Does polygenic risk influence associations between sun exposure and melanoma? A prospective cohort analysis.

BACKGROUND: Melanoma develops as the result of complex interactions between sun exposure and genetic factors. However, data on these interactions from prospective studies are scant. OBJECTIVES: To quantify the association between ambient and personal ultraviolet exposure and incident melanoma in a large population-based prospective study of men and women residing in a setting of high ambient ultraviolet radiation, and to examine potential gene-environment interactions. METHODS: Data were obtained from the QSkin Sun and Health Study, a prospective cohort study of men and women aged 40-69 years, randomly sampled from the Queensland population in 2011. Participants were genotyped and assessed for ultraviolet exposure. RESULTS: Among participants with genetic data (n = 15 373), 420 (2·7%) developed cutaneous melanoma (173 invasive, 247 in situ) during a median follow-up time of 4·4 years. Country of birth, age at migration, having > 50 sunburns in childhood or adolescence, and a history of keratinocyte cancer or actinic lesions were significantly associated with melanoma risk. CONCLUSIONS: An interaction with polygenic risk was suggested: among people at low polygenic risk, markers of cumulative sun exposure (as measured by actinic damage) were associated with melanoma. In contrast, among people at high polygenic risk, markers of high-level early-life ambient exposure (as measured by place of birth) were associated with melanoma (hazard ratio for born in Australia vs. overseas 3·16, 95% confidence interval 1·39-7·22). These findings suggest interactions between genotype and environment that are consistent with divergent pathways for melanoma development. What's already known about this topic? The relationship between sun exposure and melanoma is complex, and exposure effects are highly modified by host factors and behaviours. The role of genotype on the relationship between ultraviolet radiation exposure and melanoma risk is poorly understood. What does this study add? We found that country of birth, age at migration, sunburns in childhood or adolescence, and history of keratinocyte cancer or actinic lesions were significantly associated with melanoma risk, while other measures of continuous or more intermittent patterns of sun exposure were not. We found evidence for gene-environment interactions that are consistent with divergent pathways for melanoma development. Linked Comment: Cust. Br J Dermatol 2020; 183:205-206. Plain language summary available online.

Aspirin and nonsteroidal anti-inflammatory drug use and keratinocyte cancers: a large population-based cohort study of skin cancer in Australia.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) have been postulated as chemopreventive agents for basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), but findings from observational studies have been inconsistent, and clinical trial data are scant. OBJECTIVES: To examine the association between aspirin and NSAID (nonaspirin) use and the risk of BCC and SCC in a large cohort specifically designed for skin cancer outcomes. METHODS: We used data from the QSkin Study, a prospective cohort of 43 764 residents of Queensland, Australia (34 630 were included in this study and 23 581 were used in our primary analyses). We used Cox proportional hazards models to estimate the hazard ratios (HRs) between self-reported aspirin and NSAID use 1 year prior to study baseline and the first histologically confirmed BCC or SCC for high-risk (history of skin cancer excisions or more than five actinic lesions treated) and average-to-low-risk participants (no history of skin cancer excision and at most five actinic lesions treated). RESULTS: After a median of 3 years of follow-up, 3421 participants developed BCC and 1470 SCC (2288 BCC and 932 SCC with complete covariate information). Among the high-risk group (1826 BCC and 796 SCC), compared with never use, frequent (at least weekly) NSAID use was associated with reduced risk of BCC (HR 0·84, 95% confidence interval 0·71-0.99) but not SCC. Aspirin use was associated with reduced risk of SCC (HR 0·77, 95% confidence interval 0·64-0·93) only among infrequent (less than weekly) users and was not associated with BCC. We observed no association between NSAID or aspirin use and the risk of BCC or SCC among average-to-low-risk participants. CONCLUSIONS: While some weakly inverse associations were observed between prior use of aspirin or NSAIDs and skin cancer, the inconsistent patterns of associations do not provide convincing evidence that these medications reduce subsequent skin cancer risk. Further data on doses, duration and long-term follow-up may help us to comprehend the cumulative dose effect.

Chronic ethanol consumption induces gene expression of pancreatic monitor peptide, but not SPINK1/PSTI-56, in rats.

The primary factors that predispose humans to the development of alcoholic pancreatitis are unknown. One of the earliest observations in humans in whom this disease develops is pancreatic hypersecretion caused by unknown mechanisms. Messenger RNA (mRNA) differential display was performed in a rat model to investigate the molecular mechanisms associated with ethanol-induced pancreatic hypersecretion. Male Wistar rats were pair-fed Lieber-DeCarli diets with or without ethanol for 7 days or 4 weeks. Total RNA was extracted from the pancreas and its neurohormonal control sites. Differentially expressed complementary DNA (cDNA) tags were isolated, cloned, and sequenced. One 248-bp cDNA was consistently and strongly induced in the pancreata of rats fed ethanol for 4 weeks. The sequence was highly homologous to both rat pancreatic monitor peptide (MP) and pancreatic secretory trypsin inhibitor (PSTI-56), also known as serine protease inhibitor, Kazal type 1 (SPINK1). Confirmatory reverse-transcription-polymerase chain reaction showed that PSTI-56 expression remained unchanged, whereas MP mRNA levels were elevated more than four times in the pancreata of ethanol-fed rats. These results indicate that long-term ethanol ingestion increases MP mRNA levels in the rat pancreas. Because MP stimulates cholecystokinin release and cholecystokinin is an important stimulant of pancreatic secretion, the enhanced MP gene expression may contribute to pancreatic hypersecretion.

Potentiation of etoposide-induced apoptosis by staurosporine in human tumor cells is associated with events downstream of DNA-protein complex formation.

UNLABELLED: Protein kinase inhibitors have demonstrated potential for use in the therapy of human cancers, in particular leukemia. Staurosporine, a protein kinase inhibitor with broad specificity, enhances the cytotoxic effects of various antitumor agents with different modes of action. The topoisomerase II inhibitor, etoposide, has shown clinical activity against a wide range of tumor types. PURPOSE: The purpose of this study was to assess the effects of staurosporine on etoposide-induced cell death processes in a human tumor of epithelial origin. METHODS: Modulation of etoposide-induced apoptosis by staurosporine in HeLa cells was assessed by cell morphology, extraction of low molecular weight DNA, quantitation of DNA-protein complexes, and measurements of rates of DNA synthesis. The effects on cellular genes implicated in apoptosis were determined by Northern and Western blotting, along with assays of cyclin-dependent kinase activities. RESULTS: Staurosporine exhibited a two- to three-fold potentiation of apoptosis caused by etoposide in HeLa cells when applied concurrently, or immediately following etoposide removal, but did not alter the quantity of DNA-protein complexes produced by etoposide. Etoposide-induced apoptosis, and its potentiation by staurosporine, were associated with reduced c-myc expression, and a moderate increase in p21WAF1/CIP1 mRNA and protein levels. Inhibitors of cyclic AMP-dependent protein kinase and protein kinase C, which exhibit greater specificity than staurosporine, were without effect on apoptosis caused by etoposide, whereas use of the tyrosine phosphatase inhibitor, vanadate, resulted in its abrogation. The potentiation of etoposide-induced apoptosis by staurosprine was associated with a significant increase in cyclin A-dependent kinase activity. In addition, etoposide caused substantial inhibition of DNA synthesis. CONCLUSION: These results indicate that staurosporine potentiates apoptosis through events which occur downstream of DNA damage, and implicate unscheduled activation of cyclin A-dependent kinase during inhibition of DNA synthesis as a possible cause.