, Lindor NM, Honchel R, Cunningham
JM, French AJ, et al. Microsatellite instability and mutation analysis of hMSH2 and hMLH1 in
patients with sporadic, familial and hereditary colorectal cancer. Hum Mol Genet 1996;5:1245-52.
27
Cunningham JM, Shan A, Wick MJ, McDonnell SK, Schaid DJ,
Tester DJ, et al. Allelic imbalance and microsatellite instability in prostatic adenocarcinoma. Cancer Res 1996;56:4475-82.
28 Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457-81.[CrossRef][Web of Science]
29 Cox DR. Regression models and life tables. J R Stat Soc [B] 1972;34:187-220.
30
Vogelstein B, Fearon ER, Kern SE, Hamilton SR, Preisinger
AC, Nakamura Y, et al. Allelotype of colorectal carcinomas. Science 1989;244:207-11.
31 SAS/STAT user's guide, Version 6. Cary (NC): SAS Institute, Inc.; 1989.
32 Khine K, Goh HS, Smith DR. Prognostic significance of chromosome 5q and 17p deletion in colorectal adenocarcinomas. Int J Oncol 1995;7: 631-5.[Web of Science]
33 Campo E, Miquel R, Jares P, Bosch F, Juan M, Leone A, et al. Prognostic significance of the loss of heterozygosity of Nm23-H1 and p53 genes in human colorectal carcinomas. Cancer 1994;73:2913-21.[CrossRef][Web of Science][Medline]cancerlit;94258656
34 O'Connell MJ, Schaid DJ, Ganju V, Cunningham J, Kovach JS, Thibodeau SN. Current status of adjuvant chemotherapy for colorectal cancer: can molecular markers play a role in predicting prognosis? Cancer 1992;70(6 Suppl):1732-9.[CrossRef][Web of Science][Medline]
35 Ogunbiyi OA, Goodfellow PJ, Herfarth K, Gagliardi G, Swanson PE, Birnbaum EH, et al. Confirmation that chromosome 18q allelic loss in colon cancer is a prognostic indicator. J Clin Oncol 1998;16:427-33.[Abstract]cancerlit;98129227
36 Martinez-Lopez E, Abad A, Font A, Monzo M, Ojanguren I, Pifarre A, et al. Allelic loss on chromosome 18q as a prognostic marker in stage II colorectal cancer. Gastroenterology 1998;114:1180-7.[CrossRef][Web of Science][Medline]cancerlit;98282355
37 Carethers JM, Hawn MT, Greenson JK, Hitchcock CL, Boland CR. Prognostic significance of allelic loss at chromosome 18q21 for stage II colorectal cancer. Gastroenterology 1998;114:1188-95.[CrossRef][Web of Science][Medline]cancerlit;98282356
38
Fujiwara Y, Emi M, Ohata H, Kato Y, Nakajima T, Mori T, et
al. Evidence for the presence of two tumor suppressor genes on chromosome 8p for colorectal
carcinoma. Cancer Res 1993;53:1172-4.
39 Kelemen PR, Yaremko ML, Kim AH, Montag A, Michelassi F, Westbrook CA. Loss of heterozygosity in 8p is associated with microinvasion in colorectal carcinoma. Genes Chromosomes Cancer 1994;11:195-8.[Web of Science][Medline]cancerlit;95134711
40 Michelassi F, Vannucci L, Ayala JJ, Chappell R, Goldberg R, Block GE. Local recurrence after curative resection of colorectal adenocarcinoma. Surgery 1990;108:787-92; discussion 792-3.[Web of Science][Medline]
41 Michelassi F, Ayala JJ, Balestracci T, Goldberg R, Chappell R, Block GE. Verification of a new clinicopathologic staging system for colorectal adenocarcinoma.Ann Surg 1991;214:11-8.[Web of Science][Medline]cancerlit;91290933
42
Scholnick SB, Haughey BH, Sunwoo JB, el-Mofty SK, Baty JD,
Piccirillo JF, et al. Chromosome 8 allelic loss and the outcome of patients with squamous cell
carcinoma of the supraglottic larynx. J Natl Cancer Inst 1996;88:1676-82.
43 Jenkins R, Takahashi S, DeLacey K, Bergstralh E, Lieber M. Prognostic significance of allelic imbalance of chromosome arms 7q, 8p, 16q, and 18q in stage T3N0M0 prostate cancer. Genes Chromosomes Cancer 1998;21:131-43.[CrossRef][Web of Science][Medline]cancerlit;98152025
44
Bova GS, Carter BS, Bussemakers MJ, Emi M, Fujiwara Y,
Kyprianou N, et al. Homozygous deletion and frequent allelic loss of chromosome 8p22 loci in
human prostate cancer. Cancer Res 1993;53:3869-73.
45 Knowles MA, Shaw ME, Proctor AJ. Deletion mapping of chromosome 8 in cancers of the urinary bladder using restriction fragment length polymorphisms and microsatellite polymorphisms. Oncogene 1993;8:1357-64.[Web of Science][Medline]cancerlit;93241738
46 Yaremko ML, Wasylyshyn ML, Paulus KL, Michelassi F, Westbrook CA. Deletion mapping reveals two regions of chromosome 8 allele loss in colorectal carcinomas. Genes Chromosomes Cancer 1994;10:1-6.[Web of Science][Medline]cancerlit;94331356
47 Fujiwara Y, Ohata H, Emi M, Okui K, Koyama K, Tsuchiya E, et al. A 3-Mb physical map of the chromosome region 8p21.3-p22, including a 600-kb region commonly deleted in human hepatocellular carcinoma, colorectal cancer, and non-small cell lung cancer. Genes Chromosomes Cancer 1994;10:7-14.[Web of Science][Medline]cancerlit;94331365
48 Cunningham C, Dunlop MG, Wyllie AH, Bird CC. Deletion mapping in colorectal cancer of a putative tumour suppressor gene in 8p22-p21.3. Oncogene 1993;8:1391-6.[Web of Science][Medline]cancerlit;93241743
49
Gustafson CE, Wilson PJ, Lukeis R, Baker E, Woollatt E,
Annab L, et al. Functional evidence for a colorectal cancer tumor suppressor gene at
chromosome 8p22-23 by monochromosome transfer. Cancer Res 1996;56:5238-45.
50 Farrington SM, Cunningham C, Boyle SM, Wyllie AH, Dunlop MG. Detailed physical and deletion mapping of 8p with isolation of YAC clones from tumour suppressor loci involved in colorectal cancer. Oncogene 1996;12:1803-8.[Web of Science][Medline]cancerlit;96201661
51 Wu CL, Roz L, Sloan P, Read AP, Holland S, Porter S, et al. Deletion mapping defines three discrete areas of allelic imbalance on chromosome arm 8p in oral and oropharyngeal squamous cell carcinomas. Genes Chromosomes Cancer 1997;20:347-533.[CrossRef][Web of Science][Medline]
52 Cunningham C, Dunlop MG, Bird CC, Wyllie AH. Deletion analysis of chromosome 8p in sporadic colorectal adenomas. Br J Cancer 1994;70:18-20.[Web of Science][Medline]cancerlit;94289268
53 Paredes-Zaglul A, Kang JJ, Esiig YP, Mao W, Irby R, Wloch M, et al. Analysis of colorectal cancer by comparative genomic hybridization: evidence for induction of the metastatic phenotype by loss of tumor suppressor genes. Clin Cancer Res 1998;4:879-86.[Abstract]cancerlit;98223370
54 Gerdes H, Chen Q, Elahi AH, Sircar A, Goldberg E, Winawer D, et al. Recurrent deletions involving chromosomes 1, 5, 17, and 18 in colorectal carcinoma: possible role in biological and clinical behavior of tumors. Anticancer Res 1995;15:13-24.[Web of Science][Medline]cancerlit;95251335
55 Bubb VJ, Curtis LJ, Cunningham C, Dunlop MG, Carothers AD, Morris RG, et al. Microsatellite instability and the role of hMSH2 in sporadic colorectal cancer. Oncogene 1996;12:2641-9.[Web of Science][Medline]cancerlit;96293410
56 Cawkwell L, Li D, Lewis FA, Martin I, Dixon MF, Quirke P. Microsatellite instability in colorectal cancer: improved assessment using fluorescent polymerase chain reaction. Gastroenterology 1995;109:465-71.[CrossRef][Web of Science][Medline]cancerlit;95340102
57 Lukish JR, Muro K, DeNobile J, Katz R, Williams J, Cruess DF, et al. Prognostic significance of DNA replication errors in young patients with colorectal cancer. Ann Surg 1998;227:51-6.[CrossRef][Web of Science][Medline]cancerlit;98105855
58 Lynch HT, Bardawil WA, Harris RE, Lynch PM, Guirgis HA, Lynch JF. Multiple primary cancers and prolonged survival: familial colonic and endometrial cancers. Dis Colon Rectum 1978;21:165-8.[Web of Science][Medline]
59 Sankila R, Aaltonen LA, Jarvinen HJ, Mecklin JP. Better survival rates in patients with MLH1-associated hereditary colorectal cancer. Gastroenterology 1996;110:682-7.[CrossRef][Web of Science][Medline]cancerlit;96177721
60
Aaltonen LA, Peltomaki P, Leach FS, Sistonen P, Pylkkanen L,
Mecklin JP, et al. Clues to the pathogenesis of familial colorectal cancer. Science 1993;260:812-6.
61 Liu B, Parsons R, Papadopoulos N, Nicolaides NC, Lynch HT, Watson P, et al. Analysis of mismatch repair genes in hereditary nonpolyposis colorectal cancer patients. Nat Med 1996;2:169-74.[CrossRef][Web of Science][Medline]cancerlit;96160364
62
Kane MF, Loda M, Gaida GM, Lipman J, Mishra R, Goldman
H, et al. Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in
sporadic colon tumors and mismatch repair-defective human tumor cell lines. Cancer Res 1997;57:808-11.
63
Cunningham JM, Christensen ER, Tester DJ, Kim CY, Roche
PC, Burgart LJ, et al. Hypermethylation of the hMLH1 promoter in colon cancer with
microsatellite instability. Cancer Res 1998;58:3455-60.
64
Herman JG, Umar A, Polyak K, Graff JR, Ahuja N, Issa JP, et
al. Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal
carcinoma. Proc Natl Acad Sci U S A 1998;95:6870-5.
65
Veigl ML, Kasturi L, Olechnowicz J, Ma AH, Lutterbaugh JD,
Periyasamy S, et al. Biallelic inactivation of hMLH1 by epigenetic gene silencing, a novel
mechanism causing human MSI cancers. Proc Natl Acad Sci U S A 1998;95:8698-702.
66 Offerhaus GJ, De Feyter EP, Cornelisse CJ, Tersmette KW, Floyd J, Kern SE, et al. The relationship of DNA aneuploidy to molecular genetic alterations in colorectal carcinoma. Gastroenterology 1992;102:1612-9.[Web of Science][Medline]cancerlit;92234119
67 Dix BR, Robbins P, Soong R, Jenner D, House AK, Iacopetta BJ. The common molecular genetic alterations in Dukes' B and C colorectal carcinomas are not short-term prognostic indicators of survival. Int J Cancer 1994;59:747-51.[Web of Science][Medline]cancerlit;95080850
68 Riggins GJ, Thiagalingam S, Rozenblum E, Weinstein CL, Kern SE, Hamilton SR, et al. Mad-related genes in the human. Nat Genet 1996;13:347-9.[CrossRef][Web of Science][Medline]cancerlit;96259564
69 Thiagalingam S, Lengauer C, Leach FS, Schutte M, Hahn SA, Overhauser J, et al. Evaluation of candidate tumour suppressor genes on chromosome 18 in colorectal cancers. Nat Genet 1996;13:343-6.[CrossRef][Web of Science][Medline]cancerlit;96259563
70 Eppert K, Scherer SW, Ozcelik H, Pirone R, Hoodless P, Kim H, et al. MADR2 maps to 18q21 and encodes a TGF-ß-regulated MAD-related protein that is functionally mutated in colorectal carcinoma. Cell 1996;86:543-52.[CrossRef][Web of Science][Medline]cancerlit;96361352
71
Baker SJ, Preisinger AC, Jessup JM, Paraskeva C, Markowitz
S, Willson JK, et al. p53 gene mutations occur in combination with 17p allelic deletions as late
events in colorectal tumorigenesis. Cancer Res 1990;50:7717-22.
72
Campo E, de la Calle-Martin O, Miquel R, Palacin A, Romero
M, Fabregat V, et al. Loss of heterozygosity of p53 gene and p53 protein expression in human
colorectal carcinomas. Cancer Res 1991;51:4436-42.
73
Cunningham J, Lust JA, Schaid DJ, Bren GD, Carpenter HA,
Rizza E, et al. Expression of p53 and 17p allelic loss in colorectal carcinoma. Cancer Res 1992;52:1974-80.
74
Rodrigues NR, Rowan A, Smith ME, Kerr IB, Bodmer WF,
Gannon JV, et al. p53 mutations in colorectal cancer. Proc Natl Acad Sci U S A 1990;87:7555-9.
75 Smith DR, Goh HS. p53 and prognosis in colorectal cancer. Ann Acad Med Singapore 1996;25:107-12.[Medline]cancerlit;96260432
76
Goh HS, Yao J, Smith DR. p53 point mutation and survival in
colorectal cancer patients. Cancer Res 1995;55:5217-21.
77 Smith DR, Ji CY, Goh HS. Prognostic significance of p53 overexpression and mutation in colorectal adenocarcinomas. Br J Cancer 1996;74:216-23.[Web of Science][Medline]cancerlit;96302457
78 Hamelin R, Laurent-Puig P, Olschwang S, Jego N, Asselain B, Remvikos Y, et al. Association of p53 mutations with short survival in colorectal cancer. Gastroenterology 1994;106:42-8.[Web of Science][Medline]cancerlit;94102504
Manuscript received August 23, 1998; revised May 14, 1999; accepted June 8, 1999.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  S. Ogino, K. Nosho, N. Irahara, K. Shima, Y. Baba, G. J. Kirkner, J. A. Meyerhardt, and C. S. Fuchs Prognostic Significance and Molecular Associations of 18q Loss of Heterozygosity: A Cohort Study of Microsatellite Stable Colorectal Cancers J. Clin. Oncol., September 20, 2009; 27(27): 4591 - 4598. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. C. KIM, S. A. ROH, D. H. CHO, T. W. KIM, S. N. YOON, C. W. KIM, C. S. YU, S. Y. KIM, and Y. S. KIM Chemoresponsiveness Associated with Canonical Molecular Changes in Colorectal Adenocarcinomas Anticancer Res, August 1, 2009; 29(8): 3115 - 3123. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. DES GUETZ, B. UZZAN, P. NICOLAS, O. SCHISCHMANOFF, G.-Y. PERRET, and J.-F. MORERE Microsatellite Instability does not Predict the Efficacy of Chemotherapy in Metastatic Colorectal Cancer. A Systematic Review and Meta-analysis Anticancer Res, May 1, 2009; 29(5): 1615 - 1620. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H.-J. Lenz Established Biomarkers for Colon Cancer ASCO Educational Book, January 1, 2009; 2009(1): 215 - 219. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. N. Poynter, K. D. Siegmund, D. J. Weisenberger, T. I. Long, S. N. Thibodeau, N. Lindor, J. Young, M. A. Jenkins, J. L. Hopper, J. A. Baron, et al. Molecular Characterization of MSI-H Colorectal Cancer by MLHI Promoter Methylation, Immunohistochemistry, and Mismatch Repair Germline Mutation Screening Cancer Epidemiol. Biomarkers Prev., November 1, 2008; 17(11): 3208 - 3215. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. A. Sinicrope, R. L. Rego, K. Okumura, N. R. Foster, M. J. O'Connell, D. J. Sargent, and H. E. Windschitl Prognostic Impact of Bim, Puma, and Noxa Expression in Human Colon Carcinomas Clin. Cancer Res., September 15, 2008; 14(18): 5810 - 5818. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Jiang, G. Casey, I. C. Lavery, Y. Zhang, D. Talantov, M. Martin-McGreevy, M. Skacel, E. Manilich, A. Mazumder, D. Atkins, et al. Development of a Clinically Feasible Molecular Assay to Predict Recurrence of Stage II Colon Cancer J. Mol. Diagn., July 1, 2008; 10(4): 346 - 354. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. J. French, D. J. Sargent, L. J. Burgart, N. R. Foster, B. F. Kabat, R. Goldberg, L. Shepherd, H. E. Windschitl, and S. N. Thibodeau Prognostic Significance of Defective Mismatch Repair and BRAF V600E in Patients with Colon Cancer Clin. Cancer Res., June 1, 2008; 14(11): 3408 - 3415. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-Z. Pang, L.-X. Qin, N. Ren, Z.-Y. Hei, Q.-H. Ye, W.-D. Jia, B.-S. Sun, G.-L. Lin, D.-Y. Liu, Y.-K. Liu, et al. Loss of Heterozygosity at D8S298 Is a Predictor for Long-term Survival of Patients with Tumor-Node-Metastasis Stage I of Hepatocellular Carcinoma Clin. Cancer Res., December 15, 2007; 13(24): 7363 - 7369. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Malesci, L. Laghi, P. Bianchi, G. Delconte, A. Randolph, V. Torri, C. Carnaghi, R. Doci, R. Rosati, M. Montorsi, et al. Reduced Likelihood of Metastases in Patients with Microsatellite-Unstable Colorectal Cancer Clin. Cancer Res., July 1, 2007; 13(13): 3831 - 3839. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Y. Locker, S. Hamilton, J. Harris, J. M. Jessup, N. Kemeny, J. S. Macdonald, M. R. Somerfield, D. F. Hayes, and R. C. Bast Jr ASCO 2006 Update of Recommendations for the Use of Tumor Markers in Gastrointestinal Cancer J. Clin. Oncol., November 20, 2006; 24(33): 5313 - 5327. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R Jover, P Zapater, A Castells, X Llor, M Andreu, J Cubiella, V Pinol, R M Xicola, L Bujanda, J M Rene, et al. Mismatch repair status in the prediction of benefit from adjuvant fluorouracil chemotherapy in colorectal cancer Gut, June 1, 2006; 55(6): 848 - 855. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Lanza, R. Gafa, A. Santini, I. Maestri, L. Guerzoni, and L. Cavazzini Immunohistochemical Test for MLH1 and MSH2 Expression Predicts Clinical Outcome in Stage II and III Colorectal Cancer Patients J. Clin. Oncol., May 20, 2006; 24(15): 2359 - 2367. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. A. Sinicrope, R. L. Rego, K. C. Halling, N. R. Foster, D. J. Sargent, B. La Plant, A. J. French, C. J. Allegra, J. A. Laurie, R. M. Goldberg, et al. Thymidylate synthase expression in colon carcinomas with microsatellite instability. Clin. Cancer Res., May 1, 2006; 12(9): 2738 - 2744. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Yamamoto, H. Matsuyama, S. Kawauchi, T. Furuya, X. P. Liu, K. Ikemoto, A. Oga, K. Naito, and K. Sasaki Biological characteristics in bladder cancer depend on the type of genetic instability. Clin. Cancer Res., May 1, 2006; 12(9): 2752 - 2758. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Watanabe, T. Kanazawa, Y. Kazama, J. Tanaka, T. Tanaka, S. Ishihara, and H. Nagawa TP53 Mutation and Microsatellite Instability Status for the Prediction of Survival in Adjuvant-Treated Colon Cancer Patients J. Clin. Oncol., December 10, 2005; 23(35): 9031 - 9032. [Full Text] [PDF]
|
|
|
|
|
|
P. Benatti, R. Gafa, D. Barana, M. Marino, A. Scarselli, M. Pedroni, I. Maestri, L. Guerzoni, L. Roncucci, M. Menigatti, et al. Microsatellite Instability and Colorectal Cancer Prognosis Clin. Cancer Res., December 1, 2005; 11(23): 8332 - 8340. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. L. Westra, M. Schaapveld, H. Hollema, J. P. de Boer, M. M.J. Kraak, D. de Jong, A. ter Elst, N. H. Mulder, C. H.C.M. Buys, R. M.W. Hofstra, et al. Determination of TP53 Mutation Is More Relevant Than Microsatellite Instability Status for the Prediction of Disease-Free Survival in Adjuvant-Treated Stage III Colon Cancer Patients J. Clin. Oncol., August 20, 2005; 23(24): 5635 - 5643. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. S. Samowitz, C. Sweeney, J. Herrick, H. Albertsen, T. R. Levin, M. A. Murtaugh, R. K. Wolff, and M. L. Slattery Poor Survival Associated with the BRAF V600E Mutation in Microsatellite-Stable Colon Cancers Cancer Res., July 15, 2005; 65(14): 6063 - 6069. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. R.J. Kohonen-Corish, J. J. Daniel, C. Chan, B. P.C. Lin, S. Y. Kwun, O. F. Dent, V. S. Dhillon, R. J.A. Trent, P. H. Chapuis, and E. L. Bokey Low Microsatellite Instability Is Associated With Poor Prognosis in Stage C Colon Cancer J. Clin. Oncol., April 1, 2005; 23(10): 2318 - 2324. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Popat, R. Hubner, and R.S. Houlston Systematic Review of Microsatellite Instability and Colorectal Cancer Prognosis J. Clin. Oncol., January 20, 2005; 23(3): 609 - 618. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. J. French, G. Petroni, S. N. Thibideau, M. Smolkin, E. Bissonette, F. Roviello, J. C. Harper, B. R. Koch, S. A. Anderson, S. J. Hebbring, et al. Allelic Imbalance of 8p Indicates Poor Survival in Gastric Cancer J. Mol. Diagn., August 1, 2004; 6(3): 243 - 252. [Abstract] [Full Text]
|
|
|
|
|
|
G. Bardi, C. Fenger, B. Johansson, F. Mitelman, and S. Heim Tumor Karyotype Predicts Clinical Outcome in Colorectal Cancer Patients J. Clin. Oncol., July 1, 2004; 22(13): 2623 - 2634. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Gill, C. L. Loprinzi, D. J. Sargent, S. D. Thome, S. R. Alberts, D. G. Haller, J. Benedetti, G. Francini, L. E. Shepherd, J. Francois Seitz, et al. Pooled Analysis of Fluorouracil-Based Adjuvant Therapy for Stage II and III Colon Cancer: Who Benefits and by How Much? J. Clin. Oncol., May 15, 2004; 22(10): 1797 - 1806. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Wang, T. Jatkoe, Y. Zhang, M. G. Mutch, D. Talantov, J. Jiang, H. L. McLeod, and D. Atkins Gene Expression Profiles and Molecular Markers To Predict Recurrence of Dukes' B Colon Cancer J. Clin. Oncol., May 1, 2004; 22(9): 1564 - 1571. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y Parc, S Gueroult, N Mourra, L Serfaty, J-F Flejou, E Tiret, and R Parc Prognostic significance of microsatellite instability determined by immunohistochemical staining of MSH2 and MLH1 in sporadic T3N0M0 colon cancer Gut, March 1, 2004; 53(3): 371 - 375. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Kambara, G. B. Sharp, T. Nagasaka, M. Takeda, H. Sasamoto, H. Nakagawa, H. Isozaki, D. G. MacPhee, J. R. Jass, N. Tanaka, et al. Allelic Loss of a Common Microsatellite Marker MYCL1: A Useful Prognostic Factor of Poor Outcomes in Colorectal Cancer Clin. Cancer Res., March 1, 2004; 10(5): 1758 - 1763. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Emterling, A. Wallin, G. Arbman, and X.-F. Sun Clinicopathological significance of microsatellite instability and mutated RIZ in colorectal cancer Ann. Onc., February 1, 2004; 15(2): 242 - 246. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. L. Ward, K. Cheong, S.-L. Ku, A. Meagher, T. O'Connor, and N. J. Hawkins Adverse Prognostic Effect of Methylation in Colorectal Cancer Is Reversed by Microsatellite Instability J. Clin. Oncol., October 15, 2003; 21(20): 3729 - 3736. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Ishikawa, T. Fujita, Y. Suzuki, S. Okabe, Y. Yuasa, T. Iwai, and Y. Kawakami Tumor-specific Immunological Recognition of Frameshift-mutated Peptides in Colon Cancer with Microsatellite Instability Cancer Res., September 1, 2003; 63(17): 5564 - 5572. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Mori, F. M. Selaru, F. Sato, J. Yin, L. A. Simms, Y. Xu, A. Olaru, E. Deacu, S. Wang, J. M. Taylor, et al. The Impact of Microsatellite Instability on the Molecular Phenotype of Colorectal Tumors Cancer Res., August 1, 2003; 63(15): 4577 - 4582. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. M. Ribic, D. J. Sargent, M. J. Moore, S. N. Thibodeau, A. J. French, R. M. Goldberg, S. R. Hamilton, P. Laurent-Puig, R. Gryfe, L. E. Shepherd, et al. Tumor Microsatellite-Instability Status as a Predictor of Benefit from Fluorouracil-Based Adjuvant Chemotherapy for Colon Cancer N. Engl. J. Med., July 17, 2003; 349(3): 247 - 257. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Graziano and S. Cascinu Prognostic molecular markers for planning adjuvant chemotherapy trials in Dukes' B colorectal cancer patients: how much evidence is enough? Ann. Onc., July 1, 2003; 14(7): 1026 - 1038. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. B. Diep, L. Thorstensen, G. I. Meling, E. Skovlund, T. O. Rognum, and R. A. Lothe Genetic Tumor Markers With Prognostic Impact in Dukes' Stages B and C Colorectal Cancer Patients J. Clin. Oncol., March 1, 2003; 21(5): 820 - 829. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Nakata, Y. Qing Wang, M. Yashiro, N. Nishioka, H. Tanaka, M. Ohira, T. Ishikawa, H. Nishino, and K. Hirakawa Prognostic Value of Microsatellite Instability in Resectable Pancreatic Cancer Clin. Cancer Res., August 1, 2002; 8(8): 2536 - 2540. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-W. Choi, K. J. Lee, Y.-A. Bae, K.-O. Min, M.-S. Kwon, K.-M. Kim, and M.-G. Rhyu Genetic Classification of Colorectal Cancer Based on Chromosomal Loss and Microsatellite Instability Predicts Survival Clin. Cancer Res., July 1, 2002; 8(7): 2311 - 2322. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Dolcetti, M. Guidoboni, A. Viel, M. Boiocchi, W. S. Samowitz, and M. L. Slattery Correspondence re: Samowitz et al., Microsatellite instability in sporadic colon cancer is associated with an improved prognosis at the population level. Cancer Epidemiol. Biomark. Prev., 10: 917-923, 2001 Cancer Epidemiol. Biomarkers Prev., May 1, 2002; 11(5): 499 - 500. [Full Text] [PDF]
|
|
|
|
|
|
S. Halford, P. Sasieni, A. Rowan, H. Wasan, W. Bodmer, I. Talbot, N. Hawkins, R. Ward, and I. Tomlinson Low-Level Microsatellite Instability Occurs in Most Colorectal Cancers and Is a Nonrandomly Distributed Quantitative Trait Cancer Res., January 1, 2002; 62(1): 53 - 57. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Kambara, N. Matsubara, H. Nakagawa, K. Notohara, T. Nagasaka, T. Yoshino, H. Isozaki, G. B. Sharp, K. Shimizu, J. Jass, et al. High Frequency of Low-Level Microsatellite Instability in Early Colorectal Cancer Cancer Res., November 1, 2001; 61(21): 7743 - 7746. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. S. Samowitz, K. Curtin, K.-N. Ma, D. Schaffer, L. W. Coleman, M. Leppert, and M. L. Slattery Microsatellite Instability in Sporadic Colon Cancer Is Associated with an Improved Prognosis at the Population Level Cancer Epidemiol. Biomarkers Prev., September 1, 2001; 10(9): 917 - 923. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Guidoboni, R. Gafa, A. Viel, C. Doglioni, A. Russo, A. Santini, L. Del Tin, E. Macri, G. Lanza, M. Boiocchi, et al. Microsatellite Instability and High Content of Activated Cytotoxic Lymphocytes Identify Colon Cancer Patients with a Favorable Prognosis Am. J. Pathol., July 1, 2001; 159(1): 297 - 304. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R Ward, A Meagher, I Tomlinson, T O'Connor, M Norrie, R Wu, and N Hawkins Microsatellite instability and the clinicopathological features of sporadic colorectal cancer Gut, June 1, 2001; 48(6): 821 - 829. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Watanabe, T.-T. Wu, P. J. Catalano, T. Ueki, R. Satriano, D. G. Haller, A. B. Benson, and S. R. Hamilton Molecular Predictors of Survival after Adjuvant Chemotherapy for Colon Cancer N. Engl. J. Med., April 19, 2001; 344(16): 1196 - 1206. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Yamamoto, F. Itoh, H. Nakamura, H. Fukushima, S. Sasaki, M. Perucho, and K. Imai Genetic and Clinical Features of Human Pancreatic Ductal Adenocarcinomas with Widespread Microsatellite Instability Cancer Res., April 1, 2001; 61(7): 3139 - 3144. [Abstract] [Full Text]
|
|
|
|
|
|
J. Andreyev and D. Cunningham Markers, Markers Everywhere . . . . . Prognosis in Colorectal Cancer--Time for a New Approach J. Clin. Oncol., January 15, 2001; 19(2): 286 - 288. [Full Text] [PDF]
|
|
|
|
|
|
M. Ponz de Leon, L. Roncucci, K. Heinimann, H. Muller, Z. Dobbie, R. Gryfe, M. Redston, and S. Gallinger Microsatellite Instability in Colorectal Cancer N. Engl. J. Med., May 25, 2000; 342(21): 1607 - 1608. [Full Text]
|
|
|
|
|
|
R. Gryfe, H. Kim, E. T.K. Hsieh, M. D. Aronson, E. J. Holowaty, S. B. Bull, M. Redston, and S. Gallinger Tumor Microsatellite Instability and Clinical Outcome in Young Patients with Colorectal Cancer N. Engl. J. Med., January 13, 2000; 342(2): 69 - 77. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Offit Genetic Prognostic Markers for Colorectal Cancer N. Engl. J. Med., January 13, 2000; 342(2): 124 - 125. [Full Text]
|
|
|
|
 |
|
 I. D. Nicholl and M. G. Dunlop Molecular Markers of Prognosis in Colorectal Cancer J Natl Cancer Inst, August 4, 1999; 91(15): 1267 - 1269. [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Ionov, H. Yamamoto, S. Krajewski, J. C. Reed, and M. Perucho Mutational inactivation of the proapoptotic gene BAX confers selective advantage during tumor clonal evolution PNAS, September 26, 2000; 97(20): 10872 - 10877. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||