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Repair of UV-Induced DNA Damage and Melanoma Risk
Qingyi Wei
C
ONTENTSEPIDEMIOLOGY OF MELANOMA
SUNLIGHT EXPOSURE AND MELANOMA
GENETIC FACTORS IN MELANOMA
UV LIGHT-INDUCED DNA DAMAGE IN MELANOMA ETIOLOGY
NUCLEOTIDE EXCISION REPAIR IN MELANOMA ETIOLOGY
DNA REPAIR GENE POLYMORPHISMS IN MELANOMA ETIOLOGY
CONCLUSIONS AND PERSPECTIVES
REFERENCES
24
Summary
Melanoma is relatively uncommon compared with nonmelanoma skin cancers, but it causes a vast majority of skin-cancer deaths. Sunlight exposure, particularly intermittent sun exposure early in life, is a well-established risk factor for melanoma. Because only a fraction of those exposed to sunlight ever developed melanoma, genetic susceptibility has long been suspected to be an etiological factor in sun- light-induced melanoma. For example, people who have a strong family history of dysplastic nevus syn- drome have an increased risk of melanoma. The extremely high frequency and early onset of melanomas in patients with xeroderma pigmentosum (XP), a rare autosomal-recessive disease of mutated DNA repair genes that confer hypersensitivity to ultraviolet light, suggest that DNA repair is involved in the etiology of melanoma. Until recently, not enough population-based data were available to support the idea that DNA repair plays a role in the etiology of sporadic melanoma, but recent studies suggest that patients with sporadic melanoma, particularly those with sunlight-sensitive skin, have a low DNA repair capacity (DRC). This theory was also supported by studies showing that patients with melanomas on sun-exposed skin had a lower DRC than did patients with melanomas on unexposed skin. Furthermore, studies found that the risk of melanoma increased as DRC decreased. Taken together, these new data suggest that reduced DRC contributes to genetic susceptibility to sunlight-induced sporadic melanoma in the general population. More studies are needed to validate that DRC is a marker for genetic susceptibility to mela- noma. With advances in high-throughput technology, individuals at increased risk for melanoma could be screened for functional variants of DNA repair genes, leading to primary prevention of sunlight- induced melanoma in the general population.
Key Words: Biomarker; DNA repair; genetic susceptibility; genotype; molecular epidemiology;
phenotype; skin cancers.
From: From Melanocytes to Melanoma: The Progression to Malignancy Edited by: V. J. Hearing and S. P. L. Leong © Humana Press Inc., Totowa, NJ
EPIDEMIOLOGY OF MELANOMA
Melanoma is relatively uncommon compared with nonmelanoma skin cancers (NMSC), but it is the most lethal cancer of the skin, causing the vast majority of skin cancer-related deaths. Since the 1970s, a melanoma “epidemic” has been occurring in the United States (1,2) and in other parts of the industrialized world, including Australia, New Zealand, and southern Europe (3,4). The incidence rate of melanoma has increased by approx 3 to 7% per year since the 1970s, although it has leveled off lately. In 2004, an estimated 7910 people died of melanoma and 55,000 new melanoma cases were diagnosed in the United States (5). It is predicted that the incidence rate of melanoma will continue to increase as the concentration of stratospheric ozone continues to decrease (6,7) and as people spend more time doing sunlight-related recreational activities, such as sunbathing (8).
SUNLIGHT EXPOSURE AND MELANOMA
Sunlight exposure, particularly intermittent sun exposure early in life, as opposed to cumulative sun exposure, is a well-established risk factor for melanoma development in humans (9–11). Increased sensitivity to the acute effects of sunlight exposure—erythema and sunburns—is also a risk factor for developing melanoma (12,13). For example, children immigrating to Australia, where ambient ultraviolet (UV) light exposure is the highest in the world, have an increased risk of melanoma compared with those who stayed in their original countries, and the risk increases with age and in those with light skin color, who freckle, sunburn easily, and are unable to tan (14,15). These data suggest that sunlight plays a very important role in the etiology of melanoma. Risk of melanoma is also associated with recreational sunlight exposure and exposure to artificial sunlight or UV radiation (UVR) (16,17). Other minor risk factors are related to occupations (18,19), diet (20,21), and hormones (22,23), although reported results have been contra- dictory (24).
UV light induces melanocytes to proliferate in both exposed and shielded areas of the skin (25). Fibroblasts and lymphocytes from melanoma patients are more sensitive to genetic damage induced by UVR than are cells from the controls (26). Several molecular mechanisms of UV light-induced carcinogenesis have been postulated, including alter- ations in growth factors, mutations of tumor suppressor genes, and immune suppression (27). However, unlike NMSC, in which the incidence is clearly related to solar radiation exposure, the incidence of melanoma is much less dependent on sunlight exposure (17).
Furthermore, some melanomas occur on unexposed body sites and some melanoma patients have a strong family history of melanoma and premalignant lesions, such as inherited cutaneous moles or nevi that are not directly related to sun exposure (28).
Therefore, the exact role of UV light in the etiology of melanoma warrants further investigation.
GENETIC FACTORS IN MELANOMA
Epidemiological studies found that a high frequency of common nevi in childhood is also associated with an increased risk of melanoma (29,30). In familial atypical multiple- mole melanoma syndrome, inherited cutaneous moles or nevi appear to be the precursors of malignant lesions (31,32). The relative risk of developing melanoma is greater than
300-fold for people whose relatives have melanoma and greater than 85-fold in those whose relatives have dysplastic nevi (33). Several high-penetrance melanoma susceptibility genes, including p16/MTS1/CDKN2A/p14ARF and CDK4, have been cloned and mapped to the human chromosomes 9p and 12q respectively, in familial melanoma patients (34–38), but hereditary melanoma cases account for only about 10%
of all melanomas (39).
Therefore, some low-penetrance melanoma susceptibility genes exist, whose poly- morphisms or variants appear to modify the risk associated with sunlight exposure.
However, to date, no published study has been large enough to provide solid evidence for an association between variants of these low-penetrance genes and risk of melanoma.
One of these genes is the melanocortin 1 receptor (MC1R) gene, whose variants are associated with red hair and fair skin and have been shown to be risk factors for mela- noma (40,41). However, later studies have produced mixed results (42–44). Two poly- morphisms of CDKN2A (C500G and C540T) were found to be associated with an increased risk of developing melanoma (45,46), but a later study did not confirm these findings (47). A newly identified functional epidermal growth factor was found to be associated with an increased risk of risk of developing melanoma (48), but a later study could not replicate these findings, instead observing that this factor play a role in mela- noma progression (49). The results from one study on polymorphisms of the GSTM1, GSTT1, CYP2D6, and VDR genes were inconclusive (50).
Because benign, atypical, and dysplastic nevi are also independent predictors of sporadic melanomas (51–53), with about 40% of patients with sporadic melanoma having dysplastic nevi compared with 7% of the general population (52), additional host susceptibility factors other than the known susceptibility genes may play a role in the etiology of sporadic melanoma in the general population. The high frequency and early onset of melanoma in patients with xeroderma pigmentosum (XP)—a rare autosomal recessive disease of mutated DNA repair genes that confers hypersensitivity to UV light and has an incidence rate of 1 in 250,000 in the United States (54)—suggest that geneti- cally determined DNA repair capacity (DRC) may be involved in the pathogenesis of human melanoma.
UV LIGHT-INDUCED DNA DAMAGE IN MELANOMA ETIOLOGY
UV light induces DNA damage, also called photoproducts, which are usually thought of as bulky lesions involving more than one nucleotide in the skin; UV light also pro- duces free radicals that cause oxidative damage to DNA, resulting in oxidative stress in the cells (55). Several glutathione-S-transferase (GST) isoenzymes encoded by the GST supergene family, which includes the GSTM, GSTT, and GSTP gene families, catalyze the conjugation of reduced glutathiones with a wide range of carcinogenic electrophiles and oxidized DNA (56,57). Therefore, it is biologically plausible that a deficiency in these isoenzymes contributes to the risk of UV light-induced melanoma. Studies of polymorphisms in the GST supergene family have shown that individuals who carry the null GSTM1 or GSTT1 alleles and who have light skin (and thus are prone to photoprod- uct formation after exposure to sunlight) have a higher risk of developing multiple basal cell carcinomas (BCCs) than do controls (58,59). Immunohistochemistry showed that the human GSTM1 protein is present in normal skin, nevi, and melanocytes (60), and that individuals who have the GSTM1-null genotype tend to have an increased risk of devel-oping melanoma (61). GSTM1 may also be involved in the DNA repair associated with drug resistance (56,62). Therefore, to understand the extent to which the GSTM1-null and GSTT1-null genotypes contribute to the risk of developing melanoma, studies that evaluate both GST genotypes and DRC are needed to determine the genotypes’ indi- vidual and combined roles in the etiology of melanoma (50).
NUCLEOTIDE EXCISION REPAIR IN MELANOMA ETIOLOGY
The role of DNA repair in human skin carcinogenesis was first demonstrated in XP patients (63,64), in whom there was a defect in the repair system for UV light-induced DNA damage coupled with a 2000-fold increased frequency of having sunlight-induced skin cancers compared with the general population (54). Malignant skin neoplasms are present in 70% of patients with XP and appear at a median age of 8 yr, which is 50 yr younger than in the general US, non-Hispanic, white population (65). Unrepaired UV light-induced damage in DNA undergoing replication leads to mutation fixation (66), as seen in the mutations frequently found in the ras and p53 genes (often CoT or CCoTT, the so-called UV signature mutations) of skin tumors on sun-exposed body sites of both XP patients (67,68) and persons with sporadic skin cancers (69,70).UV light-induced DNA damage is effectively removed by the nucleotide excision repair (NER) pathway, which involves at least 20 genes (71). XP is genetically hetero- geneous, and mutations in seven genes (XPA through XPG) are known to cause this disease. All seven XP gene products are involved in NER, which removes a wide variety of DNA damages by incision on both sides of the lesion (71). An in vitro NER system for UV light-induced damage can be reconstituted with the proteins XPA, replication protein A, XPC–HR23B complex, transcription factor II H (containing XPD), XPF–ERCC1 complex, XPG, and damage DNA-binding protein (72). A number of NER genes are so-called core factors that participate in NER activities; any functional mutation in these genes will lead to NER abnormalities and therefore susceptibility to cancers, including skin cancer in XP patients.
One study found a nonsignificant difference in DRC between patients with hereditary dysplastic nevi and healthy controls (73). Other studies with fibroblast and lympho- blastoid cell lines derived from patients with and without melanoma and dysplastic nevi suggested that patients with familial melanoma had abnormal sensitivity to sunlight (74) and a defect in the repair of UV light-induced DNA damage (75). These relatively small studies suggest that inherited DRC plays a role in the pathogenesis of sporadic melanoma.
DRC Phenotype and Risk of Skin Cancers
XP provides an excellent disease model with which to study the etiology of skin cancers. Kraemer et al. published the first comprehensive estimation of the risk of developing neoplasms in 726 XP patients from 41 countries from 1874 to 1982. Com- pared with the general population, XP patients younger than 20 yr had an estimated 2000- fold increased risk of having BCCs and squamous cell carcinoma (SCC) of the skin, cutaneous melanoma, and other cancers involving UV light exposure (76). However, until recently, the role of DRC in sunlight-induced skin cancers in the general population was largely unknown.
BASAL CELL CARCINOMAS
Because the incidence of BCC, compared with SCC, is less dependent on exposure to sunlight (17), genetic factors are more likely to play a role in the etiology of BCC than of SCC. Furthermore, an extraordinarily high incidence rate of BCC among XP patients suggests that abnormal DRC plays a role (77). Therefore, BCC serves as an excellent disease model for studying the role of DRC and gene–environment interactions in skin cancer. In the 1990s, investigators began to design laboratory assays that would allow the role of DRC in the etiology of BCC to be studied in the general population.
The first hospital-based, case–control study of skin cancer and DRC was the Balti- more Study, which was conducted between 1987 and 1990 (78). To increase the study’s efficiency for testing genetic susceptibility, investigators enrolled subjects between 20 and 60 yr of age because genetically determined cancer risk is characterized by an early onset of cancer, as seen in XP patients. Patients with BCC and selected controls free of known hereditary skin diseases and cancers were frequency matched by age. This kind of study design allowed the investigators to control for confounding by age and other genetic factors. Blood samples were drawn from the subjects, and the lymphocytes were cryopreserved and later assayed in batches. This approach was designed to avoid experi- mental variation in the assays caused by differences in daily laboratory procedures. The DRC was measured by a newly developed host cell reactivation (HCR) assay (79), with the plasmids harboring the chloramphenicol acetyltransferase reporter gene. The plas- mids were damaged by an incident dose of 254 nm of UVR (700 J/m2; 30 J/m2produces one pyrimidine dimer per plasmid) before transfection. Preliminary data from 88 pa- tients with BCC and 135 cancer-free controls suggested that the distribution of DRCs among subjects was approximately normal, with a fivefold variation between individu- als; however, the DRC decreased significantly as age increased (78). DRCs below the upper 30th percentile of the controls were associated with a greater than twofold in- creased risk for BCCs. This risk was even higher in subgroups with lighter skin (>three- fold); six or more severe sunburns in a lifetime (>fourfold); and moderate or severe actinic elastosis (>fourfold), who had low DRC but not in those subgroups with high DRC (80). Furthermore, the number of skin tumors among patients with BCCs signifi- cantly increased as the DRC decreased, after adjustment for age (81). The inverse rela- tionship between DRC and risk of BCCs is consistent with the notion that the underlying mechanism for sunlight-induced BCC is defective DRC.
The results of the Baltimore Study were not confirmed by a later population-based, case–control study of NMSC (including BCC and SCC) in Western Australia (82). This study used the same HCR–DRC assay as that used in the Baltimore Study, but with a lower dose of UVR (254 nm, 350 J/m2) to damage the plasmids. The investigators performed the assays on T-lymphocytes isolated from 86 skin cancer cases (76 BCCs and 25 SCCs) and 87 healthy controls between the ages of 44 and 68 yr. They found no evidence for a difference in DRC between the cases and controls.
Differences between the Baltimore Study and the Australian Study, including differ- ent BCC patient sample sizes, different age ranges of the subjects, and, more impor- tantly, different degrees of ambient sunlight exposure, may account for the observed discrepancies. For example, the incidence of BCCs was not sunlight dependent but the incidence of SCC was in Maryland fishermen (83); in Australia, both BCC and SCC were sunlight dependent, but the incidence of SCCs was more sunlight-dependent than that of BCCs, and the incidence of melanoma was the least sunlight-dependent (17).
These incidence data suggest that the BCCs in Maryland may be more genetically determined, with a low threshold of sunlight exposure, whereas BCC in Australia may be more sunlight related, because saturated sunlight exposure could have overcome even a proficient DRC. However, this hypothesis needs to be further tested.
In 1999, D’Errico et al. (84) investigated the role of DRC in 49 patients with BCC and 68 cancer-free controls in Italy. This study used the same HCR–DRC assay as that used in the Baltimore and Australian studies. The authors found a statistically significant age- related decline in DRC observed among controls from 20 to 70 yr of age but not among BCC cases. They also found significant differences in DRC between the cases and controls. These findings are similar to those of the Baltimore Study (78,80). More inter- estingly, the authors of the Italian study also found that tobacco smoking may enhance DRC among older patients, a finding that was later confirmed by a larger study (85).
Using the same HCR assay, Dybdahl et al. (86) studied DRC among patients with psoriasis in Denmark; they were investigating the importance of DRC in chemically induced skin cancer. They observed a significantly lower DRC among 20 psoriasis patients with skin cancer than among 20 psoriasis patients without skin cancer. Individu- als who had a low DRC had a greater than sixfold increased risk of skin cancer compared with individuals with high DRC. The lower the level of DRC, the earlier the patients had their first skin tumor. Interestingly, they found no difference in DRC between 20 BCC patients without psoriasis and 20 healthy controls.
More recently, Matta et al. (87) conducted a larger study of 288 NMSC patients (78%
had BCC) and 177 cancer-free controls in Puerto Rico. They measured DRC using a modified HCR assay with a luciferase reporter gene instead of a chloramphenicol acetyltransferase reporter gene. The authors found a clear age-related decline in DRC among the controls; the patients had a 42% reduction in DRC compared with the con- trols, and this difference contributed to a nearly fourfold increased risk of skin cancer.
The number of tumors increased as DRC decreased. These findings further confirmed the findings from the Baltimore Study (78,81,88).
MELANOMA
The link between the occurrence of melanoma and defective DRC is supported by analyses of skin cancers in XP patients, but is less obvious in the general population because of a lack of data from population-based studies. Kraemer et al. (76) analyzed published reports of 132 XP patients and found that 22% of these patients had melanoma.
The frequency of melanomas was increased greater than 1000-fold in patients with XP who were younger than 20 yr compared with the general population. These findings suggest that sunlight exposure and poor DRC cause melanoma in patients with XP. Until recently, there was a lack of evidence showing that defective DRC leads to an increased risk of developing melanoma in the general population.
An Italian Hospital-Based, Case–Control Study. Landi et al. (89) conducted a molecular epidemiological study on DRC and melanoma in Italy between 1994 and 1999. This study included 183 patients with melanoma and 179 control subjects who were recruited from the Dermatology Unit of the Bufalini Hospital in Cesena, Italy.
Approximately 85% of the melanoma patients were from the Northern Marche and Southern Romagna areas, and approx 55% of the control subjects were spouses or close friends of the case patients. The majority of subjects had no occupational sun exposure but did have prolonged recreational (intermittent) sun exposure. The final analysis included 132 patients with melanoma and 145 control subjects whose DRC was tested
by the HCR assay (17); the plasmids were damaged by one 254-nm dose of UVR (350 J/m2).
The investigators found that overall melanoma risk and DRC were not associated in this Italian population. Among cases with dysplastic nevi, DRC was not associated with known risk factors for melanoma (except for recreational lifetime sun exposure) includ- ing age; the color of the hair, eyes, and skin; and skin response to sunlight exposure; nor was between DRC associated with melanoma characteristics. DRC decreased with increasing age among control subjects without dysplastic nevi or with few nevi, but increased with increasing age among control subjects with dysplastic nevi or with many nevi. These findings suggest that the effect of dysplastic nevi on risk of melanoma is independent of DRC. In other words, dysplastic nevi and DRC may have different genetic implications and play different roles in the etiology of melanoma. Low DRC was a risk factor only in subjects who had a low tanning ability. Individuals with a low tanning ability and a low DRC had a greater than eightfold increased risk of melanoma compared with subjects with a high or medium tanning ability and a high DRC. This finding suggests low DRC may have played a role in the development of sunlight- induced melanoma in this Italian population.
An American Hospital-Based, Case–Control Study. Between 1994 and 2001, we conducted a molecular epidemiological study on DRC and melanoma in Texas (90), where exposure to ambient sunlight is much higher than in Northern Italy. This study is perhaps the largest case–control study of its kind to date; 312 melanoma patients were recruited at The University of Texas M. D. Anderson Cancer Center in Houston, TX, and 324 cancer-free subjects were selected from genetically unrelated clinic visitors (83%) and spouses (17%). The melanoma patients and cancer-free controls were frequency matched by age (r5 yr) and sex; all subjects were non-Hispanic whites who resided in Texas. DRC was measured by the HCR assay (17), with the plasmids damaged by an incident dose of 800 J/m2 of UVR. The results revealed that an increased risk for mela- noma was associated with having naturally blonde or red hair (>twofold) compared with black or brown hair; blue eye color (>1.5-fold) compared with other eye colors; fair or light brown skin (>3.5-fold) compared with dark skin; poor or low tanning ability (nearly twofold) compared with good or high tanning ability; and more than one sunburn (>twofold) compared with zero or one sunburn throughout life. These find- ings suggest that sunlight exposure played a role in the etiology of melanomas in this study population.
Overall, the melanoma patients in our study had a significant reduction in mean DRC (by 19%) compared with cancer-free controls. Low DRC was associated with a nearly twofold increased risk of melanoma. Notably, female patients had significantly lower DRC than did male patients, and this sex-related difference was not observed among the controls. This sex difference in patients with cancer was also observed in our previous studies on BCC and lung cancer (78,85). Among the patients only, the subgroups that tended to have low DRC were those with blonde or red hair, blue eyes, fair skin, and poor tanning ability, but the differences were not statistically significant. These data suggest that low DRC is the underlying molecular mechanism for these known risk factors, as well as for the genetic susceptibility that contributes to the risk of UV light-induced melanoma.
When the control subjects’ DRC values were divided into tertiles (i.e., efficient, medium, and poor), a dose–response relationship was observed between increased risk and decreased DRC in an unconditional logistic model after adjustment for age, sex, hair
color, eye color, skin color, tanning ability after prolonged sun exposure, lifetime sun- burns with blisters, freckling after sun exposure as a child, and presence of moles and dysplastic nevi. These findings provide evidence that low DRC is an independent risk factor for melanoma and may play a role in the etiology of sporadic melanoma. Not only are these results consistent with the results of previous studies of XP patients, in which defective DRC was associated with sunlight-induced skin cancers, including melanoma;
but also they are consistent with results of earlier studies of NMSC, in which reduced DRC was shown to be associated with increased risk of BCC in the general population.
Modification of DRC Phenotype by Genotypes of DNA Repair Genes
Phenotypic studies have revealed that DRC varies among individuals up to fivefold and may be modulated by genetic and environmental factors (81,85,91). Because the DRC phenotype assay is labor intensive, costly, and potentially influenced by environ- mental factors, there is a need to identify genotypes that are correlated with DRC and amenable to high-throughput analysis. The advantage of genotypic assays is that the assays are not affected by environmental factors. In our pilot studies of 102 cancer-free subjects, we performed the chloramphenicol acetyltransferase and luciferase HCR–DRC assays and genotyped for four variants of the XPC and XPD genes (XPC PAT+ in intron 9 and XPD 156Arg, 312Asn, and 751Gln) (91,92).Based on the DRC data generated by the chloramphenicol acetyltransferase assay, we found that individuals with the XPC PAT+/+ genotype, but not the heterozygotes (PAT–/+), had statistically significantly lower DRC than those with wild-type homozygotes (PAT–/–).
Similarly, XPD homozygotes, but not XPD heterozygotes, were consistently correlated with lower DRC than were wild-type homozygotes, but none of the differences was statistically significant. These results suggest that these variant alleles have a recessive effect on DRC phenotype. Because relatively few individuals were homozygous for the XPC and XPD variant alleles compared with other genotypes, we combined individuals with these variant homozygotes into one group. Based on the data generated by the luciferase assays, which appeared to improve precision and reduce variation in the measurements, the group with one or more XP variant homozygous genotypes (n = 45) had a significantly lower DRC than did the other genotype group (n = 57); more inter- estingly, the DRC measured by the luciferase assay decreased as the number of variant homozygous genotypes increased (91).
These phenotype and genotype correlation data suggest that DRC for NER is modu- lated by genetic polymorphisms of NER genes, such as XPC and XPD. Furthermore, each variant NER allele or genotype may partially contribute to the NER phenotype and, thus, to genetic susceptibility to cancer. Therefore, a combination of several variant genotypes of the NER genes that determine the DRC phenotype should be identifiable.
In molecular epidemiology studies of the association between DRC and genetic suscep- tibility to cancer, a large number of samples need to be evaluated for the DRC phenotype.
Further investigations are needed to identify a DNA repair pathway genotype that pre- dicts the DRC phenotype and that can then be used for population-based studies, even- tually leading to mass screening for individuals at risk.
DNA REPAIR GENE POLYMORPHISMS IN MELANOMA ETIOLOGY
Recent completion of the Human Genome Project has provided timely information on sequence variations of known DNA repair genes. In their pioneer work to identify themolecular basis for variations in DRC, Mohrenweiser and colleagues resequenced 37 DNA repair genes in 164 biologically unrelated individuals and identified 127 amino acid-substitution variants resulting from single-nucleotide polymorphisms (93,94). The single-nucleotide polymorphism databases on DNA repair genes will be a huge resource for future molecular epidemiology studies on the DNA repair gene genotype and phe- notype correlation and their associations with cancer risk. The findings of Mohrenweiser et al. have stimulated a large number of studies that contribute to our understanding of the role of variants of DNA repair genes in individual susceptibility to cancer (95).
However, relatively few studies on melanoma and DNA repair gene polymorphisms have been conducted to date.
The first United Kingdom case–control study on melanoma and DNA repair gene polymorphisms was reported by Winsey et al. (96). They investigated the association between polymorphisms of five DNA repair genes (XRCC1, ERCC1, XPD, XPF, and XRCC3) and the risk for developing melanoma in 125 patients with melanoma and 211 cancer-free controls. Except for XRCC3, none of the variants selected was associated with an increased risk of melanoma. XRCC3 is involved in double-strand break repair and the variant is a T-allele in exon 7 (position 18067 and codon 241 [Thr241Met]) of XRCC3, and was found to be associated with an approximately twofold increased risk of developing melanoma (96). However, this finding was not confirmed in our larger study of 305 patients with melanoma and 319 non-Hispanic white controls in Texas (97) or in subsequent studies on NMSC in Denmark (98). A later study investigated the role of polymorphisms in exon 4 of ERCC1 (GoA) and exons 6 (AoC), 22 (CoT), and 23 (AoC) of XPD in 56 patients with melanoma and 66 cancer-free controls (99). Although this study was small, the XPD exon 22 (CoT) and 23 (AoC) polymorphisms appeared to be associated with an increased risk of melanoma. In a more recent study, an Italian research group investigated the genetic basis for reduced DRC in melanoma and genotyped the XPD Asp312Asn (exon 10) and Lys751Gln (exon 23) polymorphisms (100). Although the Italian researchers did not observe an association between these XPD polymorphisms and increased melanoma risk in 176 cases and 177 cancer-free controls, they found an increased risk for melanoma among subgroups of older subjects (>50 yr), subjects without dysplastic nevi, and subjects with low tanning ability. These findings provide further support for a role of inherited low DRC in sunlight-induced, sporadic melanoma in the general population.
CONCLUSIONS AND PERSPECTIVES
Emerging data, both from laboratory and population studies, suggest that variations in NER capacity phenotype and polymorphisms in NER genes are potential risk factors for sporadic melanoma and that polymorphisms in NER genes contribute to variations in DRC phenotype in the general population. A combined NER pathway genotype could be identified that may predict the NER phenotype and risk of melanoma better than any single genotype; therefore, this combined pathway genotype may serve as a better tool for studying interactions between genetic factors and sunlight exposure in the etiology of sporadic melanoma. More studies are needed to further validate DRC as a marker for genetic susceptibility to melanoma and to search for genetic variants that could better predict DRC phenotype and risk of melanoma. With advances in high-throughput tech- nology, individuals at increased risk for melanoma could be screened for several func- tional variants of DNA repair genes, leading to primary prevention of sunlight-induced melanoma in the general population.
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