RESUMEN
Mutations in succinate dehydrogenase complex genes predispose to familial paraganglioma-pheochromocytoma syndrome (FPG) and gastrointestinal stromal tumors (GIST). Here we describe cancer patients undergoing agnostic germline testing at Memorial Sloan Kettering Cancer Center and found to harbor germline SDHA mutations. Using targeted sequencing covering the cancer census genes, we identified 10 patients with SDHA germline mutations. Cancer diagnoses for these patients carrying SDHA germline mutations included neuroblastoma (n = 1), breast (n = 1), colon (n = 1), renal (n = 1), melanoma and uterine (n = 1), prostate (n = 1), endometrial (n = 1), bladder (n = 1), and gastrointestinal stromal tumor (GIST) (n = 2). Immunohistochemical staining and assessment of patient tumors for second hits and loss of heterozygosity in SDHA confirmed GIST as an SDHA-associated tumor and suggests SDHA germline mutations may be a driver in neuroblastoma tumorigenesis.
Asunto(s)
Complejo II de Transporte de Electrones/genética , Mutación de Línea Germinal , Neoplasias/genética , Adolescente , Adulto , Línea Celular Tumoral , Niño , Preescolar , Femenino , Frecuencia de los Genes , Células HEK293 , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: New branches within the embryonic chicken lung form via apical constriction, in which epithelial cells in the primary bronchus become trapezoidal in shape. These branches form at precise locations along the primary bronchus that scale relative to the size of the organ. Here, we examined the extent to which this scaling relationship and branching mechanism are conserved within lungs of three species of birds. FINDINGS: Analyzing the development of embryonic lungs from chicken, quail, and duck, as well as lungs explanted and cultured ex vivo, revealed that the patterns of branching are remarkably conserved. In particular, secondary bronchi form at identical positions in chicken and quail, the patterns of which are indistinguishable, consistent with the close evolutionary relationship of these two species. In contrast, secondary bronchi form at slightly different positions in duck, the lungs of which are significantly larger than those of chicken and quail at the same stage of development. Confocal analysis of fixed specimens revealed that each secondary bronchus forms by apical constriction of the dorsal epithelium of the primary bronchus, a morphogenetic mechanism distinct from that used to create branches in mammalian lungs. CONCLUSIONS: Our findings suggest that monopodial branching off the primary bronchus is driven by apical constriction in lungs of chicken, quail, and duck. The relative positions at which these branches form are also conserved relative to the evolutionary relationship of these species. It will be interesting to determine whether these mechanisms hold in more distant species of birds, and why they differ so significantly in mammals.