RESUMEN
Mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene have been shown to predispose to pituitary adenoma predisposition, a condition characterized by growth hormone (GH)-secreting pituitary tumors. To study AIP-mediated tumorigenesis, we generated an Aip mouse model. Heterozygous mice developed normally but were prone to pituitary adenomas, in particular to those secreting GH. A complete loss of AIP was detected in these lesions, and full penetrance was reached at the age of 15 months. No excess of any other tumor type was found. Ki-67 analysis indicated that Aip-deficient tumors have higher proliferation rates compared with Aip-proficient tumors, suggesting a more aggressive disease. Similar to human AIP-deficient pituitary adenomas, immunohistochemical studies showed that expression of aryl hydrocarbon receptor nuclear translocator 1 or 2 (ARNT or ARNT2) protein was lost in the mouse tumors, suggesting that mechanisms of AIP-related tumorigenesis involve aberrant ARNT function. The Aip(+/-) mouse appears to be an excellent model for the respective human disease phenotype. This model constitutes a tool to further study AIP-associated pituitary tumorigenesis and may be potentially valuable in efforts to develop therapeutic strategies to treat pituitary adenomas.
Asunto(s)
Translocador Nuclear del Receptor de Aril Hidrocarburo/metabolismo , Adenoma Hipofisario Secretor de Hormona del Crecimiento/etiología , Adenoma Hipofisario Secretor de Hormona del Crecimiento/patología , Péptidos y Proteínas de Señalización Intracelular/fisiología , Animales , Translocador Nuclear del Receptor de Aril Hidrocarburo/genética , Western Blotting , Proliferación Celular , Femenino , Adenoma Hipofisario Secretor de Hormona del Crecimiento/metabolismo , Humanos , Técnicas para Inmunoenzimas , Pérdida de Heterocigocidad , Masculino , Ratones , Ratones Endogámicos C57BL , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
It is estimated that up to 35% of colorectal cancers (CRC) can be explained by hereditary factors. However, genes predisposing to highly penetrant CRC syndromes account for only a small fraction of all cases. Thus, most CRCs still remain molecularly unexplained. A recent systematic sequencing study on well-annotated human protein coding genes identified 280 somatically mutated candidate cancer genes (CAN genes) in breast and colorectal cancer. It is estimated that 8% of all reported cancer genes show both somatic and germline mutations. Therefore, the identified CAN genes serve as a distinct set of candidates for being involved in hereditary susceptibility. The aim of this study was to evaluate the role of colorectal CAN genes in familial CRC. Samples from 45 familial CRCs without known cancer predisposing mutations were screened for somatic and germline variants in 15 top-ranked CAN genes. Six of the genes were found to be somatically mutated in our tumor series. We identified 22 nonsynonymous somatic mutations of which the majority was of missense type. In germline, three novel nonsynonymous variants were identified in the following genes: CSMD3, EPHB6 and C10orf137, and none of the variants were present in 890 population-matched healthy controls. It is possible that the identified germline variants modulate predisposition to CRC. Functional validation and larger sample sets, however, will be required to clarify the role of the identified germline variants in CRC susceptibility.
Asunto(s)
Biomarcadores de Tumor/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , ADN de Neoplasias/genética , Variación Genética/genética , Mutación de Línea Germinal/genética , Anciano , Estudios de Casos y Controles , Colon/metabolismo , Colon/patología , Neoplasias Colorrectales Hereditarias sin Poliposis/patología , Femenino , Humanos , Masculino , Proteínas de la Membrana/genética , Linaje , Pronóstico , Estudios Prospectivos , Proteínas Tirosina Quinasas Receptoras/genética , Receptores de la Familia Eph , Recto/metabolismo , Recto/patologíaRESUMEN
Pituitary adenomas are common in the general population. Although most of them are sporadic, some occur in a familial setting. In familial pituitary adenoma patients it is common that no germline defects are found after screening of aryl hydrocarbon receptor interacting protein (AIP) and other genes known to underlie the condition, suggesting the existence of yet unknown predisposition genes. Recently, the RET proto-oncogene was found to be a novel in vivo interaction partner of AIP in the pituitary gland. Here, we have screened patients from 16 AIP mutation negative (AIPmut-) pituitary adenoma families for RET germline mutations to assess whether RET could play a role in pituitary adenoma predisposition, similar to AIP. We found five novel germline RET changes: one in RET Exon 4 and the rest in noncoding regions of RET. Two changes, c.1560*G > A and -1285 G > A, were segregated in affected family members. We also analyzed the RET region with enhancer element locator (EEL) to identify RET regulatory elements, and to see whether the changes resided in these. None of the variants mapped to the regions predicted by EEL. Expression of RET was examined in ten AIPmut- and seven AIP mutation positive (AIPmut+) somatotropinomas by immunohistochemistry, with a trend showing reduced expression in the latter (P = 0.05). We conclude that the RET variants are presumably not related to pituitary adenoma predisposition, although reduced RET expression may play a role in AIP-related genesis of somatotropinomas.