Tumor Microsatellite Instability and Clinical Outcome in Young Patients with Colorectal Cancer
Robert Gryfe, M.D., Hyeja Kim, M.Sc., Eugene T.K. Hsieh, M.D., Melyssa D. Aronson, M.Sc., Eric J. Holowaty, M.D., Shelley B. Bull, Ph.D., Mark Redston, M.D., and Steven Gallinger, M.D.
Background Colorectal cancer can arise through two distinctmutational pathways: microsatellite instability or chromosomalinstability. We tested the hypothesis that colorectal cancersarising from the microsatellite-instability pathway have distinctiveclinical attributes that affect clinical outcome.
Methods We tested specimens of colorectal cancer from a population-basedseries of 607 patients (50 years of age or younger at diagnosis)for microsatellite instability. We compared the clinical featuresand survival of patients who had colorectal cancer characterizedby high-frequency microsatellite instability with these characteristicsin patients who had colorectal cancers with microsatellite stability.
Results We found high-frequency microsatellite instability in17 percent of the colorectal cancers in 607 patients, and ina multivariate analysis, microsatellite instability was associatedwith a significant survival advantage independently of all standardprognostic factors, including tumor stage (hazard ratio, 0.42;95 percent confidence interval, 0.27 to 0.67; P< 0.001).Furthermore, regardless of the depth of tumor invasion, colorectalcancers with high-frequency microsatellite instability had adecreased likelihood of metastasizing to regional lymph nodes(odds ratio, 0.33; 95 percent confidence interval, 0.21 to 0.53;P< 0.001) or distant organs (odds ratio, 0.49; 95 percentconfidence interval, 0.27 to 0.89; P=0.02).
Conclusions High-frequency microsatellite instability in colorectalcancer is independently predictive of a relatively favorableoutcome and, in addition, reduces the likelihood of metastases.
Colorectal cancer is the third most common cancer in Westernsociety.1,2 Despite advances in screening, diagnosis, and treatment,it is still the second leading cause of cancer-related deathin North America.1,2 Much has been learned over the past decadeabout the molecular genetic alterations that give rise to colorectalcancer. However, this knowledge has yet to affect its clinicalmanagement substantially, and pathological staging remains thebasis for prognostication and decisions about therapy.3
It is now commonly believed that all cancers arise as a resultof the accumulation of genetic alterations that allow the growthof neoplastic cells.4,5 However, the rate of random mutationalevents alone cannot account for the number of genetic alterationsfound in most cancers in humans.6 For this reason, it has beensuggested that destabilization of the genome may be a prerequisiteearly in carcinogenesis.6,7 This "mutator phenotype" is bestunderstood in colorectal cancer, in which there are two separatedestabilizing pathways.8,9 The more common of these mutationalpathways involves chromosomal instability9,10 characterizedby allelic losses (loss of heterozygosity), chromosomal amplifications,and translocations in colorectal-cancer cells. In the secondmutational pathway, colorectal cancers display increased ratesof intragenic mutation, characterized by generalized instabilityof short, tandemly repeated DNA sequences known as microsatellites.11,12,13High-frequency microsatellite instability (instability at 40percent or more of microsatellite loci) has been found in mostcases of hereditary nonpolyposis colorectal cancer11,14 as definedby the Amsterdam criteria (which require that at least threepersons from at least two successive generations have colorectalcancer and that the disease be diagnosed in at least one ofthese persons by the age of 50).15 In addition, high-frequencymicrosatellite instability occurs in approximately 15 percentof sporadic cases of colorectal cancer.12,13,14
Normally, mismatches of nucleotides that occur when DNA polymeraseinserts the wrong bases in newly synthesized DNA are repairedby mismatch-repair enzymes. Defects in mismatch repair leadto high-frequency microsatellite instability in colorectal cancer.16,17,18,19,20Inherited germ-line mutations of mismatch-repair genes havebeen found in approximately 50 percent of persons with a familyhistory that fulfills the Amsterdam criteria.21,22 Alterationsof the MSH2 and MLH1 mismatch-repair genes account for morethan 90 percent of these cases.5,21 In addition, acquired, noninheritedalterations of the MLH1 gene occur in most sporadic cases ofcolorectal cancer with high-frequency microsatellite instability.23,24
Although colorectal cancer continues to be regarded as a singledisease, it is possible that colorectal cancers with high-frequencymicrosatellite instability constitute a clinically distinctsubtype. A number of studies have shown that high-frequencymicrosatellite instability occurs relatively frequently in colorectalcancers that arise proximal to the splenic flexure,12,13 inpoorly differentiated cancers or those of the mucinous-celltype, and in cancers with peritumoral lymphocytic infiltration.25Furthermore, it has been suggested that the survival of patientswith colorectal cancers that have arisen from the high-frequencymicrosatellite-instability pathway is longer than the survivalof patients with cancers that have microsatellite stability.12,26,27,28,29(The latter cases constitute the majority of colorectal cancers.)However, these results were obtained from small, uncontrolled,or potentially biased analyses. We therefore conducted a population-basedstudy to determine whether high-frequency microsatellite instabilityis an independent predictor of improved survival in patientswith colorectal cancer.
Methods
Study Population
Through the Ontario Cancer Registry, we identified a population-basedseries of all newly diagnosed cases of histopathologically confirmedcolorectal adenocarcinoma in patients 50 years of age or youngerwho were residing in Central-East Ontario (an area with a populationof approximately 4.7 million) between January 1, 1989, and December31, 1993. Identification through the Ontario Cancer Registryhas been estimated to identify 96 percent of all Ontario residentswith a diagnosis of colorectal cancer.30 After obtaining permissionto contact subjects from the physicians who treated the patients,we collected information on family history and clinical screeningfrom the patients or their next of kin, or by reviewing medicalcharts.
We excluded patients from the study if they did not undergoresection of the primary colorectal adenocarcinoma or if pathologicalreview did not confirm invasion of the tumor to at least thelevel of the submucosa (stage T1 or higher). In total, 640 patientstreated at 41 hospitals were eligible for inclusion in the study.Specimens of colorectal cancer from 607 of the patients (95percent) were available for retrieval and testing. The studywas approved by the Human Ethics Committee of the Universityof Toronto.
Clinical Data Base
A clinical data base was prepared by persons with no knowledgeof the results of molecular genetic testing of each patient'scancer. The date of the patient's first biopsy or resectionthat provided a histologic diagnosis of adenocarcinoma of thecolon or rectum was recorded as the date of diagnosis of cancer.
We classified cancers according to several gross and histologicfeatures. With the exception of the preoperative level of serumcarcinoembryonic antigen, we included all College of AmericanPathologists category I factors (pathological stage, tumor celltype, tumor grade, and presence or absence of extramural venousinvasion), which are well supported by the literature and aregenerally used in patient care.31 All specimens underwent histopathologicalreview by a single pathologist, who was unaware of the resultsof molecular genetic testing. In accordance with the classificationof tumors by the World Health Organization,32 we defined tumorsas signet-ring cell or mucinous if 50 percent or more of thetumor displayed the specified cell type and as undifferentiatedif features of tumor-cell differentiation were absent. Othertumors were classified as "adenocarcinoma, not otherwise specified"or, in rare cases, adenosquamous carcinoma, if malignant squamousand glandular components were present. Distant metastases werejudged to be present if they appeared in a histopathologicalspecimen or if they were identified by the Ontario Cancer Registrywithin 120 days after diagnosis. In total, 103 of the 138 casesof distant-organ metastases (75 percent) were confirmed by histopathologicalexamination.
Radiation treatment in Ontario is provided exclusively at ninespecialized oncologic-treatment centers that report to the OntarioCancer Registry. Data on radiation treatment initiated within120 days after diagnosis were extracted from Ontario CancerRegistry records and were available for all study patients.Chemotherapy for cancer may be administered either in oncologic-treatmentcenters or in other hospitals and clinics in the province. Informationon chemotherapy initiated within 120 days after diagnosis wasacquired from the data bases of both the Ontario Cancer Registryand the Ontario Institute for Clinical Evaluative Sciences andwas available for 392 of the 607 study patients (65 percent).
DNA Preparation, Microsatellite Testing, and Analysis
Blocks of surgically resected cancerous tissue that had beenfixed in formalin and embedded in paraffin were requested fromthe relevant pathology departments for all patients. For eachspecimen, regions of invasive cancer with the highest proportionof neoplastic cells (median, 80 percent; range, 40 to 100 percent)and normal tissue were microdissected, and DNA was extractedby proteinase K digestion.33 Samples of genomic DNA were usedto amplify sequences (by the polymerase chain reaction [PCR])from 5 to 10 of the following mononucleotide and dinucleotidemicrosatellite loci: BAT-25, BAT-26, D5S346, D2S123, D17S250,BAT-40, TGF-ß RII, D18S58, D18S69, and D17S787 (HumanMapPairs, Research Genetics, Huntsville, Ala.). These specificmicrosatellite loci were derived from the National Cancer Institutereference and alternative loci panel in order to ensure standardizedfindings.34 Primer sequences and conditions of the PCR assayand gel electrophoresis have been published previously.33,35
The presence of additional bands in the PCR product from tumorDNA, not observed in DNA from normal tissue from the same patient,was scored as instability at that particular locus. In accordancewith the National Cancer Institute consensus on microsatelliteinstability,34 any pair of samples of normal DNA and tumor DNAthat displayed instability at two or more of five loci was scoredas having high-frequency microsatellite instability, whereasa sample pair with no instability at five loci was scored ashaving microsatellite stability. Any sample pair observed tohave instability at one of five microsatellite loci underwenta second test at that locus. If instability was confirmed, additionalloci, up to a maximum of 10, were tested to determine whetherthe phenotype of the sample was low-frequency microsatelliteinstability — instability at 1 to 3 of 10 loci assayed— or high-frequency microsatellite instability —instability at 4 or more loci.
Statistical Analysis
The primary outcome of this study was overall survival, measuredfrom the date of histologic diagnosis of colorectal cancer.The study was designed to determine the prognostic importanceof high-frequency microsatellite instability in addition toknown prognostic factors. Because the genetic basis of low-frequencymicrosatellite instability remains poorly understood,34 andbecause the incidence of low-frequency microsatellite instabilitywas too low in our series to allow for meaningful statisticaltesting, we excluded from the study 20 patients (3 percent)with colorectal cancers characterized by low-frequency microsatelliteinstability before we performed the statistical analysis.
The univariate associations between the presence or absenceof high-frequency microsatellite instability and base-line prognosticfactors were analyzed with a chi-square test for categoricalvariables and an unpaired Student's t-test for continuous factors.The associations of microsatellite status and the depth of tumorinvasion with metastases to regional lymph nodes and distantorgans were evaluated with multivariate logistic regression.Survival curves were prepared according to the method of Kaplanand Meier,36 and univariate survival distributions were comparedwith use of the log-rank test. All patients were followed fromdiagnosis until death or until data were censored (and the patientconsidered to be alive) as of September 30, 1998. A multivariatesurvival analysis was evaluated according to the Cox proportional-hazardsmodel.37 A model obtained with step-down variable selection,in which all prognostic factors were initially entered intothe model and in which nonsignificant factors (P>0.1) weresuccessively rejected, was compared with the primary model,which included all prognostic factors regardless of their measuredsignificance. All factors were treated as simple categoricalvariables with the exception of age at diagnosis, which wasanalyzed as a continuous variable. All reported P values aretwo-sided, and P values of less than 0.05 were considered toindicate statistical significance.
Results
Clinical Characteristics Associated with High-Frequency Microsatellite Instability
Of the 607 specimens of colorectal cancer that we tested, 102(17 percent) were characterized by high-frequency microsatelliteinstability, 20 (3 percent) had low-frequency microsatelliteinstability, and 485 (80 percent) had microsatellite stability(Figure 1). Colorectal cancers with high-frequency microsatelliteinstability were more likely to be poorly differentiated andlocated proximal to the splenic flexure than were cancers withmicrosatellite stability (Table 1). The patients with colorectalcancer with high-frequency microsatellite instability were morelikely to have multiple synchronous or metachronous colorectalcancers and received a diagnosis at a younger age than the patientswith colorectal cancers with microsatellite stability.
Figure 1. Colorectal Cancers with High-Frequency Microsatellite Instability (MSI) and Microsatellite Stability (MSS).
The MSI colorectal cancer displays shifted bands in tumor DNA (T) as compared with normal DNA (N) at the BAT-25, BAT-26, D2S123, D5S346, and D17S250 microsatellite loci. The MSS colorectal cancer has identical bands in tumor and normal DNA at the BAT-25, BAT-26, D2S123, and D5S346 microsatellite loci. In addition, the MSS colorectal cancer displays loss of heterozygosity at the D17S250 locus — that is, a loss of the top (larger) allele in tumor DNA as compared with normal DNA.
Table 1. Characteristics of 587 Patients with Colorectal Cancer Evaluated for Microsatellite Instability.
Although colorectal cancers with high-frequency microsatelliteinstability were diagnosed at a significantly greater depthof tumor invasion, these tumors had a significantly lower overallpathological stage than cancers with microsatellite stability(Table 1). Multivariate logistic regression demonstrated thatboth high-frequency microsatellite instability and a lesserdepth of tumor invasion were independently associated with adecreased likelihood of metastases to either regional lymphnodes or distant organs (Table 2).
Table 2. Multivariate Analysis of Predictive Factors for Metastases to Regional Lymph Nodes or Distant Organs in 587 Patients with Colorectal Cancer.
To ensure that treatment did not differ in an era when the benefitsof adjuvant therapy were still being established, we comparedthe use of chemotherapy and radiation therapy in patients withcolorectal cancer with high-frequency microsatellite instabilitywith their use in patients whose cancers had microsatellitestability. Although a trend toward more frequent use of chemotherapyand radiation treatment was evident in the care of patientswhose cancers had microsatellite stability (Table 1), we foundno significant differences in treatment patterns after controllingfor pathological stage (P=0.60 for chemotherapy and P=0.14 forradiation therapy, according to logistic-regression analysis).
High-Frequency Microsatellite Instability and Standard Clinical Prognostic Factors for Survival
In total, 272 of the 587 patients (46 percent) died during amean follow-up period of 7.2±0.1 years after diagnosis.The survival of patients with colorectal cancers with high-frequencymicrosatellite instability (mean [±SE] five-year survival,76±4 percent) was significantly better than that of patientswith cancers with microsatellite stability (five-year survival,54±2 percent; P<0.001) (Figure 2). Colorectal cancerswith mucinous, signet-ring, and undifferentiated cell types,poorer grade, higher pathological stage, or extramural venousinvasion were associated with significantly lower survival (Table 3).
Figure 2. Kaplan–Meier Survival Curves for Patients with Colorectal Cancer, Stratified According to Microsatellite Status.
Panel A shows that the survival of patients who had colorectal cancer with high-frequency microsatellite instability (MSI) was significantly better than that of patients who had cancers with microsatellite stability (MSS) (P<0.001). Panels B, C, D, and E show survival curves for patients with colorectal cancer according to the microsatellite status of the cancer and according to the American Joint Committee on Cancer disease stage. The survival of patients with cancers with high-frequency microsatellite instability was better than that for patients with cancers with microsatellite stability at all disease stages.
Table 3. Univariate Analysis of Predictive Factors for Survival in 587 Patients with Colorectal Cancer.
Information on family history was available for 84 (82 percent)of the 102 patients who had colorectal cancer with high-frequencymicrosatellite instability, including 21 of the 29 patients(72 percent) who died during follow-up. In total, 13 of these84 patients (15 percent) had family histories that fulfilledthe Amsterdam criteria for hereditary nonpolyposis colorectalcancer. Among the patients who had cancer with high-frequencymicrosatellite instability, no significant difference in survivalwas found between those who fulfilled the Amsterdam criteria(five-year survival, 77±12 percent) and those who didnot (five-year survival, 78±5 percent; P=0.41). Of the84 patients, only 1 (whose family history did not fulfill theAmsterdam criteria) was asymptomatic when a diagnosis was madeby clinical screening.
In a step-down multivariate analysis, the microsatellite status,pathological stage, tumor grade, and histologic type of thecancer were found to be significantly and independently associatedwith survival (Table 4). The survival advantage of high-frequencymicrosatellite instability over microsatellite stability wassimilar in the model that included all 12 prognostic variableslisted in Table 3, regardless of their measured significance(hazard ratio, 0.42; 95 percent confidence interval, 0.27 to0.67; P<0.001). The proportionality of the survival advantageassociated with high-frequency microsatellite instability canbe seen in Kaplan–Meier survival curves stratified accordingto disease stage (Figure 2).
Table 4. Significant Predictive Factors for Survival in a Cox Proportional-Hazards Analysis of 587 Patients with Colorectal Cancer.
Discussion
Because most cancers are thought to arise from an accumulationof genetic alterations, it is not surprising that cancers thatemerge from different mutational pathways should differ clinically.We have found this to be the case for the subgroup of colorectalcancers that are characterized by high-frequency microsatelliteinstability. In our population-based series, high-frequencymicrosatellite instability was associated with prolonged survivalindependently of classic clinical prognostic factors, includingthe disease stage. Eighty-five percent of the patients who hadcancer with high-frequency microsatellite instability did nothave a family history suggestive of hereditary nonpolyposiscolorectal cancer. For this reason, the considerable survivaladvantage conferred by high-frequency microsatellite instabilityappears to be applicable to both heritable and sporadic typesof colorectal cancer. Furthermore, in only one of the patientswhose cancer had high-frequency microsatellite instability wasthe cancer diagnosed by clinical screening when he was asymptomatic;this fact eliminates lead-time bias as a likely cause of thesurvival advantage.
The association of high-frequency microsatellite instabilitywith improved clinical outcome has been suggested previously.12,26,27,28,29In other studies, however, no survival advantage was detected,38,39,40,41and a recent National Cancer Institute workshop concluded thatmicrosatellite instability had not yet been shown conclusivelyto be an independent predictor of prognosis.34 Furthermore,since the first descriptions of high-frequency microsatelliteinstability,11,12,13 the literature has been complicated byinconsistent and confusing definitions of this molecular phenotype.34The term "high-frequency microsatellite instability" is meantto describe a generalized (not occasional) instability of microsatelliteDNA in cancers that almost always lack the ability to repairmismatched bases in DNA. For this reason, the National CancerInstitute has defined high-frequency microsatellite instability,low-frequency microsatellite instability, and microsatellitestability in colorectal cancer in terms of how many microsatelliteloci and which specific loci need to be tested and shown tobe altered.34 In our study we used these consensus definitions.
We found a 17 percent incidence of high-frequency microsatelliteinstability, but in a recent large series reported by Aaltonenet al.,14 a 12 percent incidence was found. There was a similardifference in incidence among patients whose family historiesfulfilled the Amsterdam criteria for hereditary nonpolyposiscolorectal cancer (15 percent in our series and 11 percent inthe study by Aaltonen et al.14). Thus, the differences notedare likely to reflect the fact that our population was relativelyyoung (all received a diagnosis at 50 years of age or younger)and thus may have included a greater proportion of patientswith hereditary nonpolyposis colorectal cancer. Despite theirrelatively young age, less than 10 percent of the patients inour cohort had colorectal cancer associated with hereditarynonpolyposis colorectal cancer, familial adenomatous polyposis,or inflammatory bowel disease.
Previous case–control studies reported that 58 percent42and 47 percent28 of colorectal cancers in patients 35 yearsof age or younger and 40 years of age or younger, respectively,had high-frequency microsatellite instability. These resultshighlight the need for unbiased methods of case ascertainmentto use as a basis for calculating accurate frequencies of molecularmarkers such as high-frequency microsatellite instability.
In addition to high-frequency microsatellite instability, wefound that the pathological stage of colorectal cancer was anindependent and powerful predictor of clinical outcome. Thisis not surprising, because the pathological stage is the maindeterminant of outcome for most cancers.3 The fact that high-frequencymicrosatellite instability was strongly associated with a lowerstage of cancer, even after we controlled for the depth of tumorinvasion, is intriguing. These results indicate that high-frequencymicrosatellite instability contributes to improved survivalin two separate ways. First, high-frequency microsatellite instabilityis prognostic of improved survival independently of other prognosticfactors, including pathological stage. Second, high-frequencymicrosatellite instability is independently predictive of lowerpathological stage, thus further contributing to the improvedsurvival through tumor down-staging.
The mechanism by which high-frequency microsatellite instabilityinfluences clinical outcome is unknown, but it may be relatedto the kinds of mutations or the genetic targets involved incolorectal cancers that are deficient in DNA-mismatch repair.For example, colorectal cancers with high-frequency microsatelliteinstability have fewer mutations of the adenomatous polyposiscoli (APC)43 and p5313,43 genes and more frequent mutationsof the ß-catenin (CTNNB1)44,45 and transforming growthfactor ß receptor type II46 genes than colorectalcancers with microsatellite stability. Distinct clinical andpathological features, such as the intense lymphocytic infiltratesobserved in tumors with high-frequency microsatellite instability,25may result from these unique genetic alterations and contributeto the less aggressive nature of these cancers.
In addition, the therapeutic effects of DNA-damaging chemotherapeuticagents, such as fluorouracil, are likely to be influenced bythe underlying mutational mechanism. In vitro, cell lines withhigh-frequency microsatellite instability are less responsivethan cell lines with microsatellite stability to various chemotherapeuticagents.47 Furthermore, the targeting of DNA cells that are deficientin mismatch repair may offer a specific intervention that doesnot affect normal tissues that retain mismatch-repair function.48
In conclusion, we detected high-frequency microsatellite instabilityin 17 percent of colorectal-cancer specimens from a population-basedseries of relatively young patients. In most of these patients,there was no family history suggestive of hereditary nonpolyposiscolorectal cancer. High-frequency microsatellite instabilitywas found to be an independent predictor of improved survival,and tumors with this genetic phenotype were less likely to metastasizethan those characterized by microsatellite stability.
Supported by the National Cancer Institute of Canada with fundsprovided by the Canada Cancer Society. Dr. Gryfe is a ResearchFellow of the National Cancer Institute of Canada, with fundsprovided by the Terry Fox Run, and was supported by the AmericanSociety of Colon and Rectal Surgeons through the Leon HirschSurgical Research Fellowship. Dr. Bull is a National HealthResearch Scholar of the National Health Research DevelopmentProgram.
We are indebted to the treating physicians and participatingdepartments of pathology for their cooperation; to Darlene Dale,Nelson Chong, Lisa Madlensky, Dr. Andrew Smith, Dr. MalcolmMoore, and Scott Mackay for assistance in data retrieval; toDr. Susan Bondy and Marc Theriault of the Institute for ClinicalEvaluative Sciences for assistance in the analysis of chemotherapydata; to Kazy Hay and Susie Tjan for assistance in specimenhandling; and to Dr. Robin McLeod, Dr. Steven Narod, Dr. MichelleCotterchio, and Dr. Allan Detsky for helpful discussions.
Source Information
From the Centre for Cancer Genetics (R.G., H.K., E.T.K.H., M.R., S.G.) and the Division of Clinical Epidemiology (S.B.B.), Samuel Lunenfeld Research Institute; the Departments of Surgery (R.G., M.D.A., S.G.), Laboratory Medicine and Pathobiology (E.T.K.H., M.R.), and Public Health Sciences (E.J.H., S.B.B.), University of Toronto; and Cancer Care Ontario (E.J.H.) — all in Toronto.
Address reprint requests to Dr. Gallinger at Mount Sinai Hospital, 600 University Ave., Suite 1225, Toronto, ON M5G 1X5, Canada, or at sgallinger{at}mtsinai.on.ca.
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Stoehlmacher, J., Park, D. J., Zhang, W., Groshen, S., Tsao-Wei, D. D., Yu, M. C., Lenz, H.-J.
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Dolcetti, R., Guidoboni, M., Viel, A., Boiocchi, M., Samowitz, W. S., Slattery, M. L.
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Richman, S., Adlard, J.
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Park, J., Betel, D., Gryfe, R., Michalickova, K., Di Nicola, N., Gallinger, S., Hogue, C. W. V., Redston, M.
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van Rijnsoever, M., Elsaleh, H., Iacopetta, B., Guidoboni, M., Viel, A., Del Tin, L., Boiocchi, M., Dolcetti, R., Gafa, R., Lanza, G., Doglioni, C., Macri, E., Russo, A., Santini, A.
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Young, J., Simms, L. A., Biden, K. G., Wynter, C., Whitehall, V., Karamatic, R., George, J., Goldblatt, J., Walpole, I., Robin, S.-A., Borten, M. M., Stitz, R., Searle, J., McKeone, D., Fraser, L., Purdie, D. R., Podger, K., Price, R., Buttenshaw, R., Walsh, M. D., Barker, M., Leggett, B. A., Jass, J. R.
(2001). Features of Colorectal Cancers with High-Level Microsatellite Instability Occurring in Familial and Sporadic Settings : Parallel Pathways of Tumorigenesis. Am. J. Pathol.
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Kambara, T., Matsubara, N., Nakagawa, H., Notohara, K., Nagasaka, T., Yoshino, T., Isozaki, H., Sharp, G. B., Shimizu, K., Jass, J., Tanaka, N.
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Samowitz, W. S., Curtin, K., Ma, K.-N., Schaffer, D., Coleman, L. W., Leppert, M., Slattery, M. L.
(2001). Microsatellite Instability in Sporadic Colon Cancer Is Associated with an Improved Prognosis at the Population Level. Cancer Epidemiol. Biomarkers Prev.
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Guidoboni, M., Gafa, R., Viel, A., Doglioni, C., Russo, A., Santini, A., Del Tin, L., Macri, E., Lanza, G., Boiocchi, M., Dolcetti, R.
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