Background Germ-line mutations in DNA mismatch-repair genes(MSH2, MLH1, PMS1, PMS2, and MSH6 ) cause susceptibility tohereditary nonpolyposis colorectal cancer. We assessed the prevalenceof MSH2 and MLH1 mutations in families suspected of having hereditarynonpolyposis colorectal cancer and evaluated whether clinicalfindings can predict the outcome of genetic testing.
Methods We used denaturing gradient gel electrophoresis to identifyMSH2 and MLH1 mutations in 184 kindreds with familial clusteringof colorectal cancer or other cancers associated with hereditarynonpolyposis colorectal cancer. Information on the site of cancer,the age at diagnosis, and the number of affected family memberswas obtained from all families.
Results Mutations of MSH2 or MLH1 were found in 47 of the 184kindreds (26 percent). Clinical factors associated with thesemutations were early age at diagnosis of colorectal cancer,the occurrence in the kindred of endometrial cancer or tumorsof the small intestine, a higher number of family members withcolorectal or endometrial cancer, the presence of multiple colorectalcancers or both colorectal and endometrial cancers in a singlefamily member, and fulfillment of the Amsterdam criteria forthe diagnosis of hereditary nonpolyposis colorectal cancer (atleast three family members in two or more successive generationsmust have colorectal cancer, one of whom is a first-degree relativeof the other two; cancer must be diagnosed before the age of50 in at least one family member; and familial adenomatous polyposismust be ruled out). Multivariate analysis showed that a youngerage at diagnosis of colorectal cancer, fulfillment of the Amsterdamcriteria, and the presence of endometrial cancer in the kindredwere independent predictors of germ-line mutations of MSH2 orMLH1. These results were used to devise a logistic model forestimating the likelihood of a mutation in MSH2 and MLH1.
Conclusions Assessment of clinical findings can improve therate of detection of mutations of DNA mismatch-repair genesin families suspected of having hereditary nonpolyposis colorectalcancer.
The lifetime risk of colorectal cancer among whites in the Westernworld is approximately 4 percent. The cause of colorectal canceris multifactorial, involving hereditary susceptibility, environmentalfactors, and somatic genetic changes during tumor progression.1A family history of colorectal cancer is a clinically significantrisk factor and may be found in up to 15 percent of all patientswith colorectal cancer.2 Hereditary nonpolyposis colorectalcancer, or the Lynch syndrome, is the most common type of familialcolorectal cancer and is thought to account for 1 to 5 percentof all cases of the disease.3,4 Members of families with hereditarynonpolyposis colorectal cancer are also at risk for tumors atother sites, including the endometrium, stomach, small intestine,brain, hepatobiliary system, urinary tract, and ovary.2,5 Inaddition, multiple synchronous or metachronous cancers developin about 30 percent of the patients.2,5
Hereditary nonpolyposis colorectal cancer is caused by germ-linemutations in one of five DNA mismatch-repair genes: MSH2,6MLH1,7,8PMS1, PMS2,9 and MSH6 (also known as GTBP).10,11 Of the 126germ-line mutations reported to date, almost all have been foundin MSH2 and MLH1; only 3 have been reported in PMS1 and PMS2.12Recently, two germ-line mutations have been found in MSH6.10,11Inactivation of any one of these genes causes widespread genomicinstability characterized by the expansion or contraction ofshort, repeated sequences of DNA (microsatellites).13,14,15This phenomenon, known as microsatellite instability, is thoughtto be responsible for the rapid accumulation of somatic mutationsin oncogenes and tumor-suppressor genes that have crucial rolesin the initiation and progression of tumors.16,17,18
In a recent study of the risk of cancer in 19 families withhereditary nonpolyposis colorectal cancer diagnosed by mutationanalysis, we found that the inheritance of a mutated copy ofMSH2 or MLH1 is associated with an 80 percent risk of colorectalcancer by the age of 80 years, as compared with a risk of about4 percent in the general population. Female members of suchfamilies also have a 40 to 50 percent risk of endometrial cancer,as compared with a risk of less than 2 percent in the generalpopulation. Moreover, carriers of an MSH2 mutation have a higherrisk of extracolonic cancers than carriers of an MLH1 mutation.19A study of mutation carriers identified among patients withan early onset of colorectal cancer confirmed the high riskof endometrial cancer in female family members and found thatmales had a higher risk of colorectal cancer than females; therisk of colorectal cancer among female carriers was only 30percent.20
In 1990, the International Collaborative Group on HereditaryNonpolyposis Colorectal Cancer proposed a set of clinical diagnosticcriteria (later termed the Amsterdam criteria) to provide uniformityin collaborative studies. For families to be classified as havinghereditary nonpolyposis colorectal cancer, at least three membersin at least two successive generations must have colorectalcancer, with at least one case diagnosed before the age of 50years; one of the affected members should be a first-degreerelative of the other two; and familial adenomatous polyposisshould be ruled out.21 Germ-line mutations of MSH2 and MLH1occur with approximately equal frequency in kindreds who meetthe Amsterdam criteria (approximately 25 percent in each case),22,23,24,25,26,27whereas such mutations were found in only 10 percent of thekindreds that did not meet the criteria.28,29
The detection of pathogenic mutations in families with hereditarynonpolyposis colorectal cancer has made presymptomatic diagnosispossible in persons who may be at risk. Screening for mutations,however, is time consuming and expensive because of the heterogeneityof the mutations in DNA mismatch-repair genes.12,25,26,29 Moreover,the number of kindreds with an apparent familial clusteringof this common cancer is potentially high. Little is known aboutthe clinical risk factors that best predict the presence ofMSH2 or MLH1 mutations.28,30 To address this issue, we useddenaturing gradient gel electrophoresis (DGGE) with guanosineand cytidine extensions (GC clamping)31,32 to analyze the MSH2and MLH1 genes in 184 unrelated kindreds with familial clusteringof colorectal and other cancers. Using logistic-regression analysis,we devised a method for evaluating the probability of an MSH2or an MLH1 mutation that is based on several risk factors.
Methods
Subjects
A total of 184 kindreds participated in the study. The resultsof mutation analysis and assessments of the risk of cancer insome of these families have been reported previously.19,25,26,29Sixty-seven families were recruited through the Foundation forthe Detection of Hereditary Tumors in the Netherlands. Thesekindreds were referred to the foundation from all parts of theNetherlands because they were suspected of having an inheritedform of colorectal cancer. Another 56 Dutch families and 56Norwegian families were enrolled by clinicians or clinical geneticscenters. Also included were three Italian families, one Danishfamily, and one Czech family. Members of these families attendedthe clinics because of concern about familial risk factors forcolorectal cancer.
Data on family history were collected by genetic fieldworkersor clinical geneticists. Pedigrees were traced backward andlaterally as far as possible. In addition, information was collectedon the type, site, and number of cancers; the age at diagnosis;and the pathological characteristics of the individual tumorsin each of the affected persons. The pedigrees of most familiesincluded at least three generations. Eighty-seven percent ofthe cases of cancer were confirmed by medical or pathology reportsor both.
All participating family members gave informed consent, andwhen their blood samples were collected, they were informedof the possibility of genetic counseling if a pathogenic mutationwas identified. The protocol for presymptomatic testing of DNAused by the Dutch clinical genetics centers usually involvesthree sessions. The issues discussed during the first sessioninclude the reasons for DNA testing, the clinical features ofhereditary nonpolyposis colorectal cancer, the mode of inheritanceof the syndrome, and the DNA-testing procedure. In session 2,the consequences of the test results and the options for treatmentin the case of a positive result are discussed, and blood samplesare taken. The results of the DNA test are disclosed duringsession 3. All sessions are conducted by a clinical geneticistwith the support of a psychologist or a social worker who isalso responsible for the patient's follow-up.
Ninety-two families met the Amsterdam criteria for hereditarynonpolyposis colorectal cancer. Among the 92 kindreds that didnot meet the criteria, the majority (48 kindreds) had fewerthan the minimal number of three family members with colorectalcancer. In 17 families, colorectal cancer was diagnosed in allaffected patients after the age of 50 years, in 11 familiesonly one generation was affected, and in 6 families the affectedpatients were not first-degree relatives. In the remaining 10families more than one of the criteria were not met.
Mutation Analysis
Isolation of genomic DNA, amplification with the polymerasechain reaction (PCR), mutation analysis with DGGE, and determinationof the nucleotide sequences were performed as previously described.25,26,29,33In short, the general strategy was to amplify by PCR each ofthe 16 exons of MSH2 and 19 exons of MLH1 in a single affectedmember in each family and to analyze these products by GC-clampedDGGE.32 Exons with altered patterns of migration on DGGE weresequenced to determine the molecular nature of the variant.When variants were detected, the investigations were extended,when possible, to the rest of the family to verify the segregationof the nucleotide change with the disease phenotype.25,26,29
Statistical Analysis
We used univariate and multivariate analyses to examine possibleassociations between specific clinical features and the presenceof an MSH2 or MLH1 mutation. For univariate analysis, the Pearsonchi-square test was used to identify associations. The followingvariables were examined within each kindred: the mean age atdiagnosis of colorectal cancer, whether or not the Amsterdamcriteria were met, the number of family members with colorectalcancer, the number with endometrial cancer, the presence ofa patient with other cancers related to hereditary nonpolyposiscolorectal cancer, and the presence of a patient with multiplesynchronous or metachronous cancers in a family. All these variableswere also used in the multivariate analysis. Using logisticregression with backward selection, we calculated the logarithmof the odds of having a deleterious mutation as a linear functionof the variables that were significant in the multivariate analysis.To determine the probability of an MSH2 or MLH1 mutation (p),we used the following equation:
log (p/1 + p) = + 1V1 + 2V2 + . . . + kVK,
where V1, V2, and . . . VK are the variables being consideredand , 1, 2, and . . . k are the usual weighted regression valuesestimated from the data. Eleven of the 184 families were excludedfrom these analyses, 6 because of the presence of missense mutationsof unknown clinical significance and 5 because data relativeto the age at diagnosis were not available.
Results
Mutation Analysis
A total of 47 disease-causing mutations were identified in 184families (26 percent). Of these mutations 19 were in MSH2 and28 in MLH1.Table 1, Table 2, Table 3, and Table 4 show thefrequency of mutations in MSH2 and MLH1 according to the numberof patients with colorectal or endometrial cancer in a kindred,the average age at diagnosis of all colorectal cancers, thenumber of family members with multiple cancers, and the typesof extracolonic cancers, respectively. In addition, six missensemutations of unknown clinical significance were found. Threeof these mutations were in MSH2 (AlaThr at codon 305, PheValat codon 447, and AlaThr at codon 834), and three were in MLH1(GlnLys at codon 62, AsnSer at codon 64, and ValMet at codon716). Although these mutations were not found in 100 controlsubjects (including 50 with polyposis), the results of an examinationof the cosegregation of the alterations with the disease phenotypewere inconclusive. Therefore, we decided to exclude these missensemutations from the statistical analyses.
Table 4. Frequency of MSH2 and MLH1 Mutations According to the Types of Extracolonic Cancer within a Family.
Statistical Analysis
In the univariate analysis, several factors were strongly associatedwith the presence of mutations in MSH2 or MLH1: younger ageat diagnosis of colorectal cancer (P<0.001), fulfillmentof the Amsterdam criteria (P<0.001), a higher number of patientswith colorectal cancer in a family (P<0.001), the presenceof endometrial cancer (P<0.001), a higher number of patientswith endometrial cancer in a family (P<0.001), the presenceof small-bowel cancer (P<0.05), the presence of multiplecolorectal cancers in a single member of a family (P<0.001),and the presence of concomitant colorectal and endometrial cancerin a patient (P<0.001) (Table 5). No significant associationwas found between MSH2 or MLH1 mutations and tumors of the stomach,brain, urinary tract, ovary, or hepatobiliary system or withthe presence in a single family member of concomitant colorectalcancer and a tumor related to hereditary nonpolyposis colorectalcancer.
Table 5. Results of Univariate and Multivariate Analyses.
In the multivariate analysis, only a younger age at diagnosisof colorectal cancer within a family (P<0.001), fulfillmentof the Amsterdam criteria (P<0.001), and the presence ofendometrial cancer (P<0.001) were independent risk factors(Table 5). Therefore, we analyzed the probability of detectinga deleterious mutation in MSH2 or MLH1 using logistic regressionas a function of the mean age at diagnosis of colorectal cancerin a family, the presence or absence of endometrial cancer,and fulfillment or nonfulfillment of the Amsterdam criteria.The results, expressed as the log odds ratios and their 95 percentconfidence intervals, are shown in Figure 1A and Figure 1B.
Figure 1. Estimated Probability of a Deleterious MSH2 or MLH1 Mutation as a Function of the Mean Age at Diagnosis of Colorectal Cancer within a Family and Whether the Amsterdam Criteria Were Met in Families with No Members with Endometrial Cancer (Panel A) and in Families with at Least One Member with Endometrial Cancer (Panel B).
Values are the log odds ratios; the thin lines indicate the 95 percent confidence intervals.
Given these results, we calculated the predicted probabilityof detecting MSH2 or MLH1 mutations in individual families (p)with the following equation:
p = eL / (1 + eL),
where e is the exponential function and L is the log odds. Usingthe equation described in the Methods section, we calculatedthe log odds ratios with the following formula:
L = 1.4 + [–0.1]V1 + 1.7 V2 + 2.4 V3,
where V1 is the mean age at diagnosis of colorectal cancer ofall affected members of a family; V2 equals 1 if at least onemember of the family has endometrial cancer and equals 0 otherwise;and V3 equals 1 if the family meets the Amsterdam criteria andequals 0 otherwise (Table 5). For example, the estimated probabilityof detecting a deleterious mutation in a family that met theAmsterdam criteria and in which the mean age at the diagnosisof colorectal cancer was 40 years is 48 percent (95 percentconfidence interval, 31 to 65 percent). If this family alsoincludes a patient with endometrial cancer, then the estimatedprobability is 83 percent (95 percent confidence interval, 68to 92 percent). The optimal use of the equation requires a detailedfamily history and knowledge of all cases of cancer in the family.
To assess which variables are significant predictive factorsin the absence of the Amsterdam criteria, we repeated the multivariateanalysis after excluding these criteria. In this case, a youngerage at the diagnosis of colorectal cancer and a higher numberof patients with colorectal or endometrial cancer are independentrisk factors. The predicted probability of detecting MSH2 orMLH1 mutations in individual families can be calculated withthe other coefficients reported in Table 5.
Discussion
A recent review of 126 different mutations of DNA mismatch-repairgenes from 202 kindreds with hereditary nonpolyposis colorectalcancer12 confirmed that MSH2 and MLH1 are responsible for themajority of cases of hereditary nonpolyposis colorectal cancer.The mutations are scattered along the coding regions of bothgenes, with some clustering in exon 12 of MSH2 and exon 16 ofMLH1. The majority of MSH2 mutations are chain-terminating,whereas both nonsense and missense mutations are found in MLH1.The heterogeneity of the MSH2 and MLH1 mutations implies thatboth genes need to be screened exon by exon for an accuratemolecular diagnosis of hereditary nonpolyposis colorectal cancer.Such an approach is laborious and expensive. Screening costsmight be reduced if clinical factors that predict the outcomeof genetic testing could be identified.
In the present study, we found that an early age of onset ofcolorectal cancer, fulfillment of the Amsterdam criteria, andthe presence in a kindred of a patient with cancer of the endometriumor small bowel, multiple colorectal cancers, or both colorectaland endometrial cancer are strong predictive factors for thepresence of MSH2 or MLH1 mutations. For example, if a kindredthat met the Amsterdam criteria (mutation-detection rate, 45percent) also included one patient with endometrial cancer,then the observed rate of detection increases to 71 percent.And, in a family that met the Amsterdam criteria and had onemember with both colorectal and endometrial cancer, the likelihoodof finding the disease-causing germ-line mutation rises to about90 percent. Multivariate analysis indicated that only a youngerage at diagnosis, fulfillment of the Amsterdam criteria, andthe presence of endometrial cancer are independent predictivevariables. If the Amsterdam criteria are excluded as a variablein the analysis, a younger age at diagnosis of colorectal cancerand a higher number of patients in the kindred with colorectalor endometrial cancer become independent risk factors.
Our logistic model can be used to estimate the probability ofdetecting a germ-line mutation on the basis of the clinicalfeatures of a kindred with familial clustering of colorectalcancer and other tumors related to hereditary nonpolyposis colorectalcancer. The probability of finding an MSH2 or MLH1 mutationcan be deduced from Figure 1A and Figure 1B or calculated withthe use of simple software available at the Web site of theInternational Collaborative Group on Hereditary NonpolyposisColorectal Cancer (http://www.nfdht.nl). If the predicted probabilityis low, one might consider performing microsatellite-instabilityanalysis of the DNA of the colon tumor, which gives an indicationof whether there is a mutation of a mismatch-repair gene. Patientswith positive results can then undergo mutation analysis. Sincethe cost of microsatellite-instability analysis is about halfthat of mutation analysis, this type of analysis will be morecost effective than primary mutation analysis as a first steponly if the expected proportion of patients with tumors withmicrosatellite instability is less than 50 percent. Our preliminarydata, which are based on a limited number of tumor samples,indicate that most colorectal tumors from kindreds with hereditarynonpolyposis colorectal cancer that meet the Amsterdam criteriashow microsatellite instability, whereas the opposite is truefor tumors from families that do not meet the Amsterdam criteria.29Moreover, recent studies20,34 showed that 57 percent of colorectalcancers that were diagnosed in a patient before the age of 35years had microsatellite instability and that a germ-line mutationwas detected in 25 percent of all cases. These observationssuggest that the proportion of patients with tumors with microsatelliteinstability will drop below 50 percent when the probabilityof a mutation is less than 20 percent. In these cases, microsatellite-instabilityanalysis of tumor DNA should be considered as a first diagnosticstep. Figure 2 illustrates our recommended strategy.
Figure 2. Strategy of Molecular Analysis in Families Suspected of Having Hereditary Nonpolyposis Colorectal Cancer.
Aaltonen et al.4 evaluated the frequency of hereditary nonpolyposiscolorectal cancer in Finland by screening colorectal tumorsfrom 509 patients for microsatellite instability and by performingmutation analysis of the tumors with positive results. Tumorsfrom 63 patients showed microsatellite instability, and 10 ofthese patients had a germ-line mutation of MSH2 or MLH1. Nineof the 10 patients had a first-degree relative with colorectalor endometrial cancer, 7 were under 50 years of age, and 4 hadhad colorectal or endometrial cancer previously. The authorsrecommended microsatellite-instability analysis for all patientswith colorectal cancer who meet one or more of the followingcriteria: a family history of colorectal or endometrial cancer,an age at diagnosis of less than 50 years, and a history ofmultiple colorectal or endometrial cancers. We suggest calculatingthe probability of finding a mutation with our model when clinicaland family data are available and selecting patients for eithermicrosatellite-instability analysis or mutation analysis onthe basis of the outcome.
Our series of 184 families included 17 families in which noMSH2 or MLH1 mutations were found. These families met all theAmsterdam criteria except one: a diagnosis of colorectal cancerbefore the age of 50 years. Earlier studies of similar kindredswith a late onset of colorectal cancer revealed phenotypic differencesbetween these families and those with classic hereditary nonpolyposiscolorectal cancer: a predilection for tumors in the left colon,the absence of extracolonic cancers, and a relatively high ratioof adenomas to colorectal cancer.35,36 Tests for microsatelliteinstability in the colorectal tumors of these patients werenegative.36 These findings suggest that such families may representa separate genetic entity. Recently, Laken et al. reported anunusual mutation in the APC gene that is responsible for familialclustering of late-onset colorectal cancer among Ashkenazi Jews.37Moreover, the clinical picture characteristic of attenuatedfamilial adenomatous polyposis38 (later onset and fewer polypsthan in typical familial adenomatous polyposis) could easilybe misinterpreted as that of hereditary nonpolyposis colorectalcancer. Similar atypical APC mutations may also be responsiblefor a proportion of cases in the 17 families in our study.
The Amsterdam criteria were established to help ensure the uniformityof collaborative studies of hereditary nonpolyposis colorectalcancer.21 The high rate at which mutations were detected amongkindreds that meet these criteria and the low percentage ofmutations in families that do not confirmed the value of thesecriteria in selecting patients for screening for mutations ofmismatch-repair genes.29 However, the Amsterdam criteria havebeen criticized as being too stringent and for excluding extracoloniccancers known to be associated with hereditary nonpolyposiscolorectal cancer. Moreover, it is obviously harder for smallfamilies to fulfill the criteria. Our study shows that endometrialcancer and, to a lesser extent, tumors of the small bowel areimportant predictive risk factors. These findings suggest thatthe Amsterdam criteria should be modified to include these extracoloniccancers.
In conclusion, we detected mutations in DNA mismatch-repairgenes in a minority (26 percent) of 184 kindreds with familialclustering of colorectal cancers suggestive of hereditary nonpolyposiscolorectal cancer. Using logistic-regression analysis, we deviseda simple method for calculating the likelihood of detectingMSH2 or MLH1 germ-line mutations. The majority of the kindredswe studied are representative of families that are often referredto clinical geneticists for evaluation of the risk of hereditarycolorectal cancer. An accurate estimate of the probability ofMSH2 or MLH1 mutations in these families will not only allowa cost-effective strategy for molecular analyses but also helpclinicians counsel such families.
Supported in part by the Dutch Cancer Society and Praeventiefondsand by a grant (118571/320) from the Norges Forskningsraad (toDrs. Møller and Heimdal).
Source Information
From the Departments of Human Genetics (J.T.W., P.M.K., H.K., A.M., R.F.), Gastroenterology (H.F.A.V.), and Medical Statistics (A.H.Z.) and the Clinical Genetics Center (C.T.), Leiden University Medical Center, Leiden, the Netherlands; the Foundation for the Detection of Hereditary Tumors, Leiden, the Netherlands (H.F.A.V.); and the Unit of Medical Genetics, Norwegian Radium Hospital, Oslo, Norway (P.M.). Other authors were Fred Menko, M.D., Ph.D. (University Hospital Vrije Universiteit, Amsterdam, the Netherlands), Babs Taal, M.D., Ph.D. (Netherlands Cancer Institute, Amsterdam, the Netherlands), Fokko Nagengast, M.D., Ph.D., and Han Brunner, M.D., Ph.D. (Nijmegen University Hospital, Nijmegen, the Netherlands), Jan Kleibeuker, M.D., Ph.D., and Rolf Sijmons, M.D. (University Hospital Groningen, Groningen, the Netherlands), Gerrit Griffioen, M.D., Ph.D., Annette Bröcker-Vriends, M.D., Ph.D., Egbert Bakker, Ph.D., and Inge van Leeuwen-Cornelisse, B.S. (Leiden University Medical Center, Leiden, the Netherlands), Anne Meijers-Heijboer, M.D., Dick Lindhout, M.D., Ph.D., and Martijn Breuning, M.D., Ph.D. (Erasmus University, Rotterdam, the Netherlands), Jan Post, M.D. (Clinical Genetics Center Utrecht, Utrecht, the Netherlands), Cees Schaap, M.D. (Clinical Genetics Center Maastricht, Maastricht, the Netherlands), Jaran Apold, M.D., Ph.D. (Haukeland University Hospital, Bergen, Norway), Ketil Heimdal, Ph.D. (Norwegian Radium Hospital, Oslo, Norway), Lucio Bertario, M.D., Ph.D. (Istituto Nazionale Tumori, Milan, Italy), Marie Luise Bisgaard, M.D. (Danish Hereditary Nonpolyposis Colorectal Cancer Registry, Hvidovre Hospital, Hvidovre, Denmark), and Petr Goetz, M.D., Ph.D. (Charles University, Prague, Czech Republic).This work is dedicated to the memory of Dr. P. Meera Khan.
Address reprint requests to Dr. Vasen at the Foundation for the Detection of Hereditary Tumors, Rijnsburgerweg 10, Poortgebouw Zuid, 2333 AA Leiden, the Netherlands.
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+
1V1 +
Thr at codon 305, Phe
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