RESUMO
Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. Since c-kit mutation occurs only in one-third of GIST, there might be other molecular mechanisms. Loss of heterozygosity (LOH), microsatellite instability (MSI) and NF2 gene mutation were investigated in 22 GISTs (9 low-risk and 13 high-risk tumors). LOH and MSI were evaluated using 41 markers on 21 chromosomal arms, and NF2 gene mutation was examined by PCR-SSCP. High frequency of LOH was observed on 14q (9 / 19, 47%), and 22q (17 / 22, 77%). The frequencies were similar in low-risk and high-risk tumors, and were unrelated with gastric or intestinal origin. Two other abnormalities, additional LOH on other chromosomes and MSI at more than two loci, were characteristic of the high-risk tumors (P < 0.05). NF2 gene mutation was identified in two cases showing 22q-LOH (8 bp deletion on the splice donor site of exon 7, and 1 bp insertion at position 432 of exon 4, which resulted in nonsense mutation). There was no significant correlation between these results and c-kit gene mutation, which was observed in 8 of 22 tumors. Suppressor genes on 14q and 22q may be involved, independently of c-kit gene mutation, in the development of GIST. NF2 contributes as a tumor suppressor in a small subset of GIST. These abnormalities are presumably followed by increased genetic instability.
Assuntos
Mapeamento Cromossômico , Cromossomos Humanos Par 14 , Cromossomos Humanos Par 22 , Neoplasias Gastrointestinais/genética , Genes da Neurofibromatose 2 , Perda de Heterozigosidade , Proteínas de Membrana/genética , Proteínas Proto-Oncogênicas c-kit/genética , Adulto , Idoso , Éxons , Feminino , Marcadores Genéticos , Humanos , Neoplasias Intestinais/genética , Masculino , Repetições de Microssatélites , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Neurofibromina 2 , Reação em Cadeia da Polimerase , Polimorfismo Conformacional de Fita Simples , Neoplasias Gástricas/genéticaRESUMO
Clonality and genetic abnormalities were evaluated to characterize proliferative lesions of the parathyroid gland. Fourteen lesions from patients with single-gland proliferation (adenomas [PA]), 6 lesions from patients with multiple-gland proliferation (primary hyperparathyroidism [PHPT]), and 47 lesions from 16 patients with secondary hyperparathyroidism (SHPT) were examined. Based on the X chromatin inactivation pattern, which was revealed by a HUMARA assay of lesions from female patients (n = 34; 24 informative cases), monoclonality was demonstrated in 6 of 10 PA (60%), 2 of 5 PHPT (40%), and 6 of 9 SHPT lesions (14 of 27 lesions, 52%). By PCR analysis using 17 microsatellite markers on eight chromosomes (chromosomes 1, 2, 3, 5, 6, 11, 13, and 17), loss of heterozygosity was sporadically observed in 4 of 14 PA, 3 of 6 PHPT, and 7 of 47 SHPT lesions, in most cases on a single locus of chromosome 11. On the other hand, microsatellite instability was observed more frequently: ie, in six PA, five PHPT, and nine SHPT lesions. The profile of microsatellite instability depended on the type of proliferation: microsatellite instability (MI) seemed to cluster in the region of chromosome 11 in PA. Microsatellite instability on TP53 was observed in 3 of 6 PHPT lesions and in 2 of 47 SHPT lesions but in no PA lesions. Microsatellite instability on Mfd47 was observed in only some cases of SHPT. Although no significant correlation was identified among histologic features, clonality, and genetic abnormalities in cases of primary proliferation, genetic abnormalities were more frequently observed in SHPT lesions that lacked fat tissues. Thus, genetic instability might be important in proliferative disorders of the parathyroid gland, either with or without uremia. However, genetic instability seems to be induced by different mechanisms in the three types of proliferation studied. In SHPT, the absence of fat tissues may indicate that the proliferation is accompanied by genetic changes.
Assuntos
Adenoma/genética , Aberrações Cromossômicas/genética , Hiperparatireoidismo/genética , Perda de Heterozigosidade , Repetições de Microssatélites , Neoplasias das Paratireoides/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Divisão Celular/genética , Transtornos Cromossômicos , Feminino , Genes Supressores de Tumor , Técnicas Histológicas , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasia Endócrina Múltipla Tipo 1/genética , Oncogenes , Reação em Cadeia da PolimeraseRESUMO
A transplantable human Epstein-Barr virus-associated gastric carcinoma (EBVaGC), designated KT, was propagated in severe combined immunodeficiency (SCID) mice for 12 passages. Mucin and cytokeratin expression and the Alu sequence in tumor DNA confirmed that the KT tumor was derived from human epithelial tissue. The identity of clonal EBV in the original and KT tumors was demonstrated by terminal repeat analysis of EBV DNA. The pattern of latency gene expression of EBV was the same in both tumors. EBER1 was presented similarly in tumor cell nuclei by in situ hybridization. Reverse transcription-PCR analysis also demonstrated Q-promoter-driven EBNA1 expression but not BZLF1, EBNA2, or LMP1 expression. Thus, the transplantable human EBVaGC KT retains the original EBV with the same latency gene expression and can serve as a model for this unique type of gastric carcinoma.
