The ubiquitously expressed transcriptional regulator Serum Response Factor (SRF) is controlled by both Ras/MAPK and Rho/actin signaling pathways, which are frequently activated in hepatocellular carcinoma (HCC). We generated SRF-VP16(iHep) mice, which conditionally express constitutively active SRF-VP16 in hepatocytes, thereby controlling subsets of both Ras/MAPK- and Rho/actin-stimulated target genes. All SRF-VP16(iHep) mice develop hyper-proliferative liver nodules that progresses to lethal HCC. Some mHCCs acquire Ctnnb1 mutations equivalent to those in hHCC. Resulting transcript signatures mirror those of a distinct subgroup of hHCCs, with shared activation of oncofetal genes including Igf2, correlating with CpG hypo-methylation at the imprinted Igf2/H19 locus. Conclusion: SRF-VP16(iHep) mHCC reveal convergent Ras/MAPK and Rho/actin signaling as highly oncogenic driver mechanism for hepato-carcinogenesis. This suggests simultaneous inhibition of Ras/MAPK and Rho/actin signaling as treatment strategy in human HCC therapy. (Hepatology 2014;).
During the past decade, the incidence of EGFR mutation has been shown to vary across different ethnicities. It occurs at the rate of 10-15% in North Americans and Europeans, 19% in African-Americans, 20-30% in various East Asian series including Chinese, Koreans, and Japanese. Frequency of EGFR mutations in India however remains sparsely explored.
Screening for EGFR mutation is a key molecular test for management of lung cancer patients. Outcome of patients with mutation receiving EGFR tyrosine kinase inhibitor is known to be better across different ethnic populations. However, frequency of EGFR mutations and the clinical response in most other ethnic populations, including India, remains to be explored. We conducted a retrospective analysis of Indian lung cancer patients who were managed with oral tyrosine kinase inhibitors. Majority of the patients in the study had adenocarcinoma and were non-smokers. 39/111 patients tested positive for EGFR kinase domain mutations determined by Taqman based real time PCR. The overall response to oral TKI therapy was 30%. Patients with an activating mutation of EGFR had a response rate of 74%, while the response rate in patients with wild type EGFR was 5%, which was a statistically significant difference. Progression free survival of patients with EGFR mutations was 10 months compared to 2 months for EGFR mutation negative patients. Overall survival was 19 months for EGFR mutation patients and 13 months for mutation negative patients. This study emphasizes EGFR mutation as an important predictive marker for response to oral tyrosine kinase inhibitors in the Indian population.
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