RESUMO
BACKGROUND: Colorectal cancer liver metastases (CRLMs) are potentially curable with resection, but most patients recur and succumb to their disease. Clinical covariates do not account for all outcomes. Circulating tumor cells (CTCs) are prognostic in the primary and metastatic settings of breast, prostate and colorectal cancer (CRC), and evolving evidence supports their role in CRLMs. Our objective was to determine whether CTCs in peripheral (PV) and hepatic venous (HV) compartments are associated with disease-free survival (DFS) and overall survival (OS) post-CRLM resection. METHODS: CTCs were measured by CellSearch assay from intraoperative HV and PV samples from 63 patients who underwent CRLM resection from June 2007 to August 2012 at a single center. DFS and OS were primary endpoints. RESULTS: HV CTCs > 3 were associated with shorter DFS and OS, but not PV CTCs, although no significant difference was found between CTC measurements in the two compartments. By univariate analysis, CRC stage and site, CRLM recurrence, and hepatic capsule invasion were also associated with OS, but only HV CTCs and CRC site were significant by multivariate Cox. Only HV CTCs were associated with DFS by multivariate analysis. Cases with elevated HV CTCs had hepatic vein invasion and lymph node metastases, and were younger with larger tumors. CONCLUSIONS: Elevated HV CTCs are prognostic for DFS and OS following CRLM resection. Clinicopathologic features associated with HV CTCs are identifiable preoperatively and should be considered in CRLM surgical decision making. We found no evidence that PV CTCs are prognostic in this setting.
Assuntos
Biomarcadores Tumorais/análise , Neoplasias Colorretais/patologia , Hepatectomia/mortalidade , Neoplasias Hepáticas/secundário , Células Neoplásicas Circulantes/patologia , Idoso , Neoplasias Colorretais/cirurgia , Feminino , Seguimentos , Humanos , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Taxa de SobrevidaRESUMO
A locus on human chromosome 11q23 tagged by marker rs3802842 was associated with colorectal cancer (CRC) in a genome-wide association study; this finding has been replicated in case-control studies worldwide. In order to identify biologic factors at this locus that are related to the etiopathology of CRC, we used microarray-based target selection methods, coupled to next-generation sequencing, to study 103 kb at the 11q23 locus. We genotyped 369 putative variants from 1,030 patients with CRC (cases) and 1,061 individuals without CRC (controls) from the Ontario Familial Colorectal Cancer Registry. Two previously uncharacterized genes, COLCA1 and COLCA2, were found to be co-regulated genes that are transcribed from opposite strands. Expression levels of COLCA1 and COLCA2 transcripts correlate with rs3802842 genotypes. In colon tissues, COLCA1 co-localizes with crystalloid granules of eosinophils and granular organelles of mast cells, neutrophils, macrophages, dendritic cells and differentiated myeloid-derived cell lines. COLCA2 is present in the cytoplasm of normal epithelial, immune and other cell lineages, as well as tumor cells. Tissue microarray analysis demonstrates the association of rs3802842 with lymphocyte density in the lamina propria (p = 0.014) and levels of COLCA1 in the lamina propria (p = 0.00016) and COLCA2 (tumor cells, p = 0.0041 and lamina propria, p = 6 × 10(-5)). In conclusion, genetic, expression and immunohistochemical data implicate COLCA1 and COLCA2 in the pathogenesis of colon cancer. Histologic analyses indicate the involvement of immune pathways.
Assuntos
Colo/metabolismo , Neoplasias Colorretais/genética , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença/genética , Sistema Imunitário/metabolismo , Polimorfismo de Nucleotídeo Único , Sequência de Aminoácidos , Western Blotting , Células CACO-2 , Linhagem Celular Tumoral , Colo/patologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Predisposição Genética para Doença/classificação , Células HCT116 , Células HEK293 , Células HL-60 , Células HT29 , Células HeLa , Humanos , Sistema Imunitário/patologia , Imuno-Histoquímica , Células Jurkat , Células K562 , Células MCF-7 , Dados de Sequência Molecular , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Filogenia , RNA , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Homologia de Sequência de Aminoácidos , Células U937RESUMO
The P239S palladin variant has recently been suggested to play a role in hereditary pancreatic cancer. We estimated the contribution of the P239S variant, and surrounding sequence, to familial and early-onset pancreatic cancer. The P239S germline variant was identified in one of 84 high-risk cases and one of 555 controls. The case reported an elderly relative with pancreas cancer. We conclude that this variant does not appear to account for a significant fraction of hereditary or early-onset pancreas cancer.
