RESUMEN
CONTEXT: CHEK2 is a cell cycle checkpoint regulator gene with a long-established role as a clinically relevant, moderate risk breast cancer predisposition gene, with greater risk ascribed to truncating variants than missense variants. METHODS: We assessed 165 individuals with pituitary adenomas for CHEK2 variants. The study consisted of a primary cohort of 29 individuals who underwent germline and tumour whole exome sequencing, and a second, independent cohort of 136 individuals who had a targeted next-generation sequencing panel performed on both germline and tumour DNA (n=52) or germline DNA alone (n=84). RESULTS: We identified rare, coding, non-synonymous germline CHEK2 variants amongst 3/29 (10.3%) patients in our primary cohort and 5/165 (3.0%) patients overall, with affected patients having a range of hormone secretion types (prolactinoma, thyrotrophinoma, somatotrophinoma and non-functioning pituitary adenoma). No somatic variants were identified. Two variants were definitive null variants (c.1100delC, c.444+1G>A), classified as pathogenic. Two variants were missense variants (p.Asn186His, p.Thr476Met), classified as likely pathogenic. Even when considering the null variants only, the rate of CHEK2 variants was higher in our cohort compared to national control data (1.8% vs. 0.5%, P=0.049). CONCLUSIONS: This is the first study to suggest a role for the breast cancer predisposition gene, CHEK2, in pituitary tumorigenesis, with pathogenic/likely pathogenic variants found in 3% of patients with pituitary adenomas. As pituitary adenomas are relatively common and typically lack classical autosomal dominant family histories, risk alleles - such as these variants found in CHEK2 - might be a significant contributor to pituitary adenoma risk in the general population.
RESUMEN
The skin barrier is broadly composed of two elements-a physical barrier mostly localised in the epidermis, and an immune barrier localised in both the dermis and epidermis. These two systems interact cooperatively to maintain skin homeostasis and overall human health. However, if dysregulated, several skin diseases may arise. Psoriasis is one of the most prevalent skin diseases associated with disrupted barrier function. It is characterised by the formation of psoriatic lesions, the aberrant differentiation and proliferation of keratinocytes, and excessive inflammation. In this review, we summarize recent discoveries in disease pathogenesis, including the contribution of keratinocytes, immune cells, genetic and environmental factors, and how they advance current and future treatments.
