RESUMEN
Paternal mutation of ATP-sensitive K(+) (K(ATP)) channel genes and loss of heterozygosity (LOH) of the 11p15 region including the maternal alleles of ABCC8, IGF2, and CDKN1C characterize the focal form of persistent hyperinsulinemic hypoglycemia of infancy (FoPHHI). We aimed to understand the actual nature of FoPHHI in comparison with insulinoma. In FoPHHI, the lesion consists in clusters of beta-cells surrounded by non-beta-cells. Compared with adjacent islets, proinsulin mRNA is similar and proinsulin production higher (P < or = 0.02), indicating regulation at a translational level, with slightly lower insulin stock and lower ABCC8 peptide labeling (P<0.05). Insulinomas, composed of beta-cell nests or cords, have similar proinsulin mRNA compared with adjacent islets, highly variable proinsulin production, lower insulin stock (P < or = 0.02), and higher ABCC8 peptide labeling (P<0.05). Proinsulin mRNA is lower than in FoPHHI (P<0.001). Islets adjacent to FoPHHI appear to be resting, in contrast to those adjacent to insulinomas, evidencing intrapancreatic regulation of islet beta-cell activity. IGF2 peptide is present inside and outside both lesions, but IGF2 mRNA is restricted to the lesions. The 11p15 LOH and absence of CDKN1C peptide staining are demonstrated in all FoPHHI but also in three of eight insulinomas. Despite some molecular similarities, FoPHHI is thus fundamentally different from insulinoma.
Asunto(s)
Transportadoras de Casetes de Unión a ATP , Hiperinsulinismo/complicaciones , Hipoglucemia/etiología , Insulinoma , Neoplasias Pancreáticas , Canales de Potasio de Rectificación Interna , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Niño , Cromosomas Humanos Par 11/genética , Inhibidor p57 de las Quinasas Dependientes de la Ciclina , Humanos , Hiperinsulinismo/genética , Hiperinsulinismo/patología , Hipoglucemia/genética , Hipoglucemia/patología , Inmunohistoquímica , Hibridación in Situ , Lactante , Insulina/metabolismo , Factor II del Crecimiento Similar a la Insulina/análisis , Factor II del Crecimiento Similar a la Insulina/genética , Insulinoma/genética , Insulinoma/patología , Islotes Pancreáticos/química , Islotes Pancreáticos/metabolismo , Islotes Pancreáticos/patología , Pérdida de Heterocigocidad , Repeticiones de Microsatélite , Persona de Mediana Edad , Mutación , Proteínas Nucleares/análisis , Proteínas Nucleares/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Canales de Potasio/análisis , Canales de Potasio/genética , Proinsulina/biosíntesis , Proinsulina/genética , ARN Mensajero/análisis , Receptores de Droga/análisis , Receptores de Droga/genética , Receptores de SulfonilureasRESUMEN
Fluorescence in situ hybridization was performed to characterize 81 cases of myeloid and lymphoid malignancies with cytogenetic 1p36 alterations not affecting the PRDM16 locus. In total, three subgroups were identified: balanced translocations (Nâ=â27) and telomeric rearrangements (Nâ=â15), both mainly observed in myeloid disorders; and unbalanced non-telomeric rearrangements (Nâ=â39), mainly observed in lymphoid proliferations and frequently associated with a highly complex karyotype. The 1p36 rearrangement was isolated in 12 cases, mainly myeloid disorders. The breakpoints on 1p36 were more widely distributed than previously reported, but with identifiable rare breakpoint cluster regions, such as the TP73 locus. We also found novel partner loci on 1p36 for the known multi-partner genes HMGA2 and RUNX1. We precised the common terminal 1p36 deletion, which has been suggested to have an adverse prognosis, in B-cell lymphomas [follicular lymphomas and diffuse large B-cell lymphomas with t(14;18)(q32;q21) as well as follicular lymphomas without t(14;18)]. Intrachromosomal telomeric repetitive sequences were detected in at least half the cases of telomeric rearrangements. It is unclear how the latter rearrangements occurred and whether they represent oncogenic events or result from chromosomal instability during oncogenesis.