Ten genetic polymorphisms in bladder cancer

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1 Jouirnl of Aledicl Genetics, 1983, 0, Ten genetic polymorphisms in ldder cncer RAYMOND A CARTWRIGHT*, RAFID ADIBt, IAN APPLEYARD+, JOHN G COXON, ROBIN W GLASHAN II, BRIAN RICHARDS, MEL R G ROBINSON**, ERIC SUNDERLANDtt, AND DENISE BARHAM-HALL+ From *the Yorkshire Regionl Cncer Orgnistion, Cookridge Hospitl, Leeds; t Clyton nd Pinderfields Hospitls, Wkefield; +Airedle Generl Hospitl, Steeton, Keighley; Hlifx Generl Hospitl, Hlifx; IlfHuddersfield Royl Infirmry, Huddersfield; York District Generl Hospitl, York; **Pontefrct Generl Hospitl, Southgte, Pontefrct; ttdeprtment of Anthropology, University of Durhm, South Rod, Durhm; nd ++Deprtment of Community Medicine nd Generl Prctice, University of Leeds, Hyde Terrce, Leeds. SUMMARY Dt re presented on group of cses of primry crcinom of the ldder, detiling red cell surfce lood group ntigenic phenotypes, serum hptogloin phenotypes, nd some red cell isoenzyme phenotypes. Account is tken of the stge of the disese t presenttion. The results re compred with corresponding phenotype frequencies in groups of presumed helthy persons originting either in Yorkshire or County Durhm. Differences in reltive incidences were found in the hptogloin, phosphoglucomutse (PGM), nd some other systems. These re oth differences etween ll cses nd controls nd etween prticulr stges t presenttion nd controls. Vrious studies hve een pulished since 1956 which investigte the reltionship etween the ABO nd few other lood group systems nd ldder cncer.'-" Some of these results re summrised y Mournt et l1 nd indicte n excess of the A gene of the ABO lood group system mong ldder cncer cses. Mny of these studies might e criticised, however, on the grounds tht they only exmine few genetic polymorphisms. One study includes esterse D sutypes13 nd other reports exist which report on two other lood group systems.1 This pper reports series of ldder cncer cses from Yorkshire whose ABO, Rhesus, nd MNSs results hve een reported elsewhere,'4 giving informtion on ten further genetic polymorphisms. Method Ptients with trnsitionl cell crcinom of the urothelium (ICD 9th edition 188 nd 33 3) include cses previously descried s 'ppillom' s well s 'crcinom'. They re, with the exception of some ptients from York nd Huddersfield, ll newly dignosed (incident) cses of ldder cncer rising in six Yorkshire hospitls from Octoer 1978 to Octoer The other (prevlent) cses were dignosed some time efore. They hve ll een Received for puliction 15 Septemer 198. involved in n epidemiologicl study of ldder cncer in West Yorkshire, some results of which hve een reported elsewhere.'5 16 The entire group is eing crefully followed nd the disese stge t presenttion is known for the mjority of ptients. The stging is the result of oth clinicl nd histopthologicl exmintion nd follows the TNM system for ldder cncer17 s follows: Tis, pre-invsive flt crcinom or crcinom in situ. TI, freely moile mss which does not invde eyond the lmin propri (this includes T). T, indurtion of the ldder wll nd superficil muscle invsion. T3, indurtion or moile mss plple fter resection nd deep muscle invsion. T4, tumour fixed to pelvis or extending to neighouring structures. Blood ws collected from cses nd sent to Durhm University y post for nlysis, usully rriving within 4 hours of venepuncture. Anlysis of the red cell surfce ntigens took plce using stndrd methods of gglutintion, the exct technique depending on the nture of ech ntiserum. Serum ws seprted nd electrophoresis on strch gels undertken for hptogloin vrition fter the method of Hrris et l.18 Red cell hemolystes were prepred, nd electrophoresis for the following polymorphisms undertken, rodly 11

2 Ten genetic polymorphisnms in ldder cncer following the techniques of the vrious uthors quoted: phosphoglucomutse (PGM),19 cid phosphtse (AP),0 denylte kinse (AK),' esterse D (EsD),13 nd denosine deminse (ADA). The comprison groups re ll from the lortory which tested the cses nd represent control series uilt up from vrious norml popultions in County Durhm. They re detiled y Willims3 nd, in generl, represent dults ged 5- to 65 yers of ge. The results were recorded nd gene frequencies nlysed y gene counting or the use of the homozygous recessive frequency, depending on the polymorphic system. Reltive incidence ws computed using the sic method of Woolf,4 ut lso computing the Mntel- Henszel chi sttistic5 nd confidence limits, fter the method of Miettinen.6 Results Tle 1 indictes the numer nd sources of the ldder cncer cses used in this study. Not ll results re ville for ech system nd few cses were t n indeterminte stge t dignosis, so the numers recorded in the susequent tles re often fewer thn this totl. The results y sex for the lood groups, serum hptogloin, nd red cell isoenzyme types hve een computed, ut s there re no sttisticl differences etween the sexes for ny system ll susequent results hve the sexes pooled. Tle gives the results of the phenotype determintions nd the corresponding gene frequencies compred with those of the vrious corresponding Durhm control series. The gene frequencies re presented together with stndrd error of frequency. Tle 3 gives the reltive incidence etween cse nd control phenotypes long with the confidence limits nd proility levels. The proility column indictes tht there is n excess of the B cid phosphtse phenotype when contrsted with the A nd BA types nd tht there re more 1 nd phenotypes in the phosphoglucomutse nd denosine deminse systems. These ltter two TABLE 1 Yorkshire ldder cncer: sources of cses. Helth districts Airedle 8 Clderdle 37 Huddersfield 143 Pontefrct 6 Wkefield 34 York No of cses TABLE Bldder cncer cses nd controls: lood group phenotypes nd gene frequencies. Kidd Duffy Kell Penney KK Kk kk K k Hptogloin Acid phosphtse A BA B BC CA All cses * * c Phosphoglucomutse * 330 Adenylte kinse I Esterse D Adenosine deminse Durhm controls No % No % * ±0 * ±0* ±0* ±0* ±0*07 59 * ±O ± * ± * ±0* * * * * *9570 0* * * ± * ±0* ± * ±0* ±0* *7 ± ± ± *0 1.0 ± ±0-0168

3 114 R A Crtwright et l TABLE 3 Reltive incidence of ldder cncer phenotypes when compred with control phenotypes. Phenotype system Comprison Reltive 95% Chi p incidence confidence (Mntellimit Henzel) Kidd / Duffy / *65-1* Kell KK+Kk/kk Penney / Hptogloin 11/ * Acid phosphtse A+BA/B *48-0*99-1*98 0*04 Phosphoglucomutse 11/ * Adenylte kinse 11/ * Esterse D 11/ Adenosine deminse 11/ TABLE 4 Blood group hptogloin nd isoenzyme phenotypes nd stge t presenttion (sexes pooled). Ti T T3 T4 Crcinom No% No% No% No% in situ No % Duffy Kell KK Kk kk Hptogloin Acid phosphtse A BA *3 B BC CA Phosphoglucomutse Adenylte kinse Esterse D Adenosine deminse results re quite wek, however, nd the 95 % confidence limits indicte tht it is possile tht no true reltionship exists given the smple sizes involved. Tle 4 gives the phenotypes of the lood group systems, hptogloin, nd isoenzyme types y stge t presenttion. The Kidd nd Penney lood groups re omitted owing to smll smple sizes. Tle 5 summrises the results from the previous tle in the form of reltive incidences, using, in ech cse, the Durhm control groups s comprison. The rckets indicte results not significnt t the 5% level of proility. The T4 stge ws comined with the T3 ecuse of smll numers. The mjority of these results re not sttisticlly different from unity. Crcinom in situ ws not included ecuse of the smll numers. The cid phosphtse nd denosine deminse systems, which showed significntly lowered reltive incidence in tle 3, give similr results t ll the stges of presenttion. The low reltive incidence of phosphoglucomutse, however, is the result of deficit of the 1-1 phenotype, ut this is lrgely confined to stge 1 nd disese. No prticulr trends re discernile in the Duffy nd Kell lood group systems. A non-significnt trend exists in the denylte kinse system with progressive deficit of the 1-1 phenotype with incresing stge. There re two other unexpected results; the hptogloin phenotypes hve gross deficit of the 1-1 phenotypes in stge disese, while there is sttisticlly significnt excess of the 1-1 esterse D phenotype in lter stge disese. TABLE 5 Reltive incidence ofphenotypes y stge t presenttion of ldder cncer. Phenotype Comprison Stge nd reltive incidence Ti T T3/T4 Duffy Fy/+ (0.86)* (1-) (1-3) Kell KK+Kk/kk (1.5) (0-64) (1.91) Hptogloin 11/1+ (11) 0.3 (146) Acid phosphtse A+BA/B (0*65) (0*75) (0*71) Phosphoglucomutse 11/ (0*50) (106) Adenylte kinse 11/1+ (1-46) (0-84) (0-65) Esterse D 11/1+ (16) (0.91) 4.43 Adenosine deminse 11/1+ (0-45) (0-38) (0-44) *Not significnt t 95% in rckets.

4 Ten genetic polymorphisms in ldder cncer Discussion Mny of the results presented here hve not previously een reported nd will need confirmtion in future studies. The discussion is concerned with the reltionship etween these genetic lood fctors nd etiology. The significnce of stge t dignosis in reltion to phenotypic ises is the second mjor theme. There is generl point, however, to discuss efore detiled exmintion of the results, nmely, the ppropriteness of the control group. The ges of the control group re different from those of the cses, eing younger y n verge of 10 yers. Sudivisions y ge strt within cses nd controls, however, reveled no sttisticl differences y ge nd it is thought unlikely tht ny significnt is rises from this source. The controls originte in County Durhm rther thn the neighouring re to the south, Yorkshire. There re two fctors in the decision to use these prticulr controls. Control dt, nlysed t Durhm, re ville only from 60 hospitl ptients in Yorkshire. Their results hve not een included in this pper, ut they re of similr ge to the control sujects from Durhm nd in no system do the results from this smll numer conflict with the Durhm results. Secondly, no lrger series for these polymorphisms exists from Yorkshire from ny other source. The ises in the reltive incidence of AP, PGM, nd ADA types re ll new oservtions which, if confirmed, could e most useful in defining high risk group susceptile to ldder cncer in the popultion. They must e considered in reltion to our previous report on the is to the ABO lood group A gene nd the S gene of the MNSs system.'4 For exmple, there will e reltively few people in the generl popultion who hve the A phenotype of the ABO system, the SS phenotype of the MNSs system, nd the B phenotype of the AP system, perhps out 1 5% if the systems re distriuted independently, while cse group would hve these three gene comintions three times more frequently. The nturl history of different cses of ldder cncer, despite rodly similr histopthologicl ppernces, is highly unpredictle nd rnges from well defined fronded tumour which does not invde or return fter tretment to most ggressive disese which invdes the ldder wll nd spreds rpidly, cusing deth within months of dignosis. There re vrious wys in which nturl histories of ldder cncer my e exmined nd recorded; these include sujective ssessment of 'degree of ggressiveness' of the tumour sed on hospitl records of cystoscopies. This ws ttempted in n erly pper" ut is poorly reproducile. Alterntively, differentil length of survivl might e mesured, ut in the cse of the present study severl more yers of oservtion would e needed to egin to exmine the prolem in this fshion. A third pproch, which is lso useful in clinicl predictive role, is to exmine the depth of invsiveness of the tumour t dignosis. One dvntge of this stging procedure is tht it is n interntionlly greed clssifiction.'7 The crcinom in situ lesions represent specil cse with respect to this clssifiction, however, in tht they re potentilly highly invsive tumours7 8 which re rre ut, where recognised, re regrded s lesions needing ggressive tretment in n ttempt to stop deep invsion. As mesure of nturl history, the T system is imperfect ut hs enough dvntges to e considered t length. The Ti nd T types re mixture of two types: ggressive lesions nd the mjority of slow growing lesions, which will rrely cuse deth. Coupled with this hypothesis re the oservtions tht cigrette smoking is only relted s risk fctor to TI nd T type tumours.9 However, nother genetic fctor, the phenotypic vrints of the liver ound enzyme N-cetyltrnsferse, hs n excess of the slower types ssocited with T3, T4, nd crcinom in situ.30 These fcts rther suggest tht despite its imperfection the T types re useful in sudividing ldder cncer into two generl types: the rodly invsive group nd the rodly non-invsive. Returning to the new results presented here, the fct tht some gene excesses in PGM, hptogloin, nd esterse re confined to either the TI nd T or the T3/T4 types is further confirmtion tht epidemiologicl differences proly exist etween different T types of ldder cncer. With respect to the results, it should e rememered tht multiple comprisons re inherently dngerous, s some results might e expected to e significnt just y chnce. A more stringent level of significnce of 1 % will still result in the sttisticlly significnt excess of the 1 gene in ESD nd the PGM nd hptogloin results found in tle 5. The significnce of these results is not redily pprent lthough it is cler tht the cell surfce ntigenic structure of cells is relted to the invsiveness or otherwise of ldder tumours3' with respect to the ABO lood groups, nd this might lso e the cse with other red cell surfce mrkers. In ddition, person's enzymic structure is undoutedly importnt in ldder crcinogenesis with respect to N-cetyltrnsferse30 nd this could lso e the cse with regrd to other enzyme systems,

5 116 the enzymes in the red lood cell eing reflection of their presence in other tissues. These oservtions nd those on the ABO nd MNSs systems14 form the sis of generl pproch to the identifiction of high risk sugroups of the generl popultion. Other studies hve prlleled these to find risk occuptions nd other environmentl fctors It is the im of this group of studies in genetics-epidemiology to link ll spects of tumour nturl history nd environmentl exposure in future work with view to disese control. This study ws finnced y n wrd from the Specil Trustees of St Jmes's Hospitl nd the Deprtment of Anthropology, University of Durhm. We would like to thnk Miss L Biley nd Miss T Horsfll for lortory ssistnce nd Miss Fion Lndells for typing the mnuscript. In ddition the nursing stff t ll the centres concerned were invlule in the conduct of this study; these include Sisters Gretorex nd Nuttll. References Wlther WW, Reurn C, Cse J. Blood groups in reltion to mlignnt diseses. Lncet 1956;ii:970-. Speiser P. Krnkheiten und Blutgruppen. Kresrzt 1958; 13: Moilio G, Torchin B. Considerzioni sttistiche fr gli emogruppi del sistem 'ABO' e le principli mlttie urologiche. Riv Ant Pt Oncol 1960;18: Visconti A, Tolio A, Cv L. Correlzione fr neoplsie e gruppi snguingni del sistem ABO. Tumori 1961 ;47: Dick W, Schneider W, Brockmuller K. Uer ds gegenstzlicke verhlten der lutgruppen Al nd A. Dtsch Med Wochenschr 196 ;87 : Munioz-Brrt C. Blood group nd disese. 8th Cong Int Soc Blood Trnsf Tokyo Biliogrphi Hemtologic 196 ;13 : Tygi SP, Prdhn S, Agrwl SS. Blood groups in mlignnt diseses. J Indin Med Assoc 1965 ;45 : Sdek AM, Guemeh N, Fhim MAS. The reltionship etween ABO lood group nd gstrointestinl diseses. Alexndri Med 1965;11: Ghooi AM, Kmlpuri SK, Jin PK, Tndon PL. Distriution of lood groups in cncer. Indin J Cncer 1970;7: Pterson PJ. ABH secretor sttus in ptients with ldder tumours, Urol Res 1976;4: Herring DW, Crtwright RA, Willims DRR. Genetic ssocition of trnsitionl cell crcinom. Br J Urol 1979 ;51 : Mournt AE, Kopec AC, Domniewsk-Soczk K. Blood group nd diseses. Oxford: Oxford University Press, R A Crtwright el l 13 Willims DRR, Crtwright RA. The esterse D polymorphism in ptients with dietes or crcinom of the ldder nd mtched smple of non-donor controls. Ann Hum Biol 1978;5: Crtwright RA, Adi R, Appleyrd 1, et l. ABO, MNSs nd Rhesus lood groups in ldder cncer. Br J Urol (in press). 15 Glshn RW, Crtwright RA. Occuptionl ldder cncer nd cigrette smoking in West Yorkshire. Br J Urol 1981 ;53: Crtwright RA, Adi RA, Glshn RW, Gry BK. The epidemiology of ldder cncer in West Yorkshire. A preliminry report on non-occuptionl etiologies. Crcinogenesis 1981 ; : UICC. TNM clssifiction of mlignnt tumours. 3rd ed. Genev: WHO, Hrris H, Roson EB, Sinisclco M. Genetics of plsm protein vrients. In: Wolstenholm GEW, O'Connor C, eds. CIBA symposium: iochemistry of humn genetics. London: Churchill, 1959: Hopkinson DA, Hrris H. Rre phosphoglucomutse phenotypes. Ann Hum Genet 1966;30: Hopkinson DA, Hrris H. Red cell cid phosphtse, phosphoglucomutse nd denylte kinse. In: Biochemicl methods in red cell genetics. New York: Acdemic Press, 1969: Rpley S, Roson EB, Hrris H, Smith MS. Dt on the incidence segregtion nd linkge reltions of the denylte kinse (AK) polymorphism. Ann Hum Genet 1967 ;31 :37-4. Hopkinson DA, Cook PJL, Hrris H. Further dt on the denosine deminse (ADA) polymorphism nd report of new phenotype. Ann Hum Genet 1969;3: Willims DRR. Genetic nd epidemiologicl spects of dietes mellitus. PhD thesis, Durhm University, Woolf B. On estimting the reltion etween lood group nd disese. Ann Hum Genet 1954;19: Mntel N, Henszel W. Sttisticl spects of the nlysis of dt from retrospective studies of diseses. J Ntl Cncer Inst 1959;: Miettinen OS. Estimility nd estimtion in csereferent studies. Am J Epidemiol 1976;103 : Crtwright RA, Glshn RW, Gry B. Survivl of trnsitionl cell crcinom in Yorkshire centres. Br J Urol 1980 ;5: Crtwright RA, Brhm-Hll D. Unpulished survivl dt. 9 Crtwright RA, Brhm-Hll D. Cigrette smoking nd ldder cncer: cse-control study from West Yorkshire. Sumitted for puliction. 30 Crtwright RA, Glshn RW, Rogers HJ, et l. The role of N-cetyltrnsferse phenotypes in ldder crcinogenesis. Lncet 198;ii: Bishop MC. Blood group ntigens nd ldder cncer. Br Med J 198;84: Requests for reprints to Dr R A Crtwright, Yorkshire Regionl Cncer Orgnistion, Cookridge Hospitl, Leeds LS16 6QB.