title: Novel mutations and expression alterations in SMAD3/TGFBR2 genes in oral carcinoma correlate with poor prognosis.
abstract: Transforming growth factor beta (TGF-β) signaling is a pleiotropic cytokine signaling pathway, which controls cellular activities ranging from embryogenesis to apoptosis. Although many molecular alterations in this pathway have been described in cancers, the central point of concern, that is how these alterations influence the treatment outcome, has been addressed to a lesser extent. In this study, we have characterized the alterations of TGF-β-SMAD signaling in 97 oral squamous cell carcinoma (OSCC) samples and assessed the association between these alterations and the outcome of the treatment. Genomic level alteration analysis using reverse transcriptase polymerase chain reaction-single-strand conformation polymorphism/sequencing revealed that there were 25% samples harboring genomic level alterations in this pathway. Altogether, 21% samples showed TGFBR2 mutations, whereas three cases were found to harbor novel SMAD3 mutations. Notably, 14 out of 24 TGFBR2 mutations are of one type (c.*6C>A), which supplemented complementarity for hsa-miR-3189-5p. These samples showed significantly low TGFBR2 transcript levels (P = 0.026). In addition, transcript level studies using quantitative real-time PCR revealed a strong association between low TGFBR2 transcript levels and poor disease-free survival (P = 0.028) as well as poor overall survival (P = 0.013). In brief, our results showed that oral cancers with TGFBR2 downregulation comprise a different group with more aggressive nature. These results suggest that in OSCCs, TGFBR2 transcript levels may be developed as a promising prognostic biomarker. Furthermore, for the first time, this study reports SMAD3 mutations in oral carcinoma.
authors.affiliation: Laboratory of Cell Cycle Regulation & Molecular Oncology, Division of Cancer Research, Regional Cancer Centre, Thiruvananthapuram, 695 011, Kerala, India.
authors.forename: Vadakke Peringode
authors.initials: VP
authors.lastname: Sivadas
authors.forename: Nebu Abraham
authors.initials: NA
authors.lastname: George
authors.forename: Jayasree
authors.initials: J
authors.lastname: Kattoor
authors.forename: S
authors.initials: S
authors.lastname: Kannan
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000401:mortality; D018572:Disease-Free Survival; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000235:genetics* / Q000401:mortality; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D051900:Smad3 Protein / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D035683:MicroRNAs; D018125:Receptors, Transforming Growth Factor beta; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II