Background: The clinical relevance of genomic imbalances in pancreatic cancer is uncertain. The aim of this study was to evaluate whether alterations in specific genes influenced clinical outcome in resected pancreatic cancer patients. Methods: Recurrent copy number alterations of cytobands and genes were analyzed by array comparative genomic hybridization (aCGH) in 44 resected pancreatic cancer specimens from a Korean cohort, including 24 patients who received adjuvant chemotherapy regimens with gemcitabine or 5-fluorouracil. Statistical analysis enabled us to assess the interaction of copy number alterations with clinicopathological variables and overall survival (OS). Prognostic markers identified by aCGH were validated by PCR gene copy number assay in an independent Italian cohort of 61 resected pT3N1Mx stage pancreatic cancers treated with gemcitabine adjuvant therapy. Results: Recurrent copy number gains were observed in chromosome 1q, 11q, 18q11.1-11.2, and 20q13.13; and losses in chromosome 2p, 9p, 10q, 14q, 15q, 18q12.2-23, 19q, 20q11.1, 21p, and 22q. Loss of cytoband 18q22.3 (in 8 patients) was significantly more frequent in patients surviving shorter than the median OS (p=0.021, Fisher-Exact test). This cytoband encodes 5 genes, including CNDP2, whose copy number was associated with OS (p=0.019, log-rank test). The copy number of this gene was subsequently assessed in the Italian cohort, where patients with deletion (N=41) had shorter OS (p=0.003, log-rank test). Multivariate analysis of the two cohorts showed that loss/deletion of 18q22.3/CNDP2 was an independent poor prognostic factor for OS (hazard ratio 2.72, p=0.0007) after adjusting for other factors influencing clinical outcome. Conclusions: Through aCGH analysis, we identified loss/deletion of 18q22.3/CNDP2 as a potentialindependent poor prognostic factor in resected pancreatic cancer. Given the heterogeneity of the two cohorts, further confirmation on a large number of patients is warranted. However, the combined Cox model suggests that this genetic alteration may have a meaningful impact on OS of pancreatic cancer patients, and its biological implications are being investigated.
Array-based comparative genomic hybridization analysis to identify prognostic markers for resected pancreatic cancer.
PETRINI, IACOPO;GIOVANNETTI, ELISA;
2011-01-01
Abstract
Background: The clinical relevance of genomic imbalances in pancreatic cancer is uncertain. The aim of this study was to evaluate whether alterations in specific genes influenced clinical outcome in resected pancreatic cancer patients. Methods: Recurrent copy number alterations of cytobands and genes were analyzed by array comparative genomic hybridization (aCGH) in 44 resected pancreatic cancer specimens from a Korean cohort, including 24 patients who received adjuvant chemotherapy regimens with gemcitabine or 5-fluorouracil. Statistical analysis enabled us to assess the interaction of copy number alterations with clinicopathological variables and overall survival (OS). Prognostic markers identified by aCGH were validated by PCR gene copy number assay in an independent Italian cohort of 61 resected pT3N1Mx stage pancreatic cancers treated with gemcitabine adjuvant therapy. Results: Recurrent copy number gains were observed in chromosome 1q, 11q, 18q11.1-11.2, and 20q13.13; and losses in chromosome 2p, 9p, 10q, 14q, 15q, 18q12.2-23, 19q, 20q11.1, 21p, and 22q. Loss of cytoband 18q22.3 (in 8 patients) was significantly more frequent in patients surviving shorter than the median OS (p=0.021, Fisher-Exact test). This cytoband encodes 5 genes, including CNDP2, whose copy number was associated with OS (p=0.019, log-rank test). The copy number of this gene was subsequently assessed in the Italian cohort, where patients with deletion (N=41) had shorter OS (p=0.003, log-rank test). Multivariate analysis of the two cohorts showed that loss/deletion of 18q22.3/CNDP2 was an independent poor prognostic factor for OS (hazard ratio 2.72, p=0.0007) after adjusting for other factors influencing clinical outcome. Conclusions: Through aCGH analysis, we identified loss/deletion of 18q22.3/CNDP2 as a potentialindependent poor prognostic factor in resected pancreatic cancer. Given the heterogeneity of the two cohorts, further confirmation on a large number of patients is warranted. However, the combined Cox model suggests that this genetic alteration may have a meaningful impact on OS of pancreatic cancer patients, and its biological implications are being investigated.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
