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Table 1. 
Baseline Characteristics of the 124 Individuals in the HLA Study*
Baseline Characteristics of the 124 Individuals in the HLA Study*
Table 2. 
Baseline Characteristics of the 124 Individuals Who Were HLA-DR7 Positive and Negative*
Baseline Characteristics of the 124 Individuals Who Were HLA-DR7 Positive and Negative*
Table 3. 
Frequency of HLR-DR7 Allele in Individuals With and Without Basal Cell Carcinoma (BCC), Stratified According to Skin Type and Family*
Frequency of HLR-DR7 Allele in Individuals With and Without Basal Cell Carcinoma (BCC), Stratified According to Skin Type and Family*
1.
Armstrong  BKKricker  A Skin cancer. Dermatol Clin. 1995;13583- 594
2.
Marks  R Squamous cell carcinoma. Lancet. 1996;347735- 738Article
3.
Brash  DERudolph  JASimon  JA  et al.  A role for sunlight in skin cancer: UV-induced p53 mutations in squamous cell carcinoma. Proc Natl Acad Sci U S A. 1991;8810124- 10128Article
4.
Ziegler  AJonason  ASLeffell  DJ  et al.  Sunburn and p53 in the onset of skin cancer. Nature. 1994;372773- 776Article
5.
Pfister  HTer Schegget  J Role of HPV in cutaneous premalignant and malignant tumors. Clin Dermatol. 1997;15335- 347Article
6.
Bouwes Bavinck  JNGissmann  LClaas  FH  et al.  Relation between skin cancer, humoral responses to human papillomaviruses, and HLA class II molecules in renal transplant recipients. J Immunol. 1993;1511579- 1586
7.
Bouwes Bavinck  JNBerkhout  RJ HPV infections and immunosuppression. Clin Dermatol. 1997;15427- 437Article
8.
Streilein  JW Immunogenetic factors in skin cancer. N Engl J Med. 1991;325884- 887Article
9.
Bouwes Bavinck  JNClaas  FH The role of HLA molecules in the development of skin cancer. Hum Immunol. 1994;41173- 179Article
10.
Rompel  RPetres  JKaupert  KMueller-Eckhardt  G HLA phenotypes and multiple basal cell carcinomas. Dermatology. 1994;189222- 224Article
11.
Emtestam  LWallberg  PAldener  AOlerup  O Multiple basal cell carcinomas: no association with HLA-DRB, HLA-DQA1 or HLA-DQB1 in Swedish patients. Br J Dermatol. 1996;134886- 891Article
12.
Cerimile  DContu  LCarcassi  C  et al.  HLA and multiple skin carcinomas. Dermatologica. 1988;176176- 181Article
13.
Czarnecki  DLewis  ANicholson  ITait  BNash  C HLA-DR1 is not a sign of poor prognosis for the development of multiple basal cell carcinomas. J Am Acad Dermatol. 1992;26717- 719Article
14.
Czarnecki  DTait  BNicholson  ILewis  A Multiple non-melanoma skin cancer: evidence that different MHC genes are associated with different cancers. Dermatology. 1994;18888- 90Article
15.
Myskowski  PLPollack  MSSchorr  EDupont  BSafai  B Human leukocyte antigen associations in basal cell carcinoma. J Am Acad Dermatol. 1985;12997- 1000Article
16.
Bouwes Bavinck  JNClaas  FHHardie  DRGreen  AVermeer  BJHardie  IR Relation between skin cancer and HLA antigens in renal transplant recipients in Queensland, Australia. J Invest Dermatol. 1997;108708- 711Article
17.
Bouwes Bavinck  JNKootte  AMvan der Woude  FJVandenbroucke  JPVermeer  BJClaas  FH On a possible protective effect of HLA-A11 against skin cancer and keratotic skin lesions in renal transplant recipients. J Invest Dermatol. 1991;97269- 272Article
18.
Czarnecki  DLewis  ANicholson  ITait  B Multiple basal cell carcinomas and HLA frequencies in southern Australia. J Am Acad Dermatol. 1991;24559- 561Article
19.
Glover  MTBodmer  JKennedy  LJ  et al.  HLA antigen frequencies in renal transplant recipients and non-immunosuppressed patients with non-melanoma skin cancer. Eur J Cancer. 1993;29A520- 524Article
20.
Czarnecki  DWatkins  FLeahy  S  et al.  Skin cancers and HLA frequencies in renal transplant recipients. Dermatology. 1992;1859- 11Article
21.
Bouwes Bavinck  JNMarugg  MEBeckers  RCYVandenbroucke  JPClaas  FHVermeer  BJ The risk of skin cancer among European migrants on Saba [abstract]. Br J Dermatol. 1994;131909
22.
Fitzpatrick  TB The validity and practicality of sun-reactive skin types I through VI. Arch Dermatol. 1988;124869- 871Article
23.
Bouwes Bavinck  JNVermeer  BJvan der Woude  FJ  et al.  Relation between skin cancer and HLA antigens in renal-transplant recipients. N Engl J Med. 1991;325843- 848Article
24.
Ray  JGHare  DBPederson  PD NIAID Manual of Tissue Typing Techniques 1979-1980.  Washington, DC Government Printing Office1979;
25.
van Rood  JJvan Leeuwen  APloem  JS Simultaneous detection of two cell populations by two-colour fluorescence and application to the recognition of B-cell determinants. Nature. 1976;262795- 797Article
26.
Neefjes  JJPloegh  HL Intracellular transport of MHC class II molecules. Immunol Today. 1992;13179- 184Article
Study
August 2000

Further Evidence for an Association of HLA-DR7 With Basal Cell Carcinoma on the Tropical Island of Saba

Author Affiliations

From the Departments of Dermatology (Drs Bouwes Bavinck, Bastiaeus, Marugg, Beckers, and Vermeer), Clinical Epidemiology (Dr Westendorp), and Immunohematology (Dr Claas) and the Bloodbank (Dr Claas), Leiden University Medical Center, Leiden, the Netherlands.

Arch Dermatol. 2000;136(8):1019-1022. doi:10.1001/archderm.136.8.1019
Abstract

Objective  To establish the association of HLA alleles (ie, HLA-DR1, HLA-DR4, and HLA-DR7) with individuals with skin cancer on the tropical island of Saba. This island was chosen because most of the white population has fair skin and excessive exposure to sunlight, which results in a high prevalence of skin cancer.

Design  HLA typing was performed in 124 white individuals with histologically proven basal cell and/or squamous cell carcinoma and in control subjects. Skin type, the presence of freckling, and the number of actinic keratoses were determined.

Setting  Population-based study.

Subjects  Inhabitants of Saba with and without skin cancer.

Main Outcome Measure  Presence of HLA-DR1, HLA-DR4, and HLA-DR7 alleles.

Results  Associations of HLA alleles with basal cell and squamous cell carcinoma have been reported. The presence of the HLA-DR7 allele was positively associated with the development of basal cell carcinoma (odds ratio, 3.8; 95% confidence interval, 1.1-13.4). Adjustment for skin type, which is a potentially confounding factor for the association between HLA alleles and skin cancer, did not substantially alter this association. No other associations between HLA alleles and skin cancer were found, possibly because of the small size of the study population.

Conclusion  This study presented further evidence for an association between HLA-DR7 and basal cell carcinoma.

THE DEVELOPMENT of skin cancer is governed by a complex interplay of environmental and genetic factors.1,2 The most important environmental factors are exposure to sunlight,3,4 exposure to chemicals, and infection with human papillomaviruses.5 Genetic factors, such as skin type, freckling, tendency to develop actinic keratoses, and resistance to infection with human papillomaviruses, are also important.6,7 In addition, age and sex should always be considered.

The HLA system plays a role in the development of skin cancer,8,9 although the exact mechanisms have not yet been resolved. Associations of HLA alleles with basal cell carcinomas and squamous cell carcinomas have been described both in the immunocompetent population and in renal transplant recipients.917

In the immunocompetent population, the most consistent reported association is of the HLA-DR1 allele with (usually multiple) basal cell carcinoma12,15,18,19 and a negative association of basal cell carcinoma with the HLA-DR4 allele,10,12,18 although these associations could not always be confirmed.11 Several studies of renal transplant recipients reported a positive association between the HLA-DR7 allele and squamous cell carcinomas or basal cell carcinomas.16,20

Because of the small sample size in this study of inhabitants on the tropical island of Saba, we limited our study to the association of basal cell carcinoma and squamous cell carcinoma with the HLA alleles, which have previously been reported to be associated with one of these skin cancers (ie, HLA-DR1, HLA-DR4, and HLA-DR7).

PATIENTS AND METHODS
SELECTION OF PATIENTS AND CASE DEFINITION

The study was performed on Saba, a small island in the Caribbean Sea. Most whites living on this island are descendants of English, Scottish, Irish, and Dutch settlers who arrived on the island between 1660 and 1685. The population born on Saba consists of about 450 whites and 500 nonwhites. The white population largely consists of 5 families. Excessive exposure to sunlight and the fair skin of most of the white population result in a high prevalence of actinic keratoses and skin cancer.21

The surveys were undertaken in May and November 1993. During the first visit to the island, the available data in the government registry office were used to make a list of all 256 white individuals (51% women) who were born on Saba before 1960. The list was primarily based on the family names of the 5 largest families and, with the help of government employees, was completed by adding the names of white individuals with different names who were also born on the island.

Data regarding the history of skin cancer were collected from the medical charts of all white individuals. Only histologically confirmed squamous cell carcinomas and basal cell carcinomas were counted as skin cancers.

A skin cancer clinic was announced, which resulted in 50 persons spontaneously visiting our clinic in May, 16 of whom had had skin cancer. During the second survey, an additional 87 persons were seen. Family members of patients with skin cancer from the first survey were telephoned to attend the clinic. Individuals who came to the clinic spontaneously were also included in the study.

CLINICAL INVESTIGATION

The skin of all individuals visiting our clinic was examined for the presence of skin cancer. Biopsy of the suspicious lesions was performed for histological diagnosis. Skin type was determined22 and actinic keratoses were counted. Freckles were recorded as present or absent. Lifetime sun exposure was assessed by questionnaire,23 and blood was drawn for HLA typing. Briefly, each patient's cumulative exposure to sunlight was calculated by adding the exposure because of occupational activities (minimum 1 and maximum 8 hours per day) for different age groups to the exposure because of nonoccupational activities, such as outdoor recreation (minimum 1 and maximum 16 hours per week) and vacation. The complete questionnaire and the protocol for assessing exposure to sunlight are available on request from Dr Bouwes Bavinck.

Of the 137 persons attending the clinic, 10 refused to have blood drawn. Of the remaining 127 persons, HLA typing was performed successfully in 124 samples, which resulted in the 124 subjects analyzed in this study. One hundred nineteen individuals did not attend the clinic because they were not on the island when we were organizing the clinic, they were too busy to attend the clinic, or they did not want to participate in the study.

HLA TYPING

Typing for HLA-A, HLA-B, and HLA-DR antigens was performed with sets of well-defined alloantisera by means of the standard complement-dependent lymphocytotoxicity test for HLA-A and HLA-B, specified by the National Institutes of Health, Bethesda, Md,24 and the 2-color fluorescence technique for HLA-DR typing.25

STATISTICS

The continuous data concerning age, sun exposure, and number of actinic keratoses did not show a normal distribution, and therefore differences between the groups of patients with and without skin cancer regarding these values were calculated using the nonparametric Wilcoxon signed rank test. Differences regarding ordinal data, such as sex, presence of freckles, skin type, and presence of certain HLA phenotypes, were calculated using χ2 analysis. The HLA-DR1, HLA-DR4, and HLA-DR7 alleles were tested a priori and, therefore, correction for the number of antigens tested was not performed.

Relative risks were estimated with the exposure odds ratios by logistic regression. Considering the association between HLA alleles and skin cancer, only skin type is a potential confounder, a factor that can be adjusted for in the logistic model. Age and sex are not confounders, because although these features are risk factors for skin cancer, they do not depend on HLA genotype. Actinic keratoses are intermediate in the etiologic pathway between HLA alleles and skin cancer and therefore should not be adjusted for. Similarly, freckles should not be used in the model, since these spots can be considered an indicator for skin type.

The calculations were performed with the statistical software package JMP (version 2; SAS Institute Inc, Cary, NC) with the help of Epi Info (version 6.04b, January 1997, Centers for Disease Control and Prevention, Atlanta, Ga, and World Health Organization, Geneva, Switzerland).

RESULTS
RELATIONSHIP OF RISK FACTORS TO SKIN CANCER

The basic characteristics of the 124 individuals whose HLA alleles were studied are presented in Table 1. Of the 14 patients with a history of 1 or more squamous cell carcinomas, 8 patients had also developed 1 or more basal cell carcinomas. These patients were analyzed as having squamous cell carcinoma.

In the population of Saba, common risk factors, such as age, exposure to sunlight, freckles, and number of actinic keratoses, tended to be associated with both basal cell and squamous cell carcinoma, although statistical significance was not always reached (Table 1).

Skin type was strongly associated with freckles, and age, skin type, freckles, and sun exposure were risk factors for actinic keratoses (data not shown).

POSITIVE ASSOCIATION BETWEEN HLA-DR7 AND SKIN CANCER

The basic characteristics of the HLA-DR7–positive and –negative individuals are presented in Table 2. The presence of the HLA-DR7 allele was significantly associated with a history of basal cell carcinomas only (Table 1 and Table 3). The nonadjusted odds ratio for developing basal cell carcinoma in HLA-DR7–positive individuals compared with HLA-DR7–negative individuals was 3.8 (95% confidence interval, 1.1-13.4); after adjusting for skin type, the odds ratio became 3.4 (95% confidence interval, 1.1-13.8). The odds ratios were similar in the largest 2 families (families 1 and 4), informative in the smaller families (families 3 and 5), and not informative in family 2 (Table 3). The HLA-DR7 allele was not associated with a history of squamous cell carcinoma (Table 1).

The HLA-DR1 allele was not associated with an increased risk of basal cell carcinoma; the risk for developing squamous cell carcinomas was marginally increased, but was not statistically significant (Table 1). The frequency of the HLA-DR4 allele was only slightly decreased in individuals with both types of skin cancer, and no statistically significant associations were observed between skin cancer and the other HLA-DR alleles or with homozygosity for HLA-DR (data not shown). In addition, no statistically significant association between the presence of any of the HLA-A or HLA-B alleles and any type of skin cancer was found.

COMMENT

A statistically significant association was found between the presence of the HLA-DR7 allele and basal cell carcinoma only, in concurrence with earlier findings in the renal transplant population. This association was independent of skin type. The direction of the association was similar in 4 of the 5 families studied, so that genetic relatedness of the individuals is not the most likely explanation for the association between the presence of the HLA-DR7 allele and basal cell carcinoma.

The positive association of HLA-DR1 with basal cell carcinoma and the negative association of HLA-DR4 with this type of tumor could not be confirmed in the small population of Saba, which is in agreement with a Swedish study.11 We cannot exclude, however, the possibility that an association between these alleles and skin cancer still exists but could not be detected in our study because of the small size of the study population.

This study supports the hypothesis that HLA alleles may be involved in the development of skin cancer, but no conclusions can be drawn as to the stage of tumor development in which these antigens may be important. The immune response to premalignant cells may be of equal or more importance than the response against the tumor cells. The association with HLA class II antigens indicates that during the induction phase of this immune response, CD4-positive regulatory T cells may be involved in recognizing HLA class II–associated peptides, which may be tumor antigens, viral antigens, photoantigens, or other, as yet undetermined antigens.26

In conclusion, much larger studies are needed to unravel the complex associations between HLA alleles and the development of skin cancer. Data on basal cell carcinoma and squamous cell carcinoma should be analyzed separately, since the pathogenesis of and the antigenic determinants in these tumors are likely to be different.

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Article Information

Accepted for publication January 1, 2000.

The research of Dr Bouwes Bavinck has been made possible by a fellowship of the Royal Netherlands Academy of Arts and Sciences, Amsterdam.

We would like to thank Jan P. Vandenbroucke, MD, PhD, for helpful advising during the design phase of the study; the technicians of the HLA typing laboratory (head, G. M. T. Schreuder, MD, PhD) for their cooperation; and Viña C. R. Snijders, MD, for critically reviewing the manuscript. Last but not least, we would like to acknowledge the enthusiastic participation of the population of Saba in this study.

This study was inspired by the thesis of R. Mol, MD, author of Doctor on Saba: Health Care and Disease in a Caribbean Family Practice. Delft, the Netherlands: Eburon; 1989.

Corresponding author: Jan N. Bouwes Bavinck, MD, PhD, Department of Dermatology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, the Netherlands (e-mail: dermatol@euronet.nl).

References
1.
Armstrong  BKKricker  A Skin cancer. Dermatol Clin. 1995;13583- 594
2.
Marks  R Squamous cell carcinoma. Lancet. 1996;347735- 738Article
3.
Brash  DERudolph  JASimon  JA  et al.  A role for sunlight in skin cancer: UV-induced p53 mutations in squamous cell carcinoma. Proc Natl Acad Sci U S A. 1991;8810124- 10128Article
4.
Ziegler  AJonason  ASLeffell  DJ  et al.  Sunburn and p53 in the onset of skin cancer. Nature. 1994;372773- 776Article
5.
Pfister  HTer Schegget  J Role of HPV in cutaneous premalignant and malignant tumors. Clin Dermatol. 1997;15335- 347Article
6.
Bouwes Bavinck  JNGissmann  LClaas  FH  et al.  Relation between skin cancer, humoral responses to human papillomaviruses, and HLA class II molecules in renal transplant recipients. J Immunol. 1993;1511579- 1586
7.
Bouwes Bavinck  JNBerkhout  RJ HPV infections and immunosuppression. Clin Dermatol. 1997;15427- 437Article
8.
Streilein  JW Immunogenetic factors in skin cancer. N Engl J Med. 1991;325884- 887Article
9.
Bouwes Bavinck  JNClaas  FH The role of HLA molecules in the development of skin cancer. Hum Immunol. 1994;41173- 179Article
10.
Rompel  RPetres  JKaupert  KMueller-Eckhardt  G HLA phenotypes and multiple basal cell carcinomas. Dermatology. 1994;189222- 224Article
11.
Emtestam  LWallberg  PAldener  AOlerup  O Multiple basal cell carcinomas: no association with HLA-DRB, HLA-DQA1 or HLA-DQB1 in Swedish patients. Br J Dermatol. 1996;134886- 891Article
12.
Cerimile  DContu  LCarcassi  C  et al.  HLA and multiple skin carcinomas. Dermatologica. 1988;176176- 181Article
13.
Czarnecki  DLewis  ANicholson  ITait  BNash  C HLA-DR1 is not a sign of poor prognosis for the development of multiple basal cell carcinomas. J Am Acad Dermatol. 1992;26717- 719Article
14.
Czarnecki  DTait  BNicholson  ILewis  A Multiple non-melanoma skin cancer: evidence that different MHC genes are associated with different cancers. Dermatology. 1994;18888- 90Article
15.
Myskowski  PLPollack  MSSchorr  EDupont  BSafai  B Human leukocyte antigen associations in basal cell carcinoma. J Am Acad Dermatol. 1985;12997- 1000Article
16.
Bouwes Bavinck  JNClaas  FHHardie  DRGreen  AVermeer  BJHardie  IR Relation between skin cancer and HLA antigens in renal transplant recipients in Queensland, Australia. J Invest Dermatol. 1997;108708- 711Article
17.
Bouwes Bavinck  JNKootte  AMvan der Woude  FJVandenbroucke  JPVermeer  BJClaas  FH On a possible protective effect of HLA-A11 against skin cancer and keratotic skin lesions in renal transplant recipients. J Invest Dermatol. 1991;97269- 272Article
18.
Czarnecki  DLewis  ANicholson  ITait  B Multiple basal cell carcinomas and HLA frequencies in southern Australia. J Am Acad Dermatol. 1991;24559- 561Article
19.
Glover  MTBodmer  JKennedy  LJ  et al.  HLA antigen frequencies in renal transplant recipients and non-immunosuppressed patients with non-melanoma skin cancer. Eur J Cancer. 1993;29A520- 524Article
20.
Czarnecki  DWatkins  FLeahy  S  et al.  Skin cancers and HLA frequencies in renal transplant recipients. Dermatology. 1992;1859- 11Article
21.
Bouwes Bavinck  JNMarugg  MEBeckers  RCYVandenbroucke  JPClaas  FHVermeer  BJ The risk of skin cancer among European migrants on Saba [abstract]. Br J Dermatol. 1994;131909
22.
Fitzpatrick  TB The validity and practicality of sun-reactive skin types I through VI. Arch Dermatol. 1988;124869- 871Article
23.
Bouwes Bavinck  JNVermeer  BJvan der Woude  FJ  et al.  Relation between skin cancer and HLA antigens in renal-transplant recipients. N Engl J Med. 1991;325843- 848Article
24.
Ray  JGHare  DBPederson  PD NIAID Manual of Tissue Typing Techniques 1979-1980.  Washington, DC Government Printing Office1979;
25.
van Rood  JJvan Leeuwen  APloem  JS Simultaneous detection of two cell populations by two-colour fluorescence and application to the recognition of B-cell determinants. Nature. 1976;262795- 797Article
26.
Neefjes  JJPloegh  HL Intracellular transport of MHC class II molecules. Immunol Today. 1992;13179- 184Article
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