Background/Aims IGF signaling has a relevant role in a variety of human malignancies. We analyzed the underlying molecular mechanisms of IGF signaling activation in early hepatocellular carcinoma (HCC; BCLC class 0 or A) and assessed novel targeted therapies blocking this pathway Methods An integrative molecular dissection of the axis was conducted in a cohort of 104 HCCs analyzing gene and miRNA expression, structural aberrations and protein activation. The therapeutic potential of a selective IGF-1R inhibitor, the monoclonal antibody A12, was assessed in vitro and in a xenograft model of HCC Results Activation of the IGF axis was observed in 21% of early HCCs. Several molecular aberrations were identified, such as overexpression of IGF2 –resulting from reactivation of fetal promoters P3 and P4-, IGFBP3 downregulation and allelic losses of IGF2R 25% of cases). A gene signature defining IGF-1R activation was developed. Overall, activation of IGF signaling in HCC was significantly associated with mTOR signaling (p=0.035) and was clearly enriched in the Proliferation subclass of the molecular classification of HCC (p=0.001). We also found an inverse correlation between IGF activation and miR-100/miR-216 levels (FDR<0.05). In vitro studies showed that A12-induced abrogation of IGF-1R activation and downstream signaling significantly decreased cell viability and proliferation. In vivoA12 delayed tumor growth and prolonged survival, reducing proliferation rates and inducing apoptosis Conclusions Integrative genomic analysis showed enrichment of activation of IGF signaling in the Proliferation subclass of HCC. Effective blockage of IGF signaling with A12 provides the rationale for testing this therapy in clinical trials.
BACKGROUND:The role of human papillomavirus (HPV) in the pathogenesis of squamous cell carcinomas (SCCs) of the sinonasal tract and its clinicopathological implications were evaluated.METHODS:All SCCs of the sinonasal tract diagnosed in the Hospital Clinic of Barcelona from 1981 to 2006 were retrospectively evaluated (N = 60). Clinical and pathological data were reviewed. HPV infection was determined and typed by amplification of HPV DNA by polymerase chain reaction using the SPF‐10 primers. p16INK4a expression was determined by immunohistochemistry. Overall and progression‐free survival for HPV‐positive and ‐negative patients was estimated by Kaplan‐Meier analysis and by the use of a multivariate Cox proportional hazards model.RESULTS:HPV DNA was detected in tumor tissue of 12 of 60 (20%) patients. HPV16 was identified in 11 tumors and HPV35 in 1. Immunohistochemistry for p16INK4a stained all HPV‐positive and no HPV‐negative tumors (P < .001). No differences were observed in terms of site and histological grade or stage at presentation between HPV‐positive and ‐negative tumors. However, HPV‐positive patients had a significantly better 5‐year progression‐free survival (62%; 95% confidence interval [CI], 23%‐86% vs 20%; 95% CI, 9%‐34%; P = .0043, log‐rank test) and overall survival (80%; 95% CI, 20%‐96% vs 31%; 95% CI, 15%‐47%; P = .036, log‐rank test) than patients with HPV‐negative tumors. In multivariate analysis, HPV‐positive tumors were associated with improved progression‐free survival (hazard ratio, 0.21; 95% CI, 0.17‐0.98; P = .012).CONCLUSIONS:A subgroup of sinonasal SCCs is associated with HPV infection. These tumors have a significantly better prognosis. Cancer 2009. © 2009 American Cancer Society.
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