Y. Tajima1, Y. Shimada1, M. Nagahashi1, H. Ichikawa1, H. Kameyama1, M. Nakano1, J. Sakata1, T. Kobayashi1, H. Nogami2, S. Maruyama2, Y. Takii2, S. Okuda3, K. Takabe4,5, T. Wakai1 1Niigata University Graduate School Of Medical And Dental Sciences,Division Of Digestive And General Surgery,Niigata, NIIGATA, Japan 2Niigata Cancer Center Hospital,Department Of Surgery,Niigata, NIIGATA, Japan 3Niigata University Graduate School Of Medical And Dental Sciences,Division Of Bioinformatics,Niigata, NIIGATA, Japan 4Roswell Park Cancer Institute,Breast Surgery,Buffalo, NEW YORK, USA 5The State University Of New York,Department Of Surgery, University At Buffalo Jacobs School Of Medicine And Biomedical Sciences,Buffalo, NEW YORK, USA
Introduction:
he PI3K/AKT/mTOR pathway is related with cell proliferation and frequently activated in many human cancers. On the other hand, PTEN is a tumor suppressor gene inhibiting PI3K-initiated signaling. Loss of PTEN can be occurred in various types of tumor and associated with progression and worse prognosis. However, the association between PTEN mutation and prognosis in colorectal cancer (CRC) remains unclear. Our aim was to analyze the clinical impact of PTEN mutation in patients with colorectal cancer.
Methods:
Two-hundred-one Stage I–IV CRC patients who underwent colorectal resection were analyzed. We investigated genetic alterations associated with CRC using 415-gene panel. The association between PTEN mutation status and clinicopathological characteristics was analyzed using Fisher’s exact test. The association between PTEN mutation status and relapse-free survival (RFS) was analyzed using log-rank test and Cox proportional hazards model.
Results:
Fifty-five (27%) of 201 patients had PTEN mutation. Tumor diameter < 50 mm, lymphatic invasion, venous invasion, distant metastasis, poorly differentiated cluster grade 2/3 and Ki67 < 60 % were significantly associated with PTEN mutation (P < 0.001, P = 0.036, P = 0.003, P = 0.002, P = 0.009 and P = 0.003, respectively). Univariate analysis showed that PTEN mutation was significantly associated with the worse RFS in patients with Stage III CRC (P = 0.002) (Fig.1). On the other hand, PTEN mutation was not significantly associated with the RFS in patients with Stage I/II CRC and the overall survival in patients with Stage IV CRC (Fig.1). Of 415 genes, 18 genes had mutations in over 10% of patients with Stage III CRC. Those 18 genes were ACVR2A (10.9%), APC (71.7%), BRAF (10.9%), BRCA2 (10.9%), CDH1 (10.9%), CIC (10.9%), ERBB2 (13.0%), FAT1 (10.9%), FBXW7 (23.9%), KRAS (41.3%), PIK3CA (15.2%), PTEN (15.2%), RNF43 (19.6%), SMAD2 (10.9%), SMAD4 (21.7%), SPEN (13.0%), STK11 (15.2%), TP53 (78.3%). Among the 18 genes, PTEN mutation was significantly associated with CIC mutation (P = 0.020). Univariate analysis in patients with Stage III CRC showed that the RFS was significantly worse in mucinous type, CIC mutation, ERBB2 mutation and PTEN mutation (P = 0.005, P = 0.009, P = 0.037, P = 0.002, respectively). Multivariate analysis in patients with Stage III showed that only PTEN mutation was significantly affected the RFS (hazard ratio 6.18, 95% confidence interval 1.63–23.5, P = 0.007).
Conclusion:
PTEN mutation was associated with worse prognosis in Stage III CRC. We speculate that PTEN is one of potential driver genes in CRC.
