RESUMO
BACKGROUND AND AIMS: Gastric intestinal metaplasia (GIM) is a gastric cancer precursor. Narrow-band imaging (NBI) may improve detection of GIM. We compared detection of GIM with high-definition white-light (HD-WL) endoscopy, NBI, and mapping biopsies in a population with increased gastric cancer risk. METHODS: Patients undergoing upper endoscopy had HD-WL examination by 1 endoscopist, followed by an NBI examination by a second endoscopist blinded to HD-WL findings. The location of abnormalities detected by HD-WL and NBI were recorded by a research coordinator, and targeted biopsies of abnormal areas were performed after NBI. Subsequently, 5 mapping biopsies were performed per patient. Biopsy specimens were read by a pathologist blinded to mode of acquisition. The primary outcome was the proportion of patients with GIM. RESULTS: We enrolled 112 patients: 107 (96%) were Hispanic or Asian, and 34 (30%) had GIM. Higher proportions of patients with GIM were detected by NBI (22/34 [65%]) and mapping (26/34 [76%]) versus HD-WL (10/34 [29%]) (P < .005 for both comparisons). GIM was detected by NBI in only 6 patients and only by mapping biopsy in 10 patients; no patient had GIM detected solely by HD-WL. Higher proportions of sites with GIM also were detected with NBI (30/57 [53%]) and mapping biopsies (38/57 [67%]) than HD-WL (16/57 [28%]) (P < .005 for both comparisons). The median number of biopsies per patient with mapping biopsies (5) was significantly higher than with NBI (2) or HD-WL (1). CONCLUSIONS: HD-WL endoscopy is insufficient for detection of GIM in patients at increased risk for gastric cancer. NBI-targeted biopsies plus mapping biopsies should be used. (Clinical trial registration number: NCT02197351.).
Assuntos
Adenocarcinoma/patologia , Gastroscopia/métodos , Metaplasia/patologia , Lesões Pré-Cancerosas/patologia , Neoplasias Gástricas/patologia , Estômago/patologia , Adenocarcinoma/diagnóstico por imagem , Adulto , Biópsia/métodos , Feminino , Humanos , Luz , Masculino , Metaplasia/diagnóstico por imagem , Pessoa de Meia-Idade , Imagem de Banda Estreita/métodos , Lesões Pré-Cancerosas/diagnóstico por imagem , Estudos Prospectivos , Medição de Risco , Método Simples-Cego , Estômago/diagnóstico por imagem , Neoplasias Gástricas/diagnóstico por imagemRESUMO
The KRAS oncogene influences angiogenesis, metastasis and chemoresistance in colorectal cancers (CRCs), and these processes are all enhanced in hypoxic conditions. To define functional activities of mutant KRAS in a hypoxic microenvironment, we first performed cDNA microarray experiments in isogenic DKs5 and DKO3 colon cancer cell lines that differ only by their expression of mutant KRAS (K-ras(D13)). Adrenomedullin (ADM) was identified as one of the most significantly upregulated genes in DKs5 cells that express the KRAS oncogene in hypoxia (3.2-fold, p = 1.47 × 10(-5)). Ectopic expression of mutant KRAS (K-ras(V12)) in Caco-2 cells (K-ras(WT)) induced ADM, whereas selective knockdown of mutant KRAS alleles (K-ras(D13) or K-ras(V12)) in HCT116, DLD1 and SW480 colon cancer cells suppressed the expression of ADM in hypoxia. Knockdown of ADM in colon tumor xenografts blocked angiogenesis and stimulated apoptosis, resulting in tumor suppression. Furthermore, ADM also regulated colon cancer cell invasion in vitro. Among 56 patients with CRC, significantly higher expression levels of ADM were observed in samples harboring a KRAS mutation. Collectively, ADM is a new target of oncogenic KRAS in the setting of hypoxia. This observation suggests that therapeutic targets may differ depending upon the specific tumor microenvironment.
Assuntos
Adrenomedulina/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas ras/genética , Animais , Hipóxia Celular/fisiologia , Linhagem Celular Tumoral , Feminino , Humanos , Imuno-Histoquímica , Camundongos Nus , Análise de Sequência com Séries de Oligonucleotídeos , Proteínas Proto-Oncogênicas p21(ras) , Microambiente Tumoral/fisiologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND AND AIMS: Proteases play a critical role in tumorigenesis and are upregulated in colorectal cancer and neoplastic polyps. In animal models, cathepsin B (CTSB)-activatable imaging agents show high enzyme activity within intestinal tumors. METHODS: We conducted a prospective cohort study of 558 men and women with colon cancer with tumors that were accessible for immunohistochemical assessment. We used Cox proportional hazards models, stratified by stage, to compute colon cancer-specific and overall mortality according to tumoral expression of CTSB. RESULTS: Among 558 participants, 457 (82%) had tumors that expressed CTSB (CTSB positive) and 101 (18%) had tumors that did not express CTSB (CTSB negative). CTSB expression was not associated with disease stage (P = 0.19). After a median follow-up of 11.6 years, there were 254 total and 155 colon cancer-specific deaths. Compared with participants with CTSB-negative tumors, participants with CTSB-positive tumors experienced a multivariate hazard ratio for colon cancer-specific mortality of 1.99 (95% confidence interval, 1.19-3.34) and overall mortality of 1.71 (95% confidence interval, 1.16-2.50). CTSB expression was independently associated with KRAS (P = 0.01) and BRAF mutation (P = 0.04), but not microsatellite instability status, CpG island methylator phenotype status, PIK3CA mutation, LINE-1 methylation, TP53 expression, or PTGS2 (cyclooxygenase-2) expression. Among 123 individuals with adenomas, 91% expressed CTSB. CONCLUSIONS: As assessed by immunohistochemistry, CTSB is expressed in the vast majority of colon cancers, independent of stage, and is significantly associated with higher risk of colon cancer-specific and overall mortality. IMPACT: These results support the potential of CTSB a target for image detection of neoplastic lesions in humans.
Assuntos
Biomarcadores Tumorais/análise , Catepsina B/biossíntese , Neoplasias do Colo/metabolismo , Neoplasias do Colo/mortalidade , Biomarcadores Tumorais/metabolismo , Estudos de Coortes , Neoplasias do Colo/patologia , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Estadiamento de NeoplasiasRESUMO
Neuroblastoma is remarkable for its clinical heterogeneity and is characterized by genomic alterations that are strongly correlated with tumor behavior. The specific genes that influence neuroblastoma biology and are targeted by genomic alterations remain largely unknown. We quantified mRNA expression in a highly annotated series of 101 prospectively collected diagnostic neuroblastoma primary tumors using an oligonucleotide-based microarray. Genomic copy number status at the prognostically relevant loci 1p36, 2p24 (MYCN), 11q23, and 17q23 was determined by PCR and was aberrant in 26, 20, 40, and 38 cases, respectively. In addition, 72 diagnostic neuroblastoma primary tumors assayed in a different laboratory were used as an independent validation set. Unsupervised hierarchical clustering showed that gene expression was highly correlated with genomic alterations and clinical markers of tumor behavior. The vast majority of samples with MYCN amplification and 1p36 loss of heterozygosity (LOH) clustered together on a terminal node of the sample dendrogram, whereas the majority of samples with 11q deletion clustered separately and both of these were largely distinct from the copy number neutral group of tumors. Genes involved in neurodevelopment were broadly overrepresented in the more benign tumors, whereas genes involved in RNA processing and cellular proliferation were highly represented in the most malignant cases. By combining transcriptomic and genomic data, we showed that LOH at 1p and 11q was associated with significantly decreased expression of 122 (61%) and 88 (27%) of the genes mapping to 1p35-36 and all of 11q, respectively, suggesting that multiple genes may be targeted by LOH events. A total of 71 of the 1p35-36 genes were also differentially expressed in the independent validation data set, providing a prioritized list of candidate neuroblastoma suppressor genes. Taken together, these data are consistent with the hypotheses that the neuroblastoma transcriptome is a sensitive marker of underlying tumor biology and that chromosomal deletion events in this cancer likely target multiple genes through alteration in mRNA dosage. Lead positional candidates for neuroblastoma suppressor genes can be inferred from these data, but the potential multiplicity of transcripts involved has significant implications for ongoing gene discovery strategies.