Functional Analysis of a Breast Cancer-Associated FGFR2 Single Nucleotide Polymorphism Using Zinc Finger Mediated Genome Editing

The authors thank Barts Charity for funding and Breast Cancer Campaign for funding the Barts Breast Tissue Bank

Nephrogenic systemic fibrosis: concepts and perspectives Fibrose nefrogênica sistêmica: conceitos e perspectivas

Nephrogenic systemic fibrosis is a chronic, progressive condition that develops in some patients with renal impairment after exposure to gadolinium-based contrast agents used in magnetic resonance imaging. Thickening of the skin is typical, usually affecting the extremities. Visceral organs can also be affected. The diagnosis of the disease requires careful clinicopathological correlation. Treatment aims at restoring renal function, which is associated with delayed progression and, eventually, remission of skin changes. Reduction and prevention of nephrogenic systemic fibrosis cases are based on limiting the use of gadolinium-based contrast agents in patients with kidney disorders (especially in patients with advanced renal failure at stages 4 and 5), and restricting their use to situations in which they are essential to diagnosis/follow-up. Other than limiting exposure to gadolinium based contrast agents, no effective preventive methods have been reported. Due to increased awareness about the disease among radiologists and nephrologists, the incidence of nephrogenic systemic fibrosis is declining.<br>Fibrose nefrogênica sistêmica é condição crônica, progressiva, desenvolvida caracteristicamente em pacientes nefropatas após exposição a contrastes radiológicos que contenham gadolínio. O espessamento cutâneo é aspecto típico, envolvendo predominantemente as extremidades. Envolvimento visceral pode ocorrer. O diagnóstico da doença requer cuidadosa correlação clínico-patológica. O tratamento visa à restauração da função renal, que se associa ao retardo da progressão e, eventualmente, remissão das alterações cutâneas. A prevenção da ocorrência e redução da incidência baseiam-se na limitação do uso de contrastes à base de gadolínio em nefropatas (especialmente na insuficiência renal avançada em estágios 4 e 5), restringindo-os às condições nas quais seja imprescindível ao diagnóstico/acompanhamento. À exceção da restrição de exposição aos agentes de contraste a base de gadolínio, não há métodos preventivos efetivos relatados. Devido à ampla divulgação da doença entre radiologistas e nefrologistas, a incidência da fibrose nefrogênica sistêmica está em declínio

Master regulators of FGFR2 signalling and breast cancer risk

The fibroblast growth factor receptor 2 (FGFR2) locus has been consistently identified as a breast cancer risk locus in independent genome-wide association studies. However, the molecular mechanisms underlying FGFR2-mediated risk are still unknown. Using model systems we show that FGFR2-regulated genes are preferentially linked to breast cancer risk loci in expression quantitative trait loci analysis, supporting the concept that risk genes cluster in pathways. Using a network derived from 2,000 transcriptional profiles we identify SPDEF, ERα, FOXA1, GATA3 and PTTG1 as master regulators of fibroblast growth factor receptor 2 signalling, and show that ERα occupancy responds to fibroblast growth factor receptor 2 signalling. Our results indicate that ERα, FOXA1 and GATA3 contribute to the regulation of breast cancer susceptibility genes, which is consistent with the effects of anti-oestrogen treatment in breast cancer prevention, and suggest that fibroblast growth factor receptor 2 signalling has an important role in mediating breast cancer risk