The effect of age on the acquisition and selection of cancer driver mutations in sun-exposed normal skin.

BACKGROUND: The accumulation of somatic mutations contributes to ageing and cancer. Sunlight is the principal aetiological factor associated with skin cancer development. However, genetic and phenotypic factors also contribute to skin cancer risk. This study aimed at exploring the role of photoaging, as well as other well-known epidemiological risk factors, in the accumulation of somatic mutations in cancer-free human epidermis. MATERIAL AND METHODS: We deeply sequenced 46 genes in normal skin biopsies from 123 healthy donors, from which phenotypic data (including age, pigmentation-related genotype and phenotype) and sun exposure habits were collected. We determined the somatic mutational burden, mutational signatures, clonal selection and frequency of driver mutations in all samples. RESULTS: Our results reveal an exponential accumulation of UV-related somatic mutations with age, matching skin cancer incidence. The increase of mutational burden is in turn modified by an individual's skin phototype. Somatic mutations preferentially accumulated in cutaneous squamous cell carcinoma cancer genes and clonally expanded with age, with distinct mutational processes underpinning different age groups. Our results suggest a loss of fidelity in transcription-coupled repair later in life. CONCLUSION: Our findings reveal that ageing is not only associated with an exponential increase in the number of somatic mutations accumulated in normal epidermis, but also with selection and expansion of cancer-associated mutations. Aged, sun-exposed normal skin is thus an extended mosaic of multiple clones with driver mutations, poised for the acquisition of transforming events.

[Analysis of lymphocyte populations in psoriatic plaques following inhibition of tumor necrosis factor alpha with etanercept]. / Estudio de las poblaciones linfocitarias en las lesiones de psoriasis tras el bloqueo del factor de necrosis tumoral alfa con etanercept.

INTRODUCTION: Psoriasis is a disease with a strong immunological component in which there is a predominant T helper 1 cell-mediated immune response. Etanercept, a receptor for tumor necrosis factor a that blocks its action, is a new drug with proven efficacy in the treatment of psoriasis. OBJECTIVES: The primary objective of this study was to assess the histological response to etanercept by analyzing the lymphocyte populations in psoriatic plaques. The secondary objectives were to assess the clinical response to the drug using the Psoriasis Area and Severity Index (PASI) and to analyze the effect of etanercept on peripheral blood lymphocyte populations. METHODS: Ten patients with plaque psoriasis and a PASI score greater than 10 were included in the study. A clinical assessment was performed in all patients along with a 4-mm skin punch biopsy of a plaque and analysis of peripheral blood lymphocyte populations at baseline and after 12 weeks of etanercept therapy at a dose of 50 mg per week. RESULTS: There was a significant reduction in different lymphocyte populations in the plaques following treatment with etanercept. The mean (SD) number of CD4+ T lymphocytes per microscopic field decreased from 16.93 (8.13) at baseline to 6.51 (3.46) after treatment with etanercept (P < 007). CD8+ T lymphocytes also decreased from 17.73 (9.77) before treatment to 10.50 (9.4) after treatment (P < 005). An overall improvement in PASI score was also observed: 33.30 (10.71) at baseline versus 15.20 (13.28) following treatment (P < 008). Nine out of 10 patients showed improvement. No significant differences were observed in peripheral blood lymphocyte populations before and after treatment. CONCLUSIONS: Etanercept leads to clinical improvement of psoriasis and reduces inflammatory infiltration of the lesions without affecting peripheral blood lymphocyte populations.

Estudio de las poblaciones linfocitarias en las lesiones de psoriasis tras el bloqueo del factor de necrosis tumoral alfa con etanercept / Analysis of lymphocyte populations in psoriatic plaques following inhibition of tumor necrosis factor alpha with Ttanercept

Introducción. La psoriasis es una enfermedad de fuerte base inmune, con un predominio de respuesta inmune celular o Th1. Entre los nuevos fármacos que han demostrado eficacia está el etanercept, un receptor para el factor de necrosis tumoral alfa que bloquea su acción. Objetivos. Como objetivos nos planteamos en primer lugar determinar la respuesta histológica a etanercept mediante la determinación de las poblaciones linfocitarias en las lesiones psoriásicas; y en segundo lugar, determinar la respuesta clínica al fármaco mediante el Psoriasis Area and Severity Index (PASI) y valorar el efecto de etanercept sobre las poblaciones linfocitarias en sangre. Métodos. Tratamos 10 pacientes con psoriasis en placas con PASI > 10. Se les realizó una evaluación clínica, un punch de 4 mm en la placa y una determinación de poblaciones linfocitarias en sangre antes del comienzo y tras 12 semanas de tratamiento con etanercept 50 mg/semana. Resultados. Hubo un descenso significativo en las distintas poblaciones linfocitarias de las lesiones tras el tratamiento con etanercept. Así, los linfocitos T CD4+ antes y después del tratamiento con etanercept registraron los siguientes valores: 16,93 ± 8,13 y 6,51 ± 3,46 (p < 0,007), respectivamente. Y los linfocitos T CD8+ antes y después del tratamiento con etanercept registraron: 17,73 ± 9,77 y 10,50 ± 9,4 (p < 0,005), respectivamente. El PASI mejoró globalmente tras 12 semanas de tratamiento. En un principio el PASI basal mostraba 33,30 ± 10,71, y tras el tratamiento se registró 15,20 ± 13,28, p < 0,008. Nueve de los diez pacientes mejoraron y una paciente se mantuvo sin mejoría. No hubo diferencias significativas en las poblaciones linfocitarias sanguíneas antes y después del tratamiento. Conclusiones. Etanercept es un fármaco que mejora clínicamente la psoriasis y disminuye la infiltración inflamatoria de las lesiones sin afectar a las poblaciones linfocitarias sanguíneas

Introduction. Psoriasis is a disease with a strong immunological component in which there is a predominant T helper 1 cell-mediated immune response. Etanercept, a receptor for tumor necrosis factor a that blocks its action, is a new drug with proven efficacy in the treatment of psoriasis. Objectives: The primary objective of this study was to assess the histological response to etanercept by analyzing the lymphocyte populations in psoriatic plaques. The secondary objectives were to assess the clinical response to the drug using the Psoriasis Area and Severity Index (PASI) and to analyze the effect of etanercept on peripheral blood lymphocyte populations. Methods. Ten patients with plaque psoriasis and a PASI score greater than 10 were included in the study. A clinical assessment was performed in all patients along with a 4-mm skin punch biopsy of a plaque and analysis of peripheral blood lymphocyte populations at baseline and after 12 weeks of etanercept therapy at a dose of 50 mg per week. Results. There was a significant reduction in different lymphocyte populations in the plaques following treatment with etanercept. The mean (SD) number of CD4+ T lymphocytes per microscopic field decreased from 16.93 (8.13) at baseline to 6.51 (3.46) after treatment with etanercept (P < 007). CD8+ T lymphocytes also decreased from 17.73 (9.77) before treatment to 10.50 (9.4) after treatment (P < 005). An overall improvement in PASI score was also observed: 33.30 (10.71) at baseline versus 15.20 (13.28) following treatment (P < 008). Nine out of 10 patients showed improvement. No significant differences were observed in peripheral blood lymphocyte populations before and after treatment. Conclusions. Etanercept leads to clinical improvement of psoriasis and reduces inflammatory infiltration of the lesions without affecting peripheral blood lymphocyte populations

Treatment of psoriasis with adalimumab.

BACKGROUND: Adalimumab is an anti-tumour necrosis factor agent of use in psoriatic arthritis. AIM: The objective of this study was to assess the efficacy and safety of adalimumab in patients with plaque psoriasis unresponsive to previous therapies. METHODS: We present nine patients with psoriasis and psoriatic arthropathy treated with adalimumab, including a woman with a history of breast cancer and a man with hepatitis C virus-related liver disease. RESULTS: After 12 weeks, 66.6%, 55.5% and 11.1% of the patients showed a Psoriasis Assessment and Severity Index response of 50%, 75% and 90%, respectively. After 20 weeks, these levels had increased to 75%, 62.5% and 37.5%, respectively. After 12 weeks, the Psoriasis Global Assessment (PGA) score was clear or almost clear in 33.3% of the patients. By week 20, this clearance rate had almost doubled (62.5%). In two patients, the treatment was prolonged for 52 weeks, with a sustained response. One patient presented nonspecific colitis and died as a result of in-hospital pneumonia; any implication of adalimumab in the death is not clear. No other serious adverse effects were observed. CONCLUSION: In this series adalimumab was found to be effective for psoriasis refractory to other treatments including infliximab and etanercept.