Interferon induced transmembrane protein 1 (IFITM1) gene is a novel candidate as a CDDP sensitivity marker in esophageal squamous cell carcinoma (ESCC)
Authors: Shoichi Fumoto, Tatsushi Shimokuni, Keiji Tanimoto, Keiko Hiyama, Tsuyoshi Noguchi, Katsunobu Kawahara, Keiko Otani, Megu Ohtaki, Eiso Hiyama, Masahiko Nishiyama
Journal: Cancer Research (2007)

1409   We previously demonstrated that simultaneous performance of two different types of comprehensive gene expression analysis, cDNA and oligonucleotide microarray analyses, might provide way to identify potent marker genes for drug sensitivity from the expression-sensitivity correlation analysis alone and the selected genes,  B4GALT5 ,  UGCG ,  XBP1  for 5-FU and  IFITM1, KIAA0685 ,  SIPA1L2  for CDDP, were likely better drug-sensitivity markers in ESCC (97th AACR Annual Meeting). Even so, the individual correlation with clinical drug response in several genes was found to be relatively weak to show potent values as practical prediction markers. We, therefore, attempted to identify more potent marker genes using a new statistical analysis based on oligomicroarray expression data, a two-dimensional mixed normal model, and selected 3 ( CARD8 ,  MGC3123 ,  Gene X ) and 6 novel candidates ( C10orf97 ,  IFITM1, MARK1 ,  MDS025, TARBP1, Gene Y ) respectively for 5-FU and CDDP, as more reliable sensitivity marker genes than the previously proposed marker genes in the novel statistical screening. Interestingly,  IFITM1  gene alone was commonly selected in both previously and newly performed screening methods, which led us to focus on the gene as the most potent predictor. The gene encodes interferon induced transmembrane  protein 1, and is now suggested as a key gene of Wnt pathway. The expression-sensitivity correlation in esophageal cancer cell lines was highly confirmative in the subsequent real-time RT-PCR analysis, and the transfection analyses and siRNA-mediated knock-down experiments revealed that expression of  IFITM1  gene closely related to cellular sensitivity to CDDP. We also attempted to predict drug sensitivity using expression data of a set of all selected marker genes including  IFITM1 , considering the fact that drug sensitivity is determined by multiple genes. Using multiple regression analyses, we developed highly predictive formulae of  in vitro  sensitivities to 5-FU and CDDP, and found that expression of  IFITM1  was of key importance in the prediction formulae for CDDP.  IFITM1  was also shown to be important in the prediction of progression-free survival (PFS) for 5-FU/CDDP combination, despite a slightly decreased relative significance in the formulae. These results indicate that  IFITM1  gene  is a novel and potent predictor of CDDP response and the use of a two-dimensional mixed normal model will contribute to improving the heretofore limited utility of microarray analysis in the selection of drug sensitivity genes. We are now planning a prospective clinical study to show the practical value of the prediction formulae of PFS for 5-FU/CDDP combination, along with continuing our search for the functional roles of the other selected genes in drug sensitivity and more powerful predictive marker genes.