Chromosome sporadic colorectal carcinoma: patterns

6J Clin Pathol 1996;49:386-390

Chromosome 1 1 q in sporadic colorectalcarcinoma: patterns of allele loss and theirsignificance for tumorigenesis

I P M Tomlinson, W F Bodmer

AbstractAims-To analyse the frequency of loss ofheterozygosity (allele loss, LOH) in a largesample of colorectal carcinomas usinghighly informative markers along chro-mosome llq.Methods-One hundred paired samples ofcolorectal cancer and normal tissue weregenotyped at six microsatellite markers onchromosome llq (cen-DllS1313-DllS901-DRD2/NCAM-D11S29-D11S968-tel). Thehigh levels of heterozygosity at thesemarkers allow allele loss to be determinedin about 80% of cases at any one locus.The frequency ofreplication errors (RERs,microsatellite instability) has also been de-termined.Results-LOH was found at frequencies of25% and 29% at the distal DIlS968 (llqter)and DllS29 (llq23.3) loci, slightly abovethe accepted baseline of 0-20%. Allele lossat NCAM, DRD2, DllS901, and D11S1313was not raised above baseline levels. Theprobable genetic mechanism of alleleloss-chromosomal non-disjunction, mi-totic recombination, deletion, or gene con-version-seemed to vary between tumoursand no consistent mechanism ofmutationwas found. Microsatellite instability wasfound in 23 (23%) tumours. No associ-ations were found between LOH and clin-ical data (patient sex, age at presentation,tumour site, and Dukes' stage).Conclusions-Although gene(s) on llqmay have a role in the development of aminority of colorectal carcinomas, thisstudyprovides evidence against the generalimportance of allele loss on chromosomeIIqin thepathogenesis ofcolorectal cancer.The results also have implications for theimportance of1lq in other cancers: itseemsless likely that a single tumour supressorgene at this location promotes the growthofalltypes oftumourwhenlost. Rather, oneor more genes with tissue specific effectsmay be involved.(JT Clin Pathol 1996;49:386-390)

Keywords: colorectal cancer, loss of heterozygosity,chromosome llq.

Table 1 The loci studied

Name Map position Repeat unit Size of alleles (bp) Heterozygosity

DllS1313 ilcen CA 184-204 0-85D11S901 llq CA 160-176 0-82DRD2 1 q22-q23 CA 80-86 0-62NCAM 11q22-q23 CA 101-119 0-79D1IS29 1lq23-3 CA 143-163 0-77DIIS968 llqter CA 137-155 0-81

There are well defined chromosomal regionsand genetic loci that undergo frequent loss ofheterozygosity (LOH, allele loss) in colorectalcancer. The DCC locus on chromosome 18q,'the APC locus (5q),2 the RB1 locus (13q),3 theTP53 locus (17p),4 and chromosome 8p5 arethe best known examples. Frequent LOH has,however, been reported at other loci in sporadiccolorectal cancer, suggesting that colorectaltumorigenesis is more complex than the basicmodel of Fearon and Vogelstein.i One regionwhere frequent LOH has been suggested usingcytogenetic methods is chromosome 1 q.7Chromosome 11 q, particularly distal to band

q22, is an interesting genetic region in manycancers. Many haematological malignanciesshow chromosomal rearrangements at thissite.'0 In addition, allele loss occurs at mod-erate-to-high frequencies distal to 11 q22 in

11-14 1516breast cancers, criacncers, ovariantumours,17 and melanomas.'8 It is not knownwhether the same loci are involved in all thesetumours, but the possibility exists that there isa locus between llq22-qter that provides aselective advantage when "lost" in many typesof tumour.

Therefore, there are two reasons for studyingLOH on the long arm of chromosome 11 incolorectal cancer: first, to determine whetherthis region really is important in colorectalcancer using a large sample of tumours andseveral marker loci; and second, to providedata to determine whether allele loss on 1 lq isa general phenomenon in cancers, or specificto certain tumour types.LOH has been searched for in 100 cases of

sporadic colorectal carcinoma using six micro-satellite markers on chromosome 11 q (table 1,fig 1). These were chosen to extend from thecentromere to the telomere (cen-D 11 S 1313-D 1 1 S90 1-DRD2/NCAM-D 1 1 S29-D 1 1 S968-tel). The DRD2 (dopamine receptor D2) andNCAM (neural cell adhesion molecule) lociwere both chosen despite their close map po-sitions, in order to provide comparisons withprevious studies, in order to increase thenumber of informative (heterozygous) cases at11 q22 and to test NCAM directly, as it is acandidate locus in colorectal tumorigenesis.'9The allele loss data can be used to suggesthow often LOH occurs by chromosomal non-disjunction and by other mechanisms (mitoticrecombination, deletion and gene conversion)in the colorectal tumours studied. Using thesesix dinucleotide repeat loci, it was also possibleto determine the frequency of replicationerrors (RERs, microsatellite instability) in thetumours studied. The following clinical data

Cancer GeneticsLaboratory, ImperialCancer ResearchFund, 44, Lincoln'sInn Fields, LondonWC2A 3PXI P M TomlinsonW F Bodmer

Correspondence to:Dr I P M Tomlinson.Accepted for publication16 January 1996

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Loss of heterozygosity on llq in colorectal cancer

Table 2 Frequency of allele loss at each of the loci studied

Locus No. of No. of casesinformative cases with LOH (%)

D11S1313 70 11 (16%)DIIS901 82 11 (13%)DRD2 61 11 (18%)NCAM 70 10 (14%)D1S29 85 25 (29%)D11S968 59 15 (25%)

were also known: patient sex, age at pre-sentation, tumour site, and Dukes' stage. Usingstandard statistical techniques, associationswere searched for between the clinical data andallele loss.

D11S901 llq

20cM

DRD2 1 1q22

NCAM

13cM

D11S29 11 q23.3

50cM

D1 1S968 1 1 q25-qter

Figure I Approximategenetic map of the locistudied. The order ofDRD2 and NCAM is stilluncertain.

MethodsPaired samples of genomic DNA from per-ipheral blood or normal tissue and from car-cinomas were extracted using standardmethods. All carcinomas consisted entirely oftumour tissue at the macroscopic level, al-though tumours were not microdisssected.PCR reactions were performed at each micro-satellite ((CA)n repeat) locus on each pairof tumour/normal DNAs, using the followingconditions: 50-250 ng DNA was used as tem-plate in a final volume of 50 pil with reactionconcentrations of 1 x standard PCR buffer(Promega, Madison, Wisconsin, USA),1-5 mM Mg2", 0-5mM dNTPs, and 0-4mMof each specific oligonucleotide primer. Oneunit Taq polymerase was added per reaction.For D1 1S968, D 1lS901 and D1 S1313, am-plification was carried out using a protocol ofone cycle of 94°C (one minute), 35 cycles of94°C (one minute)/55°C (one minute), andone cycle of 72°C (five minutes).20 ForDl S29, amplification was carried out using aprotocol of one cycle of 94°C (one minute),30 cycles of 94°C (one minute)/55°C (oneminute)/72°C (one minute), and one cycle of720C (10 minutes).21 For NCAM, am-plification was carried out using a protocol ofone cycle of 94°C (one minute), 30 cycles of940C (one minute)/500C (one minute)/720C(one minute), and one cycle of 72°C (fiveminutes).22 For DRD2, amplification was car-ried out using a protocol of one cycle of 94°C(one minute), 30 cycles 94°C (30 seconds)/58°C (30 seconds)/74°C (30 seconds), and onecycle of 74°C (five minutes).23 PCR productswere heated to 900C for five minutes and elec-trophoresed on a 6% acrylamide sequencinggel (Sequagel) under denaturing conditions fortwo to four hours. DNA was transferred byblotting onto Hybond N + membranes (Amer-sham, Little Chalfont, UK) for four to16 hours. PCR products were detected bythe enhanced chemiluminescence technique(Amersham), using a randomly elongated oli-gonucleotide primer as a specific probe for eachlocus. Products were visualised by exposingmembranes to Hyperfilm (Amersham) for oneminute to one hour. In informative cases, alleleloss was scored by eye. In this way, only un-equivocal cases were scored as loss. Extra bandsin tumour samples that differed by multiples of2 base pairs (bp) from their normal counterpart

were scored as RERs (replication errors). Lociat which RERs were found were removed fromthe LOH analysis and classed as not in-formative. Other loci from the same tumourwere included in the LOH analysis. Clinicaldata were determined from patients' notes,histopathology reports and laboratory records.x2 and t tests were used to determine the stat-istical significance of any associations betweenthe molecular data and clinical variables.

ResultsLOH was found at frequencies of25% and 29%at the distal D 1 1S968 (1 1 qter) and D11S29(11q23-3) loci, respectively (table 2). This isonly a slightly elevated frequency of LOH overthe generally accepted baseline (0-20%).Lower frequencies of allele loss were observedat NCAM, DRD2, D1lS901, and D1 S1313(table 2). Representative cases of LOH areshown in fig 2.The patterns of LOH at each of the six loci

are shown in fig 3 for all cases which had lostan allele at one of the loci studied. Of the 100cases studied, 36 showed allele loss at one ormore loci. The genetic mechanism of alleleloss-chromosomal non-disjunction, mitoticrecombination, deletion, or gene conversion-seems to vary between tumours. Figure 3 giveswhat we suggest to be the most probable mech-anism underlying the observed mutations. Sixcases showed probable chromosomal non-dis-junction, because the pattern ofLOH observedwas consistent with loss of the entire chro-mosome 11. Seventeen tumours showed ter-minal deletion or mitotic recombination(extending a variable distance from the telo-mere along the long arm of the chromosome)and two cases were constitutional homozygotesat Dl S1313 and hence consistent with bothnon-disjunction and terminal deletion or mi-totic recombination. The remaining 11 casesshowed LOH at proximal loci with retentionof distal markers (interstitial allele loss). In twoof these 11 cases two separate regions of alleleloss could be identified on the chromosomearm.

Microsatellite instability was found in 23(23%) tumours. Examples are shown in fig 2.Of these 23 cases, 16 showed novel alleles atonly one of the six loci, three showed instabilityat two loci and four were unstable at three loci.These figures are consistent with other studiesin which 7-30% of sporadic colorectal cancersshow microsatellite instability.2128 Cases withmicrosatellite instability tended to have a lowfrequency of allele loss (details not shown).

Patients presented at a mean (SD) age of65-8 (11L3) years. The female:male ratio was1 -2: 1. Ofthe cancers, 80% were left-sided, 10%were right-sided and 10% were of unknownsite in the colon. Twelve per cent of patientspresented as Dukes' stage A, 45% were stageB and 43% were stage C. None of the clinicaldata showed a significant association (X' and ttests, one-tailed, p>005) with LOH at any ofthe loci studied, or with the imputed mech-anism of LOH (non-disjunction or mutationsaffecting only part of the chromosome arm).

llcenDl 1S1313

30cM

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Figure 2 Examples of allele loss and microsatellite instability. Tumour(T)Inormal(N) pairs are shown. Arrows denote allele loss or, in cases 227 and175446, extra allelic bands indicative of microsatellite instability. Cases 564 and 668 show probable non-disjunction in the tumour and case 603 is a

case ofprobable terminal deletion or mitotic recombination distal to DRD2. Case 890 shows two regions of interstitial LOH and case 58 066 shows a

probable single region of interstitial LOH (although the patient is non-informative at DRD2). Case 227 shows extra bands indicative of microsatelliteinstability at three of the six loci, with classic allelic ladders differing by 2 bp at NCAM and D11S968 and a somewhat atypical pattern at D11S29.Case 175446 shows the classic allelic ladder of microsatellite instability at just one of the six loci (D11S1313).

For the sake of brevity, details of the statisticalanalyses are not shown. Given a study ofLOHat six loci and two possible mechanisms under-lying that LOH, together with four clinicalvariables (patient sex, age at presentation,tumour site (left- or right-sided) and Dukes'stage), it would actually be expected that one

or two associations would be significant at the5% level of probability by chance alone.

DiscussionThis study provides evidence against the hy-pothesised importance of allele loss on chro-mosome 11 q in the pathogenesis of colorectalcancers in general. LOH at theNCAM, DRD2,D11S901, and D1 1S1313 loci occurred at fre-quencies within the generally accepted back-ground range of 0-20%. LOH at the Dl1S29and Dll S968 loci was detected at frequenciesslightly above background and it remains pos-sible that a gene near these loci is important ina minority of colorectal tumours. These data donot, however, support the findings ofKeldysh etal9 that allele loss on chromosome 11 occurs

in over half of all colorectal carcinomas. Incomparison with the data of Gustafson et al29

published in the interim and which analysedonly the DRD2 locus, this study found con-sistent results, but a lower frequency of LOH(table 3).

It is possible that differences in experimentalmethod can account for the differences betweenthe results of Keldysh et al9 and the resultspresented here. Keldysh et al initially studiedtumours by cytogenetic means, which may beprone to different types and frequencies of errorthan studies at the DNA level. Keldysh et althen used restriction fragment length poly-morphism (RFLP) analysis to detect LOH,rather than the simple sequence length poly-morphism (SSLP) analysis with microsatellitemarkers used here. It is possible that er-roneously low frequencies of LOH may havebeen detected in this study owing to con-

Table 3 Comparison ofLOH at the DRD2 locus in thestudies of Gustafson et al29 and the present study

Study LOH No LOH Total

Gustafson et al 23 45 68The present study 13 48 61Total 36 93 129

Association X,=2- 5 (NS).

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Loss of heterozygosity on llq in colorectal cancer

D1 1S968 D1l1S29 NCAM DRD2 DllXS901 D1 lS131-'

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Allele retainedAllele lostNot informative

Figure 3 The patterns of allele loss on chromosome llq. The annotation denosuggested cause of the observed data. NDJ =chromosomal non-disjunction; TEterminal deletion or mitotic recombination; and INT= interstitial allele loss catconversion, deletion or mitotic recombination. Clearly, the hypothesised mechanLOH are not the only ones that can explain the data. Those presented are gensimplest mutations that can produce the observed patterns of allele loss in the stnumber of steps.

tamination of tumours with normal tthe scoring of mutations by eye. Hovconsistency of the results reported I

those of Gustafson et at9 (who also u!analysis) suggests that such errors vWe suggest that the most important cbetween this study and that of Keldmay have been between the use of S'ysis and RFLP analysis, respectively.method uses markers that sometirlevels of informativeness approachingtypical of microsatellites, but frequemuch lower heterozygosity. At Dllexample, the RFLP based markererozygosity of about 030, but td

marker's heterozygosity is about 0 75. Recently,|TER dense genetic maps of microsatellite markersNDJ have been made available by organisations such

as Genethon.20 This has allowed allele lossNDJ mapping to become much more efficient, bothNT in utilising information from most cancersINT sampled and in delimiting the extent of LOH.TESR In general, SSLP analysis produces a lowerINT frequency of LOH than comparable RFLPINT studies (for example, Tomlinson et all4 com-NDJ pared with Hampton et all2). This difference

probably results from the larger effective sampleNDJ size caused by the use of highly polymorphicTER SSLP markers and publication bias towardsTER positive results. We believe this to be the likely

NDJ TER cause of differences between our results andNDJ those of Keldysh et al9: suggestions-for ex-TER ample, that PCRbased techniques may obscureNT allele loss are unlikely to be true, as amp-

| NDJ lification techniques such as PCR should ac-

NED tually exaggerate differences in allele dosage.TEE No consistent mechanism of allele loss canINT account for the observed data (fig 3), henceINT the finding that 36% of all tumours had lostTER an allele at one of the six loci, whereas theTER maximum frequency of allele loss at an in-INT dividual locus was 29%. This is similar toTER LOH on 11q in melanoma (which occurs at asomewhat higher frequency),30 but contrasts

NDJ TEE with allele loss on 1 q in breast cancer,3' whichINT can mostly be accounted for either by chro-TER mosomal non-disjunction or by mutations in-TER volving the whole ofthe chromosome arm distalTER to band q22. The frequency of any mutationTER in a set of tumours reflects the mutation rateNT and its selective advantage. As there is no reasonNT

to suppose that one type ofLOH causing muta-tion occurs more frequently in breast cancers

TER than in colorectal cancer, the results from breastTER cancer suggest a particular selective advantageTER to the specific types of 1 1q mutation that occurTER in those tumours. In the colorectal cancers, by

contrast, the existence of varied types of alleleloss suggests no such selective advantage andprovides evidence against an important rolefor 1 q in colorectal tumorigenesis. In breastcancers'4 and melanoma,3233 moreover, there

tes the are data that suggest that 11q alleles are lostYR= relatively late in tumour development. Theused by gene absence of associations in this study betweennisms of allele loss at any of the loci studied and theierally themallest clinical data, in particular Dukes' stage, also

provides evidence against an influential tumoursuppressor gene on 1lq in colorectal cancers.

In conclusion, there is little evidence thattissue and there are loci on chromosome llq that arewever, the important in the pathogenesis of colorectal can-here with cer. It remains possible, however, that alleleLsed SSLP loss towards the telomere of the long arm in-vere rare. activates a tumour suppressor gene in a mi-difference nority of tumours. If this is actually the case,lysh et at adhesion loci such as NCAM and genes in-SLP anal- volved in maintaining genomic stability (suchThe latter as ataxia telangiectasia) are candidate targetsmes have for 11q LOH. As well as some significance forgthe 0-80 colorectal neoplasms, however, these resultsntly have have implications for the importance of chro-IS29-for mosome llq in other cancers. If colorectalhas het- cancers do not frequently lose alleles on llq,he SSLP it becomes less probable that a single tumour

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Tomlinsonz, Bodmer

supressor gene at this location promotes thegrowth of all tumours when "lost". Rather,different loci may be implicated in the growthof cancers of different sites.

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Chromosome sporadic colorectal carcinoma: patterns