RESUMO
Cancer-embryo antigens or developmentally restricted differentiation antigens (DRDAGs), such as PLAC1 (CT92) and developmental pluripotency associated-2 (DPPA2/CT100), are expressed in pluripotent embryonic cells. They are also recognized as cancer-testis antigens (CT) which are proteins normally expressed only in the human germ line but that are also present in a significant subset of malignant tumors. These antigens may prove to be markers of 'repopulating' cells with stem cell-like characteristics and could be critical targets for immunotherapy in epithelial ovarian cancer (EOC). Our objective was to define the frequency of expression and immunogenicity of PLAC1 and DPPA2 in EOC and correlate expression with clinical outcome. One-step reverse transcriptase PCR was performed on 101 EOC samples and a panel of normal tissues. Expression of PLAC1 and DPPA2 in the EOC specimens was 21/101 (21%) and 31/101 (31%) respectively. In normal tissues, PLAC1 expression was restricted to the placenta while DPPA2 expression was restricted to the placenta and testis. Immunohistochemistry (IHC) and enzyme-linked immunosorbent assay (ELISA) were also performed on a subset of specimens. Humoral immunity was demonstrable in 2/12 serum samples from patients whose tumors expressed DPPA2. There was no demonstrable antibody response to PLAC1 in patients with PLAC1 positive tumors. The presence of PLAC1 and DPPA2 did not have a statistically significant effect on recurrence-free and overall survival. The tissue-restricted expression of PLAC1 and DPPA2, their expression in a significant proportion of EOC patients, and their potential to represent markers of stem cells make DRDAGs attractive targets for antigen-specific immunotherapy in EOC.
Assuntos
Biomarcadores Tumorais/sangue , Proteínas Nucleares/sangue , Proteínas Nucleares/genética , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/genética , Proteínas da Gravidez/sangue , Proteínas da Gravidez/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos de Neoplasias , Biomarcadores Tumorais/imunologia , Proteínas de Ciclo Celular , Células Epiteliais/imunologia , Células Epiteliais/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Proteínas Nucleares/imunologia , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/patologia , Proteínas da Gravidez/imunologia , RNA Mensageiro/genética , Taxa de Sobrevida , Fatores de TranscriçãoRESUMO
PURPOSE: The assessment of prognosis and decisions on treatment for patients with non-small-cell lung cancer (NSCLC) are determined on the basis of disease stage and performance status. NSCLC frequently manifests loss of heterozygosity (LOH) at chromosome segment 11p15.5. Whether LOH at 11p15.5 is an independent prognostic variable has yet to be determined. PATIENTS AND METHODS: We developed five novel markers, which can be assessed by polymerase chain reaction and restriction enzyme digestion. LOH at 11p15.5 was assessed in 193 patients who underwent surgical resection for pathologic stage I and II of the disease. RESULTS: LOH at 11p15.5 was associated with poor survival (P =.021). Multivariate logistic regression analysis showed that after disease stage, performance status, weight loss, sex, age at diagnosis, and smoking history were controlled for, patients with LOH were two times more likely to die than those without LOH (relative risk [RR] = 2.01, P =.021). Cox regression analysis with disease stage and LOH revealed that the survival of patients with stage I disease and LOH was similar to the survival of patients with stage II disease, and it was significantly worse than the survival of stage I patients without LOH (RR = 2.38, P =.038). CONCLUSION: LOH in a 310-kb region on chromosome segment 11p15.5 that includes the gene for the regulatory subunit of the enzyme ribonucleotide reductase is highly predictive of poor survival from NSCLC. The future utility of analysis of the allelic status of this region may involve treatment decisions, such as the use of neoadjuvant and adjuvant chemotherapy for patients with stage I disease.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Cromossomos Humanos Par 11 , Perda de Heterozigosidade , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Prognóstico , Análise de Regressão , Taxa de SobrevidaRESUMO
Subtelomeric duplications of an obscure tubulin "genic" segment located near the telomere of human chromosome 4q35 have occurred at different evolutionary time points within the last 25 million years of the catarrhine (i.e., hominoid and Old World monkey) evolution. The analyses of these segments reported here indicate an exceptional level of evolutionary instability. Substantial intra- and interspecific differences in copy number and distribution are observed among cercopithecoid (Old World monkey) and hominoid genomes. Characterization of the hominoid duplicated segments reveals a strong positional bias within pericentromeric and subtelomeric regions of the genome. On the basis of phylogenetic analysis from predicted proteins and comparisons of nucleotide-substitution rates, we present evidence of a conserved b-tubulin gene among the duplications. Remarkably, the evolutionary conservation has occurred in a nonorthologous fashion, such that the functional copy has shifted its positional context between hominoids and cercopithecoids. We propose that, in a chimpanzee-human common ancestor, one of the paralogous copies assumed the original function, whereas the ancestral copy acquired mutations and eventually became silenced. Our analysis emphasizes the dynamic nature of duplication-mediated genome evolution and the delicate balance between gene acquisition and silencing.
Assuntos
Cercopithecidae/genética , Evolução Molecular , Duplicação Gênica , Genoma , Hominidae/genética , Telômero/genética , Tubulina (Proteína)/genética , Animais , Cromossomos Humanos Par 4/genética , Sequência Conservada/genética , Dosagem de Genes , Genes Duplicados/genética , Humanos , Hibridização in Situ Fluorescente , Mutagênese/genética , Fases de Leitura Aberta/genética , Pan troglodytes/genética , Papio/genética , Filogenia , Pseudogenes/genética , Saimiri/genética , Especificidade da Espécie , Fatores de TempoRESUMO
The subtelomeric region of human chromosome 4q contains the locus for facioscapulohumeral muscular dystrophy (FSHD). The FSHD mutation is a deletion within an array of 3.3-kb tandem repeats (D4Z4). The disease mechanism is unknown but is postulated to involve position effect. A closely related 3.3-kb array on chromosome 10qter, in contrast, is not associated with a disease phenotype. We show here that the 4q homology on chromosome 10 is not confined to the 3.3-kb repeats but extends both proximally (42 kb) and distally to include the telomere. We have also identified the most distal expressed gene on 10q known so far, mapping only 96 kb from the 3.3-kb repeat array. A 4q variant has also been identified; there is 92%nucleotide identity between the two 4q forms, 4qA and 4qB. The 4qter and 10qter forms show homology to other chromosome ends, including 4p, 21q, and 22q, and these regions may represent a relatively common subtelomeric domain.