With its moderate sample size (n
186), data from this case-control pilot study suggest that a low DRC does not appear to be a significant risk factor for melanoma in general in the population studied. This contrasts to what we previously reported for nonmelanoma skin cancer (NMSC)18
for this population, in which a decline in DRC was associated with a significant risk for NMSC. DRC generally declined for participants with an increased depth of melanoma tumor penetration when compared with controls and persons with localized (in situ) tumors. However, the small sample size of some groups limits statistical interpretation. This is the first study to report that an increased depth of melanoma tumor penetration is associated with a lower DRC, a phenotypic marker of this disease. DRC was influenced by the anatomical location of tumors in terms of sun exposure (protected versus exposed), for which a DRC reduction of 38% was borderline significant in malignant melanoma localized in sun-exposed areas (P
It is possible that genetic or other as yet undetermined factors may have a larger influence in determining melanoma risk in the Puerto Rican population studied. Recent studies23
involving haplogroups of 800 mitochondrial DNAs randomly and systematically selected suggest that the Puerto Rican population is genetically mixed, composed primarily of mixed African, European, and Amerindian ancestry. Through natural selection, there might be an abundance of specific genes that can provide protection against melanoma. Although this hypothesis has not been studied, it may provide a biologic explanation as to why this population, despite its chronic exposure throughout the year to high levels of UV, has a lower melanoma incidence than does the US mainland population. Another factor influencing melanoma risk in Puerto Rico could be the chronicity of sun exposure: melanoma has been associated with intermittent intense sun exposure rather than long-term, constant exposure, such as that received throughout the year in Puerto Rico.14
The present study represents the third population study that has examined the influence of DRC in terms of melanoma skin cancer risk. Two previous studies have established different conclusions; this may be a reflection of how cases are selected and the varying ethnicities and genetics in the populations that have been studied. In the Italian study17
(done with 132 cases and 1,454 age- and sex-matched control subjects), no statistically significant association between melanoma risk and DRC by itself was found (OR
1.0). However, DRC strongly influenced melanoma risk in persons with a low tanning capacity (OR
8.6) or dysplastic nevi (OR
6.7). It is noteworthy that tending to have low DRC did not appear to be a risk factor in the absence of other strong risk factors such as low tanning ability and/or dysplastic nevi. The second study done was a hospital-based case-control study involving a large population of non-Hispanic whites (312 cases, 324 controls). Case patients had a 19% lower mean DRC than did control subjects, which was statistically significant (P
< 0.001). Wei et al11
also reported that a dose-response relationship existed between decreased DRC and an increased risk of melanoma. These researchers showed that a decreased DRC is an independent risk factor for melanoma.
Our findings (from an entirely Hispanic population that is routinely exposed to high environmental UV) do not support the hypothesis that persons with melanoma have a DRC that is reduced by any statistically significant degree. The results of our study were obtained primarily from individuals in the early stages of melanoma; on the other hand, Wei et al11
studied the DRC of people at more advanced stages of the disease. This difference in test subjects may account, as well, for the differences in results. Moreover, the chronic sun exposure received by members of the Puerto Rican population could serve to constantly promote DNA repair in lymphocytes, and thus no statistically significant change can be perceived initially in the earlier stages of disease. In addition, it is important to underscore that both populations were of different ethnicities. One limitation of our study is that we were unable to obtain data on a number of dysplastic nevi. Having done so would have allowed us to compare our findings in light of what Landi et al17
From a pathologic standpoint, melanoma tumor thickness and ulceration are the two most powerful independent predictors of survival.25
This is based on the tumor, node, and metastasis staging system revised recently by the Melanoma Staging Committee of the American Joint Committee on Cancer (AJCC). The Committee used prospectively accumulated melanoma data obtained from 13 databases containing pathologic records of 13,581 patients. The AJCC classification of primary lesions is based primarily on microscopic assessment of Breslow tumor thickness.7
The preliminary findings of this study suggest that the host-cell reactivation assay used to measure DRC can at least discriminate from a localized disease (in situ) to one in which tumor thickness is more pronounced. Our preliminary results showed an increased melanoma tumor penetration associated with a lower DRC, although conclusions are limited by the small sample size of some of the subgroups. It is important to note that most of the melanoma tumors examined in this study fall in the category of thin (0-1 mm) in terms of Breslow depth. In the tumors (n
14) examined that were of intermediate thickness (>1.0-5.0 mm), DRC was reduced approximately 38% in relation to controls. This contrasts with an average increase of 8% in DRC, relative to controls, in the combined in situ and Breslow index 3 categories. One possible explanation for this seemingly paradoxical variability in DRC is that DNA repair is induced in lymphocytes in the early stages of melanoma, but as the disease progresses (ie, increased tumor penetration), this mechanism becomes progressively impaired or dysregulated.
A broader study with a larger sample size is needed to determine whether this association between melanoma tumor thickness and DRC is also evident in thick (>5.0 mm) and metastatic tumors. This is important because recent studies involving gene-expression profiling of melanoma have shown that the transition from nonmetastatic expression levels to metastatic expression levels occurs as melanoma tumors thicken.9
This transition in gene expression occurs at different thicknesses for different genes, suggesting that the “transition zone” represents a critical time for the emergence of the metastatic phenotype.
This study also provides insights as to the potential association between DRC and anatomical location of melanoma tumors in terms of sun exposure. An association between sun exposure and melanoma development was postulated nearly 50 years ago.26
Melanomas develop more commonly on the backs of white males and on the lower legs (from knees to ankles) and backs in females.7
Although melanomas can occur almost anywhere on the body, they are less common in those body parts that are protected by clothing.7
However, melanomas can also develop on the soles of the feet and in mucosal areas that are never exposed to sunlight.10
DRC was significantly (P
0.055) reduced (mean, 3.99%) in persons (n
25) with malignant melanoma tumors in sun-exposed areas of the body but not (P
0.08) in those (mean, 6.73%; n
35) with tumors in sun-protected body areas when compared with control participants (mean, 6.46%). Wei et al11
similarly found that patients in Texas with melanoma tumors on sun-exposed skin had statistically significantly (P
0.04) lower DRCs than patients with tumors on nonexposed areas. San Juan, Puerto Rico, has the second highest average UV index number (an indicator of sunlight exposure) when compared with 58 cities in the United States. In 2001, there were 210 days in which the San Juan UV index was at very high levels and 100 days in which it was at high levels.1
A study by Ramos et al1
has provided the first dose estimates of environmental UVA and UVB radiation in Puerto Rico, based on 6 years of data from a permanent UV-monitoring station that measures UVA and UVB at 4 wavelengths. The issue of UV dose in relation to melanoma risk gained national attention; the National Cancer Institute issued a press release on July 14, 2002, regarding the study by Fears et al27
titled “Average Midrange Ultraviolet Radiation Flux and Time Outdoors Predict Melanoma Risk
.” In this study, 718 patients with melanoma (non-Hispanic whites) were recruited from Philadelphia and San Francisco and compared with 945 nonmelanoma participants from the same areas. Fears et al27
concluded that a 10% percent increase in the average annual intensity of UVB was associated with a 19% increase in the individual's risk for melanoma in men and a 16% percent increase in women, at any age. It is important to consider location; for example, New Orleans receives 20% more UVB each year than Atlanta. These researchers limited the analysis to non-Hispanic whites because the numbers of cases in other racial/ethnic groups were too few for analysis; our study is the first to be performed on an entirely Hispanic population.
Despite exposure to much higher UV fluxes than is seen in most of the US population, the Puerto Rican population has a significantly lower age-adjusted melanoma incidence and mortality than those of the United States.7
In trying to resolve the questions of why and how factors affect geographic incidence rates of melanoma, it is necessary to examine whether environment (such as differing UV radiation levels between countries), genetic predisposition, or both underlie the variation seen in melanoma penetrance rates.29
To answer these questions, future population studies with large sample sizes are needed to examine how genetic (eg, DRC) and environmental (eg, UV dose) factors interact to influence melanoma risk.