Human leukocyte antigens and cancer: is it in our genes?

J. Pathol. 188: 231–236 (1999)

REVIEW ARTICLE

HUMAN LEUKOCYTE ANTIGENS AND CANCER:IS IT IN OUR GENES?

. . 1* . . 2

1Department of Histopathology, Southampton General Hospital, Southampton, U.K.2Histocompatibility and Immunogenetics Laboratory, Southampton General Hospital, Southampton, U.K.

SUMMARY

Human leukocyte antigens (HLAs) are widely expressed cell surface molecules which present antigenic peptides to T-lymphocytes,thus modulating the immune response. The efficiency of peptide presentation by HLAs is dependent on the extreme polymorphism in theHLA-encoding loci within the major histocompatibility complex (MHC). HLA polymorphism is known to alter disease susceptibility andprogression in a range of predominantly inflammatory conditions, many of which are T-lymphocyte-mediated. More recently, theimportance of alterations in HLA expression and polymorphisms within HLA-encoding loci has emerged in the development ofmalignancy. This review concentrates on the role of HLA polymorphism in malignant disease, with discussion of the major cancers inwhich HLA associations have become clear, as well as the potential mechanisms by which HLA polymorphisms may act as importantfactors, or cofactors, in the pathogenesis of malignant disease. In addition, the role of certain non-HLA genes within the MHC in thepathogenesis of malignancy is also considered briefly. Copyright ? 1999 John Wiley & Sons, Ltd.

KEY WORDS—human leukocyte antigen; genotyping; polymerase chain reaction; major histocompatibility complex; cancer

*Correspondence to: Dr Adrian C. Bateman, Department of His-topathology, Level E, South Block, Southampton General Hospital,Tremona Road, Southampton SO16 6YD, U.K.

CCC 0022–3417/99/080231–06$17.50Copyright ? 1999 John Wiley & Sons, Ltd.

Table I—HLA-associated non-neoplastic diseases (reviewedby Thorsby3)

DiseaseAssociated HLA

locus/alleleRelative

risk*

Haemochromatosis A3 6Ankylosing spondylitis B27 >150Reiter’s disease B27 >40Anterior uveitis B27 >20Narcolepsy DQ6 >38Graves’ disease DR3 4Myasthenia gravis DR3 2Addison’s disease DR3 5Rheumatoid arthritis DR4 9Juvenile rheumatoid arthritis DR8 8Coeliac disease† DQ2 250Multiple sclerosis DR2, DQ6 12Type I diabetes mellitus‡ DQ8 14

DQ6 0·02

*The relative risk is a measure of how much more frequently thedisease in question occurs in individuals possessing the particular HLAlocus allele, compared with those not carrying the allele.

†The most common HLA association with coeliac disease is with the-DQA1*0501, -DQB1*0201 combination of alleles.

‡Complex HLA associations exist with type I diabetes mellitus.

INTRODUCTION

Nineteen ninety-seven marked the thirtieth anniver-sary of the discovery of the first association between aspecific disease (Hodgkin’s disease1) and genetic vari-ation within the human leukocyte antigen (HLA) sys-tem, the most polymorphic gene complex found inhumans. Since then, a growing number of diseases havebeen shown to occur with an increased incidence inindividuals who possess particular HLA gene polymor-phisms. Some, but not all of these relationships are verystrong, such as that between coeliac disease and theDQA1*0501, DQB1*0201 alleles.2 The majority of theseHLA–disease associations involve non-neoplastic condi-tions, including several autoimmune and allergic dis-eases.3,4 Principal examples are given in Table I. This isunsurprising, since HLA molecules are intimatelyinvolved in regulation of the immune response, withHLA class I A, B, and C molecules expressed by almostall nucleated cells and presenting endogenous antigen toCD8+ (cytotoxic) T cells and HLA class II DR, DQ,and DP molecules expressed by antigen-presenting cellsand presenting exogenous antigen to CD4+ (helper) Tcells.5 However, the importance of the HLA system inregulating susceptibility to and tumour development in agrowing number of neoplastic conditions is becomingincreasingly clear.

HLA class I A, B or C and HLA class II DR, DP andDQ antigens were originally defined using serological orcellular methods relying on detection of the cell surface-

expressed molecules (‘phenotyping’). More recently,restriction fragment length polymorphism (RFLP) andpolymerase chain reaction (PCR)-based techniques haveallowed examination of the HLA genes, within themajor histocompatibility complex (MHC) on chromo-some 6, which encode these molecules (‘genotyping’).HLA class I molecules comprise one heavy chain,

Received 22 December 1998Accepted 12 January 1999

232 A. C. BATEMAN AND W. M. HOWELL

encoded by the HLA-A, B, and C loci, bound to thenon-polymorphic â2-microglobulin molecule. HLA classII molecules are heterodimers comprising two polymor-phic molecules termed the á- and â-chains, each encodedby different HLA loci. For example, an individualHLA class II DR molecule would be encoded by theHLA-DRA locus (á-chain) together with one of theHLA-DRB1, 3, 4 or 5 loci (â-chain). DNA-basedmethods are more accurate and allow higher definitionHLA typing. The individual HLA locus alleles and allelesubgroups are described using a four-digit code (WHOclassification). For example, the â-chain of the sero-logically defined HLA-DR1 molecule may be encodedby one of four HLA-DRB1 locus alleles which aredesignated as HLA-DRB1*0101, *0102, *0103, and*0104.

Down-regulation of HLA class I expression by neo-plastic cells occurs during the development of manydifferent human tumours, including malignantmelanoma;6 carcinoma of the breast,7 cervix,8 and lung;9and Burkitt’s lymphoma.10 In addition, induction ofHLA class II expression on tumour cells in some malig-nancies, such as breast cancer, has also been reported.11

Genetic mechanisms for HLA class I ablation or down-regulation have been well described (e.g. ref. 12) and sowill not be considered any further here. Rather, we wishto highlight the still relatively small but growing litera-ture which indicates that HLA polymorphism also medi-ates susceptibility to or prognosis in several neoplasticdiseases. Well-described examples are given in Table II.As can be seen, HLA-encoded relative risks for thedevelopment of specific malignancies (except the case of

Copyright ? 1999 John Wiley & Sons, Ltd.

enteropathy-associated T-cell lymphoma), while gener-ally small, are still significant. It is not the intent of thisshort article to provide an exhaustive update of all suchknown HLA associations. Rather, we wish to illustrate,with specific examples, ways in which this fascinatinggene complex may be important in the development andmaintenance of neoplastic diseases. In addition, the roleof non-HLA genes within the MHC is also consideredbriefly.

Table II—HLA-associated neoplastic diseases (reviewed by Howell and Jones46)

Disease

Associated HLAlocus/allele

Relativerisk

Hodgkin’s disease† DPB1*0301 2·0DPB1*0401 0·9DPB1*0901 —

Cutaneous T-cell lymphoma DR5 3·9DQB1*03 2·7

Burkitt’s lymphoma A1, B12, DR7 3·4 (DR7)Childhood common ALL‡ DPB1*0201 and/or DPB1*0501 2·8EATL§ DQA1*0501, DQB1*0201 44·2Cervical intraepithelial neoplasia DQB1*03 2·6

DQB1*0602 2·2Cervical squamous cell carcinoma DQB1*0301 8·7

DQB1*0303 4·5DQB1*0602 3·4

Kaposi’s sarcoma DR5 4·8Colorectal carcinomaQ DQB1*0301 —Cutaneous basal cell carcinoma DR1 2·1–3·0

†HLA-DPBA*0401 is associated with a protective effect for Hodgkin’s disease in Orientals, while DPB1*0901 isassociated with a shorter duration of disease remission in Japanese patients.

‡Acute lymphoblastic leukaemia.§Enteropathy-associated T-cell lymphoma.QHLA-DQB1*0301 may be associated with less advanced tumours.

HLA AND HAEMATOLOGICAL MALIGNANCY

Several recent studies have indicated that the HLAgene complex may mediate susceptibility to a number ofhaematological malignancies. These studies have beenaided by technological developments in HLA-typingmethods. Initial studies of HLA associations with dis-ease used serological methods to examine the HLAphenotypes of affected individuals, but these techniqueshave now been largely superseded by DNA-based geno-typing methods. In Hodgkin’s disease, application ofthese methods revealed possible associations with theHLA-DPB1 locus. More extensive study of this locus,during the Eleventh International HistocompatibilityWorkshop, revealed that the HLA-DPB1*0301 alleleconfers a small increase in risk for the development ofHodgkin’s disease in Caucasian populations, whileHLA-DPB1*0401 is associated with a protective effectin Orientals and HLA-DPB1*0901 is associated with ashorter duration of disease remission in Japanesepatients.13 A subsequent large, two-centre U.K.-based

J. Pathol. 188: 231–236 (1999)

233HUMAN LEUKOCYTE ANTIGENS AND CANCER: IS IT IN OUR GENES?

study indicated that HLA-encoded susceptibility toHodgkin’s disease may, in fact, correlate with a specificHLA-DPB1 hypervariable sequence motif, rather thanwith the DBP1*0301 allele per se.14 Similar HLAmolecular typing techniques have revealed HLA associ-ations with other haematological malignancies; forexample, the HLA class II DRB1*11(DR5) phenotypeand the HLA-DQB1*03 alleles are present at higherfrequencies in patients with cutaneous T-cell lym-phoma.15 Conflicting findings have been reported inchildhood acute lymphoblastic leukaemia (ALL), withone group suggesting that the HLA-DR53 gene product(encoded by the HLA-DRB4 gene) is associated withpredisposition to this condition and that this may be dueto molecular mimicry with a putative oncogenic virus, orlinkage disequilibrium with a nearby susceptibilitylocus.16 Studies from another centre have suggestedthat in childhood common ALL, HLA-DPB1*0201influences predisposition to disease, as do HLA-DQA1*0101/0104 and HLA-DQB1*0501 alleles inmales, which again may be suggestive of an infective

17,18
aetiology.
having a protective effect.

HLA AND CUTANEOUS MALIGNANCY

Since HLA molecules are involved in modulation ofthe immune response, tumours which are characteristi-cally associated with a local inflammatory cell reactionrepresent potential candidates for HLA-associated pre-disposition or clinical prognosis. For example, radialgrowth phase cutaneous malignant melanoma (CMM) ischaracteristically associated with a T-lymphocyte infil-trate within the underlying dermis, while the prognosisof vertical growth phase CMM is partly dependent onthe presence of tumour-infiltrating lymphocytes19,20

which can recognize antigenic peptides expressed inassociation with HLA class I21,22 and HLA class II23

molecules on the surface of CMM cells in vitro. Further-more, familial CMM may show genetic linkage to theHLA-encoding region within the MHC on chromosome6.24 These observations have prompted the evaluation ofassociations between HLA allelic polymorphisms andCMM.

Early serological studies of HLA associations withCMM identified an increase in HLA-DR4 and -DR5phenotypes in CMM patients.25,26 More recently,PCR-based HLA-DRB1, -DQA1, and -DQB1 geno-typing demonstrated an increased frequency of theHLA-DQB1*0301 allele in a series of North AmericanCaucasian CMM patients, particularly those with poorprognosis primary tumours,27 while HLA-DQB1*0301was also associated with earlier disease recurrence.28

Our own initial PCR-based study of 99 U.K.Caucasians, the first such investigation to use DNAderived from archival tissues, has confirmed the impor-tance of HLA-DQB1*03 alleles in CMM, with HLA-DQB1*0303 appearing to increase the risk of CMMdevelopment and HLA-DQB1*0301 being associatedwith poorer prognosis primary tumours.29 However, anindependent study of North American Caucasian CMMpatients, using a combination of serological HLA-A, -B,


-DR, and -DQ phenotyping and PCR-based HLA-DRBand -DQB1 genotyping, did not find statistically signifi-cant differences in HLA specificity or allele frequencybetween CMM patients and controls.30 In addition, aJapanese PCR–RFLP-based study recently identified anincrease in the frequency of the HLA-DQB1*0302 alleleand decreases in the frequencies of the HLA-DQA1*0101, *0401, and HLA-DRB1*0802 allelesamong all CMM patients, together with an increase inthe frequency of the HLA-DQA1*0103 allele in thosewith acral lentiginous CMM.31 However, these differ-ences failed to achieve statistical significance. A smallnumber of serological studies have examined HLA classI associations with CMM, with an increase in thefrequency of HLA-B13 identified with Japanese patients,together with an increase in HLA-B51 among those withacral lentiginous CMM.32 However, a second study ofItalian patients did not identify such class I associ-ations.33 The true significance of HLA associations withCMM is therefore still under evaluation!

In non-melanoma skin cancer, a small number ofstudies from different parts of the world have suggestedthat HLA-DR1 may be associated with the developmentof multiple basal cell carcinomas,34–36 although not allinvestigations appear to support this.37 It has also beensuggested that HLA-DR4 may be associated with bothmelanoma and non-melanoma skin cancers,38 althoughthis appears to ignore the more recent findings inCMM.39 In the special circumstances of skin neoplasiafollowing renal transplantation, HLA-DR7 associ-ations have been described40,41 which may relate tosusceptibility to human papilloma viruses due toimmunosuppressive therapies.

HLA AND OTHER SOLID MALIGNANCIES

HLA associations have also been identified for someother solid tumours. Individuals developing colorectaladenocarcinoma who possess the HLA-DQB1*0301allele appear to have a lower incidence of advanced stagetumours, suggesting that this HLA molecule may alterthe course of development of this tumour and thereforeconfer a relative protective effect.42 Similarly, the HLA-DRB1*0101 and *0405 alleles may be protective forboth renal cell carcinoma development and tumourprogression in Japanese patients,43 while in the sameethnic group the HLA-DRB1*0410 allele may pre-dispose to testicular cancer, with HLA-DQB1*0602

44

HLA AS A LINK BETWEEN BENIGN ANDMALIGNANT DISEASE

HLA associations with neoplastic diseases may helpto strengthen the pathogenetic relationship of theseconditions with non-neoplastic conditions from which aneoplastic clone may arise. For example, an increasein frequencies of the HLA-DRB1*03, -DQA1*0501,and -DQB1*0201 alleles has been demonstrated inpatients with uncomplicated coeliac disease and in those

J. Pathol. 188: 231–236 (1999)

these patients.


developing the high-grade intestinal non-Hodgkin’slymphoma, termed ‘enteropathy-associated T-cell lym-phoma’ (EATL), suggesting that the two conditions aregenetically related.45 Furthermore, in this study, patientswith uncomplicated coeliac disease, particularly of earlyonset, showed an increased frequency of HLA-DQB1*0201 homozygosity compared with those withEATL. These results suggest that among individualswho possess the HLA-DQA1*0501/-DQB1*0201 haplo-type, HLA-DQB1*0201 homozygosity predisposes toearly onset and therefore earlier treatment of coeliacdisease. Conversely, individuals possessing the HLA-DQA1*0501/-DQB1*0201 haplotype who developcoeliac disease in the absence of HLA-DQB1*0201homozygosity have a delayed clinical presentation,resulting in a longer period of subclinical disease, andtherefore an extended period of gluten-derived antigen-mediated T-lymphocyte stimulation, with an increased

46
risk of emergence of a neoplastic T-cell population.
HLA AS A COFACTOR FOR TUMOURDEVELOPMENT

In HLA-associated diseases, certain HLA allelesusually appear to be necessary for disease development.However, not every individual possessing a disease-associated HLA allele will develop that condition, indi-cating that other factors are required, in combinationwith or independent of the presence of particular HLAalleles, for the disease to occur.3 For example, infectiveagents and HLA may co-modulate disease susceptibility.The association of human papilloma viruses (HPV)(particularly types 16, 18, 31, and 33) with cervicalintraepithelial neoplasia (CIN) and cervical squamouscell carcinoma is well established. However, only aproportion of individuals carrying HPV will developCIN, indicating that additional factors are required forthe disease to occur. Modifying risk factors couldinclude differences in individual’s abilities to raise animmune response to HPV, due to variations in theefficiency of presentation of viral antigenic peptides toT-lymphocytes by HLA molecules. Possession of HLA-DQB1*03 alleles appears to predispose to the develop-ment of CIN,47,48 while HLA-DQB1*0602 has beenassociated with the presence of HPV 16 and 18.49,50 TheHLA-DQB1*0301, *0303, and *0602 alleles are allassociated with an increased risk of development ofcervical squamous cell carcinoma, although some vari-ation in the most strongly associated alleles occursbetween different populations.49,51 The HLA-B*07 alleleis associated with a worsened prognosis in cervicalsquamous cell carcinoma and this may be related to analteration in the ability of HPV 16-infected cells topresent a particular HPV 16 E6 oncoprotein sequencemotif to T-lymphocytes.52 Furtheremore, loss of HLA-B*07 expression may occur in this tumour and is alsoassociated with tumour metastasis and poor out-come.52,53 In other malignancies in which viruses may bea causal factor, similar HLA associations have beenreported. For example, in nasopharyngeal carcinoma, inwhich Epstein–Barr virus has been implicated, one


Greek study has shown that the HLA-B5, -DR11haplotype is associated with disease in older patients andis also associated with longer disease-free survival in

54

HLA AND PATHWAYS OF CANCERDEVELOPMENT

An HLA association with a disease process may offersome insight into the mechanism of its pathogenesis. Forexample, the disease may be primarily associated with anHLA locus or with another MHC region gene that isclosely linked with the HLA locus. Identification of theHLA locus that is primarily associated with an HLA-associated disease may be impaired by linkage disequi-librium occurring between the HLA loci. Therefore, thestrength of disease association between the differentHLA alleles present within an ‘extended haplotype’needs to be individually assessed before the HLA locusthat is primarily associated with the disease can beidentified with confidence.3 A direct disease associationwith an HLA allele suggests that the function of theHLA molecule encoded by this allele may differ signifi-cantly from the molecules encoded by alternative allelesin its ability to present antigens to T-lymphocytes.

The HLA-encoding genes are the most polymorphicloci within the human genome, with 197 HLA-DRB1and 35 HLA-DQB1 alleles currently identified.55 Themost polymorphic regions within each HLA locusencode sequence motifs within the peptide-bindinggrooves of the HLA molecules, thereby altering theconformation of the binding grooves and the efficiencyof antigenic peptide binding and presentation toT-lymphocytes. Therefore, different HLA alleles mayalter the responsiveness of an individual’s immune sys-tem to a range of antigenic peptides, whether derivedfrom self-antigens, micro-organisms or tumours. Forexample, the association of the HLA-DQB1*0301 allelewith colorectal carcinomas of less advanced stage maybe due to the ability of HLA-DQB1*0301-encodedmolecules to recognize and present processed peptidescontaining a certain K-ras mutation (13Gly-Asp) moreefficiently than other HLA molecules.42 Sequence poly-morphisms within the non-coding promoter regions ofthe HLA genes may differentially affect the expression ofthe various alleles for each locus.3 This may represent afurther mechanism that determines inter-individual dif-ferences in the efficiency of antigen presentation toT-lymphocytes. The presence of disease associationswith the same HLA alleles among different populationsindicates that HLA polymorphisms are likely to beimportant for disease pathogenesis. If different HLAalleles are associated with a disease in different popula-tions, this does not necessarily mean that HLA is not animportant factor in pathogenesis, but may suggest thepresence of different environmental cofactors (forexample, infections).

HLA AND CANCER TREATMENT

The HLA genotype may help to predict treatmentsuccess in cancer patients. For example, the HLA-DRB1

J. Pathol. 188: 231–236 (1999)

lymphoma.

235HUMAN LEUKOCYTE ANTIGENS AND CANCER: IS IT IN OUR GENES?

locus appears to modulate patient response tointerleukin-2 therapy in cutaneous malignantmelanoma, with the HLA-DRB1*03 and *04 allelesbeing associated with poor treatment tolerance andHLA-DR homozygosity reducing the chance of

30
successful treatment response.
NON-HLA MHC GENES AND MALIGNANCY

Apparent HLA–disease associations may also reflecta pathogenetic role for the more limited polymorphismsin ‘non-classical’ HLA and non-HLA-encoding geneswithin the MHC that are genetically linked to the‘classical’ HLA loci. Candidate genes would include theTAP (transporter associated with antigen processing),LMP (large multifunctional protease), and HLA-DMencoding loci. These molecules are encoded by lociwithin the MHC class II region and are involved withthe intracellular synthesis and processing of HLAmolecules. A role for polymorphisms within these loci ascontributors to the development of malignant diseasehas yet to be established in man.

Cytokines are also powerful modulators of theimmune response and the expression of certain cytokinesis known to be under genetic control. Aberrant expres-sion of particular cytokines by tumour cells, or bytumour-infiltrating lymphocytes or macrophages, maytherefore influence tumour establishment and/or pro-gression, by suppressing the anti-tumour immuneresponse. In this context, tumour necrosis factor alpha(TNFá) is of particular interest. TNFá is encoded by agene within the MHC class III region and is a multifunc-tional cytokine predominantly produced by macro-phages, which mediates necrosis of solid tumours.However, a number of independent reports suggest thatTNFá may act as an endogenous tumour promoter invivo.56 In support of this, serum TNFá concentrationshave been shown to be raised in patients with a numberof different malignancies,56,57 and in some cancers theseelevated levels are associated with a poor clinicalcourse.58 A di-allelic polymorphism in the promoterregion of TNFá (position "308) has been shown toregulate the expression of this cytokine in a number ofindependent studies.59 In addition, polymorphism in thefirst intron of the LTá gene (position +252), closelylinked to TNFá, has also been reported to define aTNFá ‘high expresser’ haplotype,60 in addition to modi-fying expression of LTá itself. These TNF2 and TNFB1(LTá) ‘high expresser’ alleles are found in strong linkagedisequilibrium with the HLA-A1, B8, DR3 haplotype.61

These findings suggest that TNFá and LTá regulatorypolymorphisms are candidates for regulating the anti-tumour immune response independently of or in associ-ation with HLA-mediated effects. They have beenimplicated in susceptibility to breast cancer and non-Hodgkin’s lymphoma62 and may also influence diseaseprogression in haematological malignancies, includingchronic lymphocytic leukaemia63 and non-Hodgkin’slymphoma.60 LTá polymorphism has also been impli-cated in the prognosis of lung and gastric cancer inJapan.64,65 Other loci in the MHC class III region may


also be important and polymorphism of the heat-shock protein 70 (HSP70) gene, independent of TNFápolymorphism, has been shown to be associated withsusceptibility to breast cancer and non-Hodgkin’s

62

CONCLUSION

In summary, the role of HLA molecules, genes, andother related MHC loci in the development and progres-sion of neoplasia is becoming increasingly clear,although much continued investigation will be requiredbefore the mechanisms of these associations are fullyunderstood. Different alleles may prove to be associatedwith malignancies in different ethnic groups, due toHLA population differences and differing exposures toenvironmental risk factors. The study of the humanMHC in neoplasia will continue to provide valuableinsights into tumour immunosurveillance and in thefuture may aid patient stratification into prognosticgroups as well as assisting the prediction of tumourresponse to immunotherapeutic intervention.

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Human leukocyte antigens and cancer: is it in our genes?