Il17f-Rs9463772 Independently Predicts Long-Term Outcome In Locally Advanced Rectal Cancer

Host genetic variation in the immune factors has the potential to highlight individual characteristics of tumor risk, prognosis, and response to treatment. In locally advanced rectal cancer (LARC) no predictive and prognostic factors are available to select patients for multimodality treatment comprising neoadjuvant chemoradiation followed by radical surgery, and possibly adjuvant chemotherapy. This work aimed at identifying immunogenetic markers of prognostic significance in LARC patients treated by multimodality treatment. A panel of 192 tagging polymorphisms (SNPs) in 34 immuno-system related genes was selected and analyzed in a Veracode (Illumina) platform on 250 LARC patients (training set) treated with neo-adjuvant therapy, and followed up for at least 24 months after radical surgery. The primary clinical end-point of the study was 2-years recurrence status which has been reported to be the most reliable long-term prognostic factor in these patients. Significant SNPs were then tested on 10-years overall survival (OS). An independent validation set comprising of 63 rectal cancer patients was used to replicate the results. Training set analysis identified 4 markers significantly associated with 2-years recurrence status by multivariate logistic regression which were still significant after bootstrap validation, according to a dominant genetic model: three of them were risk factors, IL17F-rs641701 (P = 0.002), IL17F-rs9463772 (P = 0.009), TGF-beta- rs9867701 (P = 0.020); one of them was a protective factor, STAT3-rs8069645 (P = 0.025). Three of them were also associated to 10-years OS by multivariate COX regression: IL17F-rs641701 (P = 0.003); IL17F-rs9463772 (P = 0.002) were risk factors for death; STAT3-rs8069645 (P = 0.003) was a protective factor. The prognostic effect of IL17F-rs9463772 on 10-years OS was replicated using the validation set (P = 0.045). IL17F is a cytokine with onco-suppressing and anti-angiogenic effects, previously reported to be down-regulated in colorectal tumor as compared to healthy tissue. Although no functional data are available for the intronic rs9463772, it might be involved in the regulation of IL17F expression level affecting tumor prognosis. In conclusion IL17F-rs9463772 represents a validated prognostic marker of long term survival in LARC patients, further studies are warranted to provide functional evidence to support these findings. Citation Format: Cecchin Erika, Eva Dreussi, Sara Gagno, Chiara Zanusso, Marcella Montico, Claudio Belluco, Antonino De Paoli, Salvatore Pucciarelli, Luca Quartuccio, Salvatore De Vita, Vincenzo Canzonieri, Angela Buonadonna, Maria Luisa Friso, Sara Lonardi, Giuseppe Toffoli. IL17F-rs9463772 independently predicts long-term outcome in locally advanced rectal cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1420.