A protective effect of glutathione-S-transferase GSTP1*Val(105) against polymorphic light eruption.

Polymorphic light eruption (PLE) is a common skin disease, susceptibility to which is genetically determined. The prevalence of PLE is significantly increased in patients with lupus erythematosus (LE) including subacute cutaneous lupus erythematosus (SCLE) and discoid lupus erythematosus (DLE), which may reflect a common genetic background. Experimental evidence supports a role for reactive oxygen species (ROS) in the pathogenesis of PLE, and the family of glutathione-S-transferase (GST) enzymes exerts a critical physiological role in cellular protection against this oxidative damage. Our aim was to look for association between the functional GST gene polymorphisms and PLE, SCLE, and DLE in a case-control study. The carrier frequency of GSTP1 Val(105) in subjects with PLE was 40%, significantly lower than the carrier frequency in controls (54%, P=0.019), although significance was lost on correction for multiple testing. However, the carrier frequency of the GSTP1 Val(105) allele in combined cutaneous LE (SCLE and DLE) patients with PLE was 42%, significantly lower than in those without PLE (72%), which did survive correction (corrected P=0.043). We have identified evidence supporting a protective GSTP1 allele, the first genetic association to be reported for PLE. This supports a role for ROS in the pathogenesis of PLE and may provide a therapeutic target for future treatment of this common, often disabling, condition.

Clinicopathologic features of skin cancer in organ transplant recipients: a retrospective case-control series.

BACKGROUND: Non-melanoma skin cancers (NMSCs) are increased in organ transplant recipients, but transplant and immunocompetent squamous and basal cell carcinomas (SCCs, BCCs) have not been compared previously in a single-center study. OBJECTIVE: To compare clinicopathologic features of transplant and immunocompetent NMSCs. METHODS: Consecutive transplant NMSCs (60 SCCs, 100 BCCs) and immunocompetent NMSCs (40 SCCs, 125 BCCs) presenting between 1995-1997. RESULTS: Transplant patients were 15 years younger at time of NMSC diagnosis compared with immunocompetent individuals, and transplant tumors were often more multiple and extracephalic. Spindle cell morphology was more common in transplant SCCs, a superficial component was more common in transplant BCCs, and histologic features of HPV infection were overrepresented in transplant tumors. Outcome was worse for transplant SCCs but not transplant BCCs. LIMITATIONS: Histologic features required to identify HPV infection have not been validated. CONCLUSIONS: These findings have direct implications for clinical care. The increased frequency and distribution of transplant NMSCs underscore the importance of whole-body surveillance. Transplant SCCs, particularly those with diffuse spindle cell change, may require more aggressive management, whereas transplant BCCs do not. Finally, our data support differences in the pathogenesis of transplant NMSC, which may influence future preventive and therapeutic strategies.

Isolation and structural modification of 7-deoxynarciclasine and 7-deoxy-trans-dihydronarciclasine.

As an extension of structure-activity relationship studies of pancratistatin (1), various techniques were first evaluated for separating the mixtures of 7-deoxynarciclasine (2b) and 7-deoxy-trans-dihydronarciclasine (3a) isolated from Hymenocallis littoralis. An efficient solution for that otherwise difficult separation then allowed the lactam carbonyl group of protected (4c and 5c) alcohols 2b and 3a to be reduced employing lithium aluminum hydride. Cleavage (TBAF followed by H2SO4) of the silyl ester/acetonide protected 6a gave amine 8. X-ray crystal structure determinations were employed to confirm the structures of 3,4-acetonide-5-aza-6-deoxynarciclasine (6b), 5-aza-6-deoxynarciclasine (8a), and 5-aza-6-deoxy-trans-dihydronarciclasine (9a, 9b). Against the murine P388 lymphocytic leukemia and a panel of human cancer cell lines, the parent natural products, 7-deoxynarciclasine (2b) and 7-deoxy-trans-dihydronarciclasine (3a), were found to generally be more cancer cell growth inhibitory (GI50 0.1 to <0.01 microg/mL) than the compounds with structural modifications such as amine 8 by a factor of 10 or more. The trans ring juncture of isocarbostyril 3a proved to be an important modification of narciclasine (2a) for improving cancer cell growth inhibition in this series.

Azathioprine and UVA light generate mutagenic oxidative DNA damage.

Oxidative stress and mutagenic DNA lesions formed by reactive oxygen species (ROS) are linked to human malignancy. Clinical treatments inducing chronic oxidative stress may therefore carry a risk of therapy-related cancer. We suggest that immunosuppression by azathioprine (Aza) may be one such treatment. Aza causes the accumulation of 6-thioguanine (6-TG) in patients' DNA. Here we demonstrate that biologically relevant doses of ultraviolet A (UVA) generate ROS in cultured cells with 6-TG-substituted DNA and that 6-TG and UVA are synergistically mutagenic. A replication-blocking DNA 6-TG photoproduct, guanine sulfonate, was bypassed by error-prone, Y-family DNA polymerases in vitro. A preliminary analysis revealed that in five of five cases, Aza treatment was associated with a selective UVA photosensitivity. These findings may partly explain the prevalence of skin cancer in long-term survivors of organ transplantation.

Human papillomavirus gene expression in cutaneous squamous cell carcinomas from immunosuppressed and immunocompetent individuals.

Epidermodysplasia verruciformis (EV)-type human papillomavirus (HPV) DNA have been detected by PCR in squamous cell carcinomas (SCC) from both organ transplant recipients (OTR) and immunocompetent individuals. Their role in skin cancer remains unclear, and previous studies have not addressed whether the viruses are transcriptionally active. We have used in situ hybridization to investigate the transcriptional activity and DNA localization of HPV. EV-HPV gene transcripts were demonstrated in four of 11 (36%) OTR SCC, one of two (50%) IC SCC, and one of five (20%) OTR warts positive by PCR. Viral DNA co-localized with E2/E4 early region gene transcripts in the middle or upper epidermal layers. Non-EV cutaneous HPV gene transcripts were demonstrated in one of five (20%) OTR SCC and four of 10 (40%) OTR warts. In mixed infections transcripts for both types were detected in two of six (33%) cases. Our results provide evidence of EV-HPV gene expression in SCC; although only a proportion of tumors were positive, the similarly low transcriptional activity in warts suggests this is an underestimate. These observations, together with emerging epidemiological and functional data, provide further reason to focus on the contribution of EV-HPV types to the pathogenesis of cutaneous SCC.

High frequency and diversity of cutaneous appendageal tumors in organ transplant recipients.

BACKGROUND: Recipients of organ transplant who are immunosuppressed are at greatly increased risk of nonmelanoma skin cancers compared with the general population, but their risk of appendageal tumors is unknown. OBJECTIVE: Our aim was to conduct a systematic examination of cutaneous appendageal tumors arising in recipients of organ transplants compared with individuals who were immunocompetent (ICP). METHODS: We conducted a retrospective, clinicopathologic analysis of consecutive appendageal tumors arising in 650 recipients of organ transplants and in the general population of approximately 605,000 people served by our institution. RESULTS: Between 1993 and 1998, 231 appendageal tumors were identified in 211 individuals; 23 tumors were found in 21 of 650 patients undergoing transplant (3%), 10 in individuals with other immunosuppressive conditions, 3 in 2 patients with Muir-Torre syndrome, and 195 in 178 apparently ICP. In addition to the increased frequency of appendageal tumors among recipients of transplants, malignant tumors were overrepresented (43% of transplant tumors vs 4% in ICP; P <.0001) as were tumors of sebaceous origin (30% vs 6%; P <.0001). CONCLUSIONS: Recipients of organ transplant who are immunosuppressed have a greatly increased risk of cutaneous appendageal tumors compared with apparently ICP. In addition, their tumors are more likely to be malignant and of sebaceous origin.

Relationship between p53 codon 72 polymorphism and susceptibility to sunburn and skin cancer.

Upregulation of p53 protein induces either growth arrest or apoptosis in response to cellular injury This is signaled from a highly conserved p53 domain between codons 64 and 92, where a functional polymorphism results in either a proline (p53-72P) or an arginine (p53-72R) at codon 72. Preliminary studies suggest that p53-72R may be a risk factor for cervical cancer and, consistent with this, preferential mutation and retention of the p53-72R allele has also been demonstrated in other cancers of squamous cell origin. Here we examine the relationship between allelic forms of p53 and nonmelanoma skin cancer, by determining the correlation with susceptibility to sunburn, which is a known risk factor, and then by p53 sequence analysis of a large series of tumors. We found a significant positive association between p53-72R and susceptibility to sunburn, as assessed by skin phototype and minimal erythemal dose following solar-simulated radiation (p = 0.0001 for trend). We also found a significant association between p53-72R homozygosity and nonmelanoma skin cancer in renal transplant recipients (basal cell carcinoma, p < 0.01; squamous cell carcinoma, p < 0.05) but not in immunocompetent patients compared with skin type matched controls. p53 sequence data revealed mutations in 30 of 70 (42.9%) nonmelanoma skin cancers, 28 (93%) of which were in the p53-72R allele. Loss of heterozygosity occurred more frequently in p53-72RP than in p53-72RR tumors (p = 0.0001) with preferential loss of p53-72P in heterozygotes (p = 0.016), irrespective of the mutant status of the concomitant allele. Together these data infer functional differences between polymorphic forms of p53 that are likely to be relevant to skin carcinogenesis.