Sunlight, keratotic skin lesions and skin cancer in renal transplant recipients

In a retrospective follow-up study, 36 renal transplant recipients with, and 101 without, skin cancer, who had received their first transplant before January 1981 and who were still alive with a functioning graft on 1 August 1989, were assessed to determine the risk of non-melanoma skin cancer in relation to exposure to sunlight during childhood and adolescence. The contribution of the number of keratotic skin lesions to the skin cancer risk was also assessed. The estimated relative risks (odds ratios) of skin cancer in relation to exposure to sunlight and the presence of keratotic skin lesions were calculated by maximum likelihood estimation in a logistic model. The majority of skin cancers and keratotic skin lesions were confined to sun-exposed skin. After adjustment for possible confounding variables, the odds ratios of skin cancer for moderate and high cumulative life-time exposure to sunlight, respectively, compared with low exposure, were 2·4 (95% confidence interval [CI] 0·64-9·3) and 47·6 (95% CI 5·4-418). Exposure to sunlight before the age of 30 contributed more to the risk of developing skin cancer later in life than exposure after the age of 30. No association was found between cumulative life-time exposure to sunlight and the number of keratotic skin lesions. Nevertheless, these lesions behaved as a strong independent risk factor in the development of skin cancer. The adjusted odds ratio of skin cancer for 50-99 lesions compared with >50 lesions was 4·5 (95% CI 1·1-18·2); the adjusted odds ratio for ≥100 lesions compared with >50 lesions was 20·8 (95% CI 5·3-81·7). We conclude that exposure to sunlight before the age of 30 contributes more to the risk of skin cancer in renal transplant recipients than exposure after the age of 30. Cumulative life-time exposure to sunlight does not appear to be associated with an increased number of keratotic skin lesions in these patients. The preferential localization of such lesions on sun-exposed skin suggests a possible role of recently received exposure to sunlight in the development of these lesions.     

The influence of painful sunburns and lifetime sun exposure on the risk of actinic keratoses,seborrheic warts,melanocytic nevi,atypical nevi,and skin cancer

Painful sunburns are implicated in the pathogenesis of squamous cell carcinoma, basal cell carcinoma, and malignant melanoma. Chronic exposure to ultraviolet radiation is known as the most important risk factor for the development of actinic keratoses and squamous cell carcinoma. The purpose of the study was to assess the effect of painful sunburns and lifetime sun exposure on the development of actinic keratoses and seborrheic warts in relation to the development of squamous cell carcinoma and basal cell carcinoma, and on the development of melanocytic nevi and atypical nevi in relation to the development of malignant melanoma. We made use of a cohort of 966 individuals who participated in a case-control study to investigate environmental and genetic risk factors for skin cancer. Exposure measurements for sunlight were collected and actinic keratoses, seborrheic warts, melanocytic nevi, and atypical nevi were counted. Relative risks were estimated using exposure odds ratios from cross-tabulation. Multivariate logistic regression was used to adjust for potential confounders. The recall of painful sunburns before the age of 20 y was associated with an increased risk of squamous cell carcinoma, nodular basal cell carcinoma, and multifocal superficial basal cell carcinoma as well as actinic keratoses. Odds ratios with 95% confidence intervals adjusted for age, sex, and skin type were 1.5 (0.97; 2.3); 1.6 (1.1; 2.2); 2.6 (1.7; 3.8); and 1.9 (1.4; 2.6) for the three types of nonmelanoma skin cancer and actinic keratoses, respectively. Painful sunburns before the age of 20 y were also associated with an increased risk of malignant melanoma and the development of its precursors, melanocytic nevi and atypical nevi. Odds ratios with 95% confidence intervals adjusted for age, sex, and skin type were 1.4 (0.86; 2.1); 1.5 (1.1; 2.0); and 1.4 (0.88; 2.3) for malignant melanoma and the two types of precursors, respectively. Lifetime sun exposure was predominantly associated with an increased risk of squamous cell carcinoma (p-value for trend=0.03) and actinic keratoses (p-value for trend <0.0001) and to a lesser degree with the two types of basal cell carcinoma. By contrast, lifetime sun exposure appeared to be associated with a lower risk of malignant melanoma, despite the fact that lifetime sun exposure did not diminish the number of melanocytic nevi or atypical nevi. Neither painful sunburns nor lifetime sun exposure were associated with an increased risk of seborrheic warts.     

Photodynamic therapy does not prevent cutaneous squamous-cell carcinoma in organ-transplant recipients: results of a randomized-controlled trial

A randomized-controlled trial with paired observations was performed with 40 organ-transplant recipients to assess the preventive effect of photodynamic therapy (PDT) on the development of new squamous-cell carcinomas and to evaluate the effect of PDT on the number of keratotic skin lesions. The treatment area consisted of a randomly assigned forearm and the corresponding hand, whereas the other forearm and hand served as the control area. After the initial visit, follow-up visits were scheduled at 3-monthly intervals during 2 years. No statistically significant difference was found in the occurrence of new squamous-cell carcinomas between the treated and untreated arms: after 2 years of follow-up, we observed 15 squamous-cell carcinomas in nine out of 40 PDT-treated arms and 10 squamous-cell carcinomas in nine out of 40 control arms. The number of keratotic skin lesions increased in both arms, but was less pronounced in the PDT-treated arm. After 1 year of follow-up, a trend in favor of the PDT-treated arm was observed, but statistical significance was not reached. Nearly 80% of the patients reported mild to severe adverse effects consisting of pain and a burning sensation, immediately after the treatment. No long-term adverse events were noted. In conclusion, PDT does not appear to prevent the occurrence of new squamous-cell carcinomas in organ-transplant recipients, but to some degree, reduces the increase of keratotic skin lesions.     

Human papillomavirus infection and skin cancer risk in organ transplant recipients

Warts and squamous cell carcinomas are important cutaneous complications in organ transplant recipients. The role of infection with human papillomaviruses (HPV) in the development of cutaneous squamous cell carcinoma is still unclear. An extremely diverse group of HPV types, mainly consisting of epidermodysplasia-verruciformis (EV)-associated HPV types, can be detected in benign, premalignant, and malignant skin lesions of organ transplant recipients. Frequently, there are multiple HPV types present in single skin biopsies. Typically, the prevalence of viral warts rises steadily after transplantation and a strong association exists between the number of HPV-induced warts and the development of skin cancer. The interval between the transplantation to the development of warts is clearly shorter than the interval from transplantation to the diagnosis of the first skin cancer. A comparison of transplant recipients with and without skin cancer, however, showed an equally high prevalence of EV-HPV DNA in keratotic skin lesions in both groups of patients and the detection rate and spectrum of HPV infection in hyperkeratotic papillomas, actinic keratoses, and squamous cell carcinomas was also similar. HPV DNA can frequently be detected in patients with hyperproliferative disorders like psoriasis and antibodies against HPV in patients with regenerating skin (e.g., after extensive second degree burns). Latent infection with EV-HPV seems to be widespread. The hair follicle region might be the reservoir of EV-HPV. The E6 protein from a range of cutaneous HPV types effectively inhibits apoptosis in response to UV-light induced damage. It is therefore conceivable that individuals who are infected by EV-HPV are at an increased risk of developing actinic keratoses and squamous cell carcinomas, possibly by chronically preventing UV-light induced apoptosis.     

Factors associated with nonmelanoma skin cancer following renal transplantation in Queensland,Australia

BACKGROUND: Caucasian renal transplant recipients living in Queensland, Australia, have the highest risk of nonmelanoma skin cancer in the world. OBJECTIVE: To determine clinical and environmental factors associated with posttransplantation nonmelanoma skin cancer in Queensland. METHODS: 361 Caucasian adult recipients completed a structured interview and full skin examination. Skin cancer details were obtained from hospital records. RESULTS: Squamous cell carcinoma was strongly associated with blue or hazel eyes, time resident in a hot climate, and pretransplantation squamous cell carcinoma; tumor numbers were associated with birth in a hot climate, childhood sunburn, pretransplantation actinic keratoses, and smoking. The risk of basal cell carcinoma was strongly associated with acute or intermittent sun exposure during childhood and pretransplantation basal cell carcinoma; numbers were associated with blue or hazel eyes, time spent living in a hot climate, and male gender. CONCLUSION: Clinical and environmental factors can be used to identify recipients at risk of nonmelanoma skin cancer in Queensland.     

Sun habits in kidney transplant recipients with skin cancer: a case-control study of possible causative factors

Organ transplant recipients are frequently affected by skin cancer, which might also be a major cause of long-term mortality. Excessive sun exposure is considered to be a factor in the aetiology, but uncertainty about the importance of this and other proposed risk factors remains. The purpose of this study was to investigate sun behaviour before and/or after the transplantation in kidney transplant recipients with or without cutaneous squamous cell carcinoma. A nested, population-based, case-control study was carried out on 95 kidney transplant recipients who had contracted cutaneous squamous cell carcinoma after the transplantation and on an accurately matched control population of 154 kidney transplanted patients. Information on sun exposure before and after the transplantation, skin type, use of sunbeds, warts, etc., was obtained from a questionnaire which contained 38 detailed questions. The differences between cases and control subjects were not significant for sun exposure before or after the transplantation, sun protective measures, number of sunburns, outdoor occupation, smoking habits or use of sunbeds. Compared to patients with skin type IV, the cutaneous squamous cell carcinoma odds ratio was 3.0 (95% CI = 1.3-7.0) for skin type I + II. Patients with light blond or red hair colour also had a higher odds ratio than those with dark hair, 3.2 (95% CI = 1.2-8.2), and patients with warts after the transplantation had a higher odds ratio than those without, 2.2 (95% CI = 1.2-4.2). In conclusion, poor tanning ability rather than the amount of sun exposure is associated with the development of cutaneous squamous cell carcinoma in kidney transplant recipients and warts appearing after the transplantation indicate increased risk.     

Twenty-eight-year incidence and characteristics of post-transplant skin cancers: Comparative analysis of past and recent 10-year experience

Because primary skin cancers in organ transplant recipients are rare, little is known about the characteristics and risk factors for skin cancers in organ transplant recipients. We searched the Asan Medical Center database of 13 469 organ transplant recipients for cases of all skin cancers from January 1990 to December 2018. Characteristics of and risk factors for skin cancers were analyzed and compared according to the period of transplantation. Of the identified 113 patients with skin cancers, squamous cell carcinoma was the most common cancer followed by basal cell carcinoma and Kaposi sarcoma. The cumulative incidence of skin cancers at 28 years was 5.3%. Over the 10-year period from January 2009 to December 2018, the standardized incidence ratio for premalignant in situ skin lesions increased, whereas the standardized incidence ratio for skin cancers decreased. Age at transplantation and treatment with more than two immunosuppressive agents were risk factors for the development of new skin cancers in organ transplant recipients. Over the most recent 10-year period, post-transplant skin cancers have been found earlier and diversified compared with in the previous period.     

On a possible protective effect of HLA-A11 against skin cancer and keratotic skin lesions in renal transplant recipients.

Renal transplant recipients who have skin cancer potentially related to human papillomavirus were HLA typed with a special focus on HLA-A11, which in nonimmunosuppressed patients is negatively associated with the occurrence of virus-related carcinoma of the cervix. We found also a negative association between HLA-A11 and skin cancer; none of the 66 transplant recipients with skin cancer were positive for HLA-A11. As HLA-A11 seems to have a protective effect against skin cancer, we speculate that antigens induced by squamous cell carcinomas and possibly also by human papillomavirus may be efficiently presented through HLA-A11 to cytotoxic T cells. We also investigated a possible influence of other HLA alleles on the susceptibility of renal transplant recipients to skin cancer. The frequency of HLA-B27 was significantly higher in the transplant recipients with skin cancer, with a relative risk of 3.4 relative to healthy controls. No significant differences were found for other HLA class I or class II antigens.     

Cancer/testis antigen MAGE-A4 expression pattern differs in epithelial skin tumors of organ-transplant recipients and immunocompetent patients

BACKGROUND: Lifetime risk for squamous cell carcinoma (SCC) of the skin is 1:30. Risk in organ-transplant recipients (OTR) is increased over 60-fold through long-term drug-induced immunosuppression. MAGE family-derived peptides are cancer/testis antigens recognized by specific CD8(+) T cells and employed for immunotherapy. We were interested in the frequency and distribution of MAGE-A4 in epithelial skin tumors of OTR and immunocompetent patients. METHODS: mAb 57B predominantly recognizing MAGE-A4 was used to stain 119 formalin-fixed, paraffin-embedded epithelial skin tumors (actinic keratosis, bowenoid actinic keratosis, Bowen's disease, and SCC; n = 17, 25, 61, 16, respectively) in immunocompetent patients (n = 84) and OTR (n = 35). RESULTS: All four epithelial skin tumors showed comparable immunoreactivity ranging from (25-71%, p = 0.361). Scattered immunoexpression pattern was more frequent in OTR (p = 0.025). SCC showed polarized immunoreactivity basally (p = 0.002). CONCLUSION: MAGE-A4 was expressed in a large part of epithelial skin tumors with predominantly scattered immunoexpression pattern in OTR. The difference in immunoexpression pattern for immune status was limited, suggesting important non-immunosuppressor-mediated mechanisms for increased skin carcinogenesis in OTR. mAb 57B may be a helpful tool for immunohistochemistry and micrographic surgery using formalin-fixed paraffin-embedded tissue.     

Inguinal keratotic Basal cell carcinoma mimicking giant solitary trichoepithelioma

Keratotic basal cell carcinoma may not only clinically but also histologically share more or less the same features with giant solitary trichoepithelioma. It can be difficult to distinguish these two entities from each other, even for an experienced dermatopathologist. We present an unusual case of inguinal keratotic basal cell carcinoma mimicking giant solitary trichoepithelioma in a 56-year-old woman with a finger-like tumor of 20 years duration. The patient presented with an asymptomatic, skin colored, firm, nonulcerative, nodular lesion. Scanty mitotic activity and apoptotic cells were the histopathologic findings against basal cell carcinoma, whereas absence of papillary mesenchymal bodies, presence of peritumoral lacunae detected only around the solid areas, and accumulation of amyloid-like hyalinized material were the findings in favor of basal cell carcinoma. This case illustrates that keratotic basal cell carcinoma must be taken into account in the differential diagnosis of inguinally located solitary, polypoid masses, especially giant solitary trichoepithelioma.     

The accuracy of clinical diagnosis of suspected premalignant and malignant skin lesions in renal transplant recipients

Renal transplant recipients have a greatly increased risk of nonmelanoma skin cancer. We investigated the accuracy of diagnosis of suspected skin malignancies in this population by prospectively recording all lesions detected in a specialist clinic over 5 months and comparing the provisional diagnosis with the histological diagnosis. The diagnostic accuracy was 54% in the 102 lesions that were biopsied, with the highest accuracy for the head and neck (67%). The diagnostic accuracy for squamous cell carcinoma was 48.7% (sensitivity 90.5%, specificity 75.3%) and for basal cell carcinoma 40.0% (sensitivity 66.6%, specificity 85.6%). The overall low accuracy rate implies the need for biopsy of any suspicious lesions in the renal transplant population.     

A population-based study of skin cancer incidence and prevalence in renal transplant recipients

BACKGROUND: Cancers occurring following solid organ transplantation are a rapidly growing public health concern. Defining the extent of the problem has been limited by surveillance systems with incomplete registration of cases and the paucity of reliable national incidence data. OBJECTIVES: To determine the incidence of all cancers following renal transplantation and to make a detailed examination of trends and patterns associated with postrenal transplant skin cancers. METHODS: Integration of data from the national renal transplant database and the national cancer registry in Ireland enabled accurate determination of the number of renal transplant recipients (RTRs) with skin cancers and other malignancies in the time period 1 January 1994 to 31 December 2001. RESULTS: We demonstrated a biphasic increase in skin cancer incidence following renal transplantation, determined by the age at transplantation. There was a steady increase in risk for older RTRs (age 50+ years) from year 2 post-transplant, whereas the increased risk in younger RTRs (age < 50 years) occurred later but much more significantly, reaching 200 times the risk for an age-matched nontransplanted population by year 6 post-transplant. The number of nonmelanoma skin cancers (NMSCs) registered in RTRs accounted for 1% of all NMSCs registered nationally over the study period. The standardized incidence rates for invasive NMSC (33-fold increase) and in situ carcinoma of the skin (65-fold increase) were significantly increased (P < 0.05). The risk for invasive squamous cell carcinoma (SCC) was increased 82-fold compared with the nontransplanted population. Male RTRs were at particular risk of invasive SCC at sun-exposed sites such as the scalp and the external ear. Risk of malignant melanoma and Kaposi sarcoma were also increased relative to the nontransplanted population. CONCLUSIONS: This comprehensive national study illustrates how rates of skin cancer in Irish RTRs have influenced the national incidence of skin cancer. The high incidence of SCC, basal cell carcinoma and Bowen's disease in the early post-transplant period for older patients and the cumulative risk in younger patients with increased duration of transplantation highlight the importance of implementing early and continued cancer surveillance regimens post-transplant.     

Keratotic Melanocytic Nevus

Thirty-five percent of 363 melanocytic nevi were found to have a keratotic epithelial architectural pattern that was mostly infundibular and not previously emphasized. Keratotic melanocytic nevi were commonly from the trunk of women, and most were associated with an intradermal melanocytic nevus. The clinical and histopathologic features as well as a review of the literature of these keratotic melanocytic nevi are presented.     

Skin cancer in blacks in the United States

Skin cancer is rare in blacks compared with whites in the United States. The most common form is squamous-cell carcinoma, not basal-cell carcinoma, as it is in whites. Sunlight does not appear to be an important etiologic factor in skin cancer in blacks, as most lesions occur on covered areas. Malignant melanoma is low in frequency but commonly affects acral areas and has a poor prognosis. Mycosis fungoides and dermatofibrosarcoma protuberans appear to have a high frequency among skin cancers. Squamous-cell carcinoma, malignant melanoma, and mycosis fungoides have a relatively high mortality rate in blacks. Bowen's disease and Kaposi's sarcoma occur in blacks but are rare. As there is a high frequency of squamous-cell carcinoma of the skin in blacks, prevention and early detection should benefit the patient. Considering the difficulties encountered in applying epidemiologic methods to skin cancer on a national scale, etiologic studies should be conducted in carefully selected areas. Future investigations of skin cancer in blacks should include an examination of risk factors such as burns, trauma, and diet and familial and immunologic aspects as well.     

Glutathione S-transferase and CYP1A1 gene polymorphisms and non-melanoma skin cancer risk in Italian transplanted patients

Solid organ transplant recipients are at higher risk of non-melanoma skin cancer (NMSC), especially basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Genetic alterations in the production of detoxifying enzymes such as glutathione S-transferase (GST) and CYP1A1 may enhance this risk. We investigated the frequency of GST genotypes (GSTM1, GSTM3, GSTT1 and GSTP1) and CYP1A1 in 239 transplant recipients: 107 cases with NMSC and 132 controls free from NMSC matched for type of transplanted organ, duration of transplantation, sex and age. Allele GSTP1*A was associated with a higher risk of NMSC [odds ratio (OR) 1.7 (1.1-2.5); P = 0.017]. Homozygosity for allele GSTP1 Val(105) was lower in cases [OR 0.3 (0.1-0.8); P = 0.012], especially in patients with SCC [OR 0.1 (0.0-0.7); P = 0.012]. A higher risk of BCC was found in patients with GSTM1 null/null [null/null versus A + B, OR 3.1 (1.4-6.8); P = 0.003]. Analysis of allelism and interaction between allelic variants showed significant association between combined GSTM1 and CYP1A1 Val(462) genotypes, where individuals homozygous for the risk allele GSTM1 null and carrying also the allele CYP1A1 Val(462), show a higher risk of developing NMSC [OR 4.5 (1.1-21.4); P = 0.03], especially SCC [OR 6.5 (1.4-34.4); P = 0.01]. GSTP1 polymorphisms are associated with both BCC and SCC risk. GSTM1 polymorphisms seem to be involved in BCC risk, while GSTM1 null/null genotype combined with CYP1A1 allele Val(462) are associated with a higher risk for SCC, indicating that allelism and/or interactions between allelic variants at other loci may also influence the risk of NMSC, particularly SCC.     

Current approaches to skin cancer management in organ transplant recipients

Approximately 225,000 people are living with organ transplants in the United States. Organ transplant recipients have a greater risk of developing skin cancer, including basal cell carcinoma, squamous cell carcinoma, and malignant melanoma, with an approximately 250 times greater incidence of squamous cell carcinoma in certain transplant recipients, compared with the general population. Because skin cancers are the most common posttransplant malignancy, the resultant morbidity and mortality in these high-risk patients is quite significant.     

Results of second‐stage screening for skin cancers in Oita Prefecture,Japan

We performed skin cancer screenings for 2 or 3 days annually from 2006 through 2013 in Oita Prefecture, Japan. Screening of approximately 3000 people in total allowed us to identify and treat several skin cancers, including five cases of malignant melanoma, four of squamous cell carcinoma, 16 of basal cell carcinoma, 11 of Bowen's disease, 17 of actinic keratosis, one of extramammary Paget's disease and one of metastatic breast carcinoma. The sensitivity and specificity for the category defined by an identified lesion associated with risk of cancer and requiring further examination (category C) were 92.7% and 95%, respectively. We cannot estimate the outcome of our skin cancer screenings in terms of cancer mortality because of the small number of subjects examined and the brief follow‐up period. However, we did estimate the effectiveness of these screenings in terms of stages or sizes of cancerous lesions. The relative numbers of subjects with malignant melanoma at various clinical stages, identified during skin cancer screenings and during a routine visit to our hospital, were significantly different. We also compared, statistically, the sizes of lesions in Bowen's disease that were found during cancer screenings and during a direct visit to our hospital. The former lesions were smaller than the latter. Our data suggest the benefits of our skin cancer screenings and the importance of campaigns and education to encourage people to visit dermatologists for the detection of skin cancers at an early stage.     

A prospective study of telomere length and the risk of skin cancer

Telomere length is important in tumorigenesis. Using quantitative real-time PCR, we prospectively measured relative telomere length in a nested case-control study within the Nurses' Health Study: 218 melanoma cases, 285 squamous-cell carcinoma (SCC) cases, 300 basal-cell carcinoma (BCC) cases, and 870 controls. We observed that shorter telomeres were associated with a decreased number of moles (P=0.002) and a decreased risk of melanoma. Women in the second and first quartiles, those with the shortest telomere length, had an odds ratio (OR) for melanoma of 0.54 (95% confidence interval (CI), 0.29-1.01) and 0.59 (95% CI, 0.31-1.13), respectively, compared with those in the fourth quartile (P, trend=0.09). There was no clear trend between telomere length and SCC risk. In contrast, we found that shorter telomere length was associated with an increased risk of BCC. Compared with those in the fourth quartile, women in the first quartile had an OR of 1.85 (95% CI, 0.94-3.62) (P, trend=0.09). The opposing associations observed should be interpreted with caution, and further research is needed to confirm these possible associations.     

XRCC1 Arg194Trp polymorphism, risk of nonmelanoma skin cancer and extramammary Paget’s disease in a Japanese population

The X-ray repair cross-complementing groups 1 gene plays an important role in base excision repair. At least three common single nucleotide polymorphisms frequently occur in this gene (Arg399Gln, Arg194Trp and Arg280His). Recent studies reported that these polymorphisms were associated with not only risk of visceral malignancy but also that of skin cancer such as basal cell carcinoma and squamous cell carcinoma, whereas the results of previous study vary among races. In this case-control study, we investigated whether these single nucleotide polymorphisms were associated with the risk of skin cancer in a Japanese population. The study population was composed of 197 patients with skin cancer (27 actinic keratoses, 47 basal cell carcinomas, 27 squamous cell carcinomas, 29 Bowen's diseases, 46 malignant melanomas and 21 extramammary Paget's diseases) and 93 control subjects. We genotyped two single nucleotide polymorphisms (Arg194Trp and Arg399Gln) using polymerase chain reaction-restriction fragments length polymorphism analysis. We found a significantly increased risk for basal cell carcinoma, squamous cell carcinoma and extramammary Paget's disease associated with Arg194Trp [adjusted odds ratio (AOR) = 2.347, 3.587, 3.741, 95 % confidence interval (CI) 1.02-5.39, 1.19-10.8, 1.15-12.2, respectively]. We also found a significantly decreased risk for basal cell carcinoma associated with Gln399Gln (AOR = 0.259, 95 % CI 0.07-0.96). Our data suggest that the Arg194Trp polymorphism could be associated with nonmelanoma skin cancer and extramammary Paget's disease risk in a Japanese population.     

Melanocortin 1 receptor (MC1R) gene variants are associated with an increased risk for cutaneous melanoma which is largely independent of skin type and hair color

Individuals carrying melanocortin 1 receptor gene variants have an increased risk for the development of cutaneous melanoma. Melanocortin 1 receptor gene variants are also associated with other risk factors for melanoma such as fair skin and red hair. We evaluated the relationship of melanocortin 1 receptor gene variants, fair skin, red hair and the development of melanoma in 123 patients with cutaneous melanoma and 385 control subjects. To analyze the association between melanocortin 1 receptor gene variants and skin type or hair color we also made use of 453 patients with nonmelanoma skin cancer. We analyzed the coding sequence of the melanocortin 1 receptor gene region by single-stranded conformation polymorphism analysis, followed by DNA sequence analysis. Risk of melanoma dependent on the various melanocortin 1 receptor variant alleles was estimated by exposure odds ratios. The analyses of all different melanocortin 1 receptor gene variants combined, showed that the presence of melanocortin 1 receptor gene variants amounted to a higher melanoma risk, which, in stratified analyses, was independent of skin type and hair color. The odds ratios after adjusting for skin type were 3.6 (95% CI 1.7-7.2) for two variants and 2.7 (95% CI 1.5-5.1) for one variant, respectively. Compound heterozygotes and homozygotes for the Val60Leu, Val92Met, Arg142His, Arg151Cys, Arg160Trp, Arg163Gln, and His260Pro variants had odds ratios of about 4 to develop melanoma, whereas heterozygotes for these variants had half the risk. The presence of the melanocortin 1 receptor gene variant Asp84Glu appeared to impose the highest risk for cutaneous melanoma with odds ratios of 16.1 (95% CI 2.3-139.0) and 8.1 (95% CI 1.2-55.9) in compound heterozygotes and heterozygotes, respectively. The broad confidence intervals, when the different variants were analyzed separately, however, do not allow drawing definite conclusions about the magnitude of these risks. Of the more frequently occurring melanocortin 1 receptor variant alleles the Asp84Glu, Arg142His, Arg151Cys, Arg160Trp, His260Pro, and Asp294His variants were strongly associated with both fair skin and red hair. The Val60Leu, Val92Met, and Arg163Gln variant alleles, however, were only weakly or not associated with fair skin type and/or red hair, which further illustrates the finding that skin type, hair color, and melanoma are independent outcomes of the presence of melanocortin 1 receptor gene variants. We conclude that numerous melanocortin 1 receptor variants predispose to cutaneous melanoma and that possibly the Asp84Glu variant confers the highest risk. This predisposition is largely independent of skin type and hair color.