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Sunlight exposure and certain host factors such as red hair and fair skin are established risk factors for non-melanoma skin cancers. Because deficient DNA repair capacity has contributed to the development of skin cancers in a rare genetic disease, xeroderma pigmentosum, we explored this deficiency as an etiologic factor in a recent population study. We used a new DNA repair assay, the host-cell reactivation, in a clinic-based case-control study to test the hypothesis that reduced DNA repair is the underlying molecular mechanism for the development of sunlight-induced basal cell carcinoma. The peripheral lymphocytes from 88 patients with primary BCC and 135 cancer-free controls were tested for their capacity to repair ultraviolet light-induced DNA damage in a reporter gene, chloramphenicol acetyl transferase. All subjects were between the ages of 20 and 60 years and were frequency matched by age (+/- 5) and sex. Among those who reported frequent sunbathing, poor tanning ability, a history of multiple sunburns, exposure to chemicals, or multiple medical irradiations, the BCC patients had significantly lower DNA repair capacity than controls (p < 0.05). DNA repair capacity was also found substantially lower in the basal cell carcinoma patients who had red hair and light skin (type I). Compared to controls, basal cell carcinoma cases with selected risk factors had a relative decrease in DNA repair capacity of 10-28%. These findings provided evidence that reduced DNA repair capacity is one of the underlying molecular mechanisms for sunlight-induced skin carcinogenesis in the general population.

This study investigated the role of DNA repair in susceptibility to sunlight-induced basal cell carcinoma using a host cell reactivation assay in peripheral lymphocytes. The study included Maryland basal cell carcinoma patients and cancer-free dermatologic controls who had had noncancerous skin disorders diagnosed between 1987 and 1990. Logistic regression models were used to assess the independent effect of the selected variables stratified by DNA repair level, with adjustment for age and family history. Skin type, lifetime number of severe sunburns, and actinic elastosis were also selected as risk factors for basal cell carcinoma. Cryopreserved lymphocytes from 88 cases and 135 controls were used for the DNA repair assay. When data were stratified by DNA repair level and adjusted for age and family history of skin cancer, significantly increased odds ratios associated with lighter skin (odds ratio (OR) = 3.2, 95% confidence interval (CI) 1.5-7.3), six or more severe sunburns in a lifetime (OR = 4.2, 95% CI 1.6-10.7), and moderate or severe actinic elastosis (OR = 4.4, 95% CI 1.5-12.8) were observed in persons with low DNA repair but not in those with high DNA repair. These findings suggest that impaired DNA repair may be a susceptibility factor for sunlight-induced skin cancer in the general public, as it is in patients with xeroderma pigmentosum.

Defective repair of sunlight-induced DNA photodamage, coupled with an unusually high occurrence of multiple primary basal cell carcinomas (BCCs), is the major characteristic of xeroderma pigmentosum. Our recent work has indicated that this etiological paradigm may apply to skin cancer patients without an apparent hereditary disease. The present study reports on an investigation of whether medications such as photosensitizing drugs (antibiotics, corticosteroids, and aspirin) modulate skin cancer risk through alterations in DNA repair capacity (DRC). Using a new DNA repair (host cell reactivation) assay with peripheral T-lymphocytes, we tested DRCs of 88 Caucasian BCC patients and 135 cancer-free controls. Subjects were between 20 and 60 years of age and free of known hereditary skin diseases. The age-adjusted means of DRC were calculated to compare repair levels associated with the use of specific drugs and hormones. Multiple linear regression models were used to correlate DRC with the number of skin cancers. The estimated odds ratio was used to describe the risk of BCCs. The distribution of DRCs of subjects was approximately normal, with a 5-fold variation between individuals. DRCs below the upper 30th percentile of controls were associated with an estimated 2.3-fold (95% confidence interval, 1.17-4.54-fold) increased risk for the occurrence of BCCs. The lower the DRC was, the greater the number of skin tumors in individuals (P < 0.05), after adjustment for age. Although supplemental vitamin use was associated with reduced risk of skin cancer, it was not associated with differences in subjects' DRCs. However, individuals who reported taking either tetracycline or estrogen, two photosensitizing drugs, had higher DRCs, compared with those who had not used these drugs. Low DRC or a family history of skin cancer increased the probability that patients who were overexposed to sunlight would have multiple BCCs. DNA repair levels may be influenced by the use of selected photosensitizing drugs and estrogen.

This molecular epidemiology study examines the DNA-repair capacities (DRCs) of basal cell carcinoma (BCC) skin cancer patients (88) and their controls (135) by using a plasmid/host-cell reactivation assay. In this assay UV-damaged expression vector plasmid is transfected into peripheral blood T lymphocytes from the subjects. The host-cellular repair enzymes repair the photochemical damage in the plasmid, and 40 hr later the plasmid-encoded reporter chloramphenicol acetyltransferase is measured. An age-related decline in this DRC, amounting to approximately 0.61% per yr occurred in the controls from 20 to 60 yr of age. Reduced DRC was a particularly important risk factor for young individuals with BCC and for those individuals with a family history of skin cancer. Young individuals with BCC repaired DNA damage poorly when compared with controls. As the BCC patients aged, however, differences between cases and controls gradually disappeared. The normal decline in DNA repair with increased age may account for the increased risk of skin cancer that begins in middle age, suggesting that the occurrence of skin cancer in the young may represent precocious aging. Patients with reduced DRCs and overexposure to sunlight had an estimated risk of BCC > 5-fold greater than the control group. Such a risk was even greater (10-fold) in female subjects.

A method for measuring nucleotide excision repair in response to UV irradiation and chemical-induced DNA damage has been developed, validated, and field tested in cultured human lymphocytes. The methodology is amenable to population-based screening and should facilitate future epidemiological studies seeking to investigate associations between DNA repair proficiency and cancer susceptibility. The impetus for such endeavors derives from the suggestion that the high incidence of skin cancer in the genetic disorder xeroderma pigmentosum is manifested as a result of the reduced capacity of patients' cells to repair DNA damaged by UV-mimetic agents. For the assay, damaged, nonreplicating, recombinant plasmid DNA harboring a chloramphenicol acetyltransferase (cat) reporter gene is introduced into lymphocytes by using a DEAE-dextran/DNA complex short-term transfection conditions. Excision repair of the damaged bacterial cat gene is monitored proportionately as a function of reactivated CAT enzyme activity following a 40-h repair/expression incubation period. The validity of the approach was indicated by the ability of the assay to discriminate xeroderma pigmentosum virus-transformed lymphocyte cell lines of both severe (complementation groups A and D) and moderate (complementation group C) excision repair deficiencies from repair-proficient cell lines. Similar results were observed when a mitogen-stimulated peripheral blood lymphocyte culture from an xeroderma pigmentosum A patient was assayed concurrently with mitogen-stimulated peripheral blood lymphocytes obtained from healthy individuals. Adaptation of this DNA repair assay as a field test in a pilot-tested select group of basal cell carcinoma patients and cancer-free controls led to the preliminary identification of a specific subset at risk for this disease as a consequence of significant reduction to the repair of photochemically (UV)-damaged plasmid DNA.