Y. Shimada1, Y. Tajima1, M. Nagahashi1, H. Ichikawa1, K. Yuza1, Y. Hirose1, T. Katada1, M. Nakano1, J. Sakata1, H. Kameyama1, Y. Takii2, S. Okuda3, K. Takabe4, T. Wakai1 1Niigata University,Digestive And General Surgery,Niigata, NIIGATA, Japan 2Niigata Cancer Center Hospital,Surgery,Niigata, NIIGATA, Japan 3Niigata University,Bioinformatics,Niigata, NIIGATA, Japan 4Roswell Park Cancer Institute,Breast Surgery,Buffalo, NY, USA
Introduction: Right-sided colorectal cancer (CRC) demonstrates worse survival outcome compared with left-sided CRC, and clinicopathological characteristics of right-sided CRC differ from left-sided CRC. Recently, the importance of RNF43 mutation has been reported along with BRAF mutation in serrated neoplasia pathway. We hypothesized that clinical significance of RNF43 mutation differs between right-sided and left-sided CRCs, and RNF43 mutation associates with tumor biology of right-sided CRC. To test this hypothesis, we investigated the clinicopahotlogical characteristics and survival outcome of patients with RNF43 mutation in right-sided and left-sided CRCs.
Methods: One-hundred-nine microsatellite stable Stage IV CRC patients were analyzed. Thirty-three and 76 patients were right-sided CRC and left-sided CRC, respectively. We investigated genetic alterations using a 415-gene panel, which includes RNF43 and the other genes associated with tumor biology. We analyzed clinicopathological characteristics between RNF43 wild-type and RNF43 mutant-type using Fisher’s exact test. Moreover, we classified RNF43 mutant-type according to primary tumor sidedness, i.e., right-sided RNF43 mutant-type or left-sided RNF43 mutant-type, and compared clinicopathological characteristics between the two groups. Overall survival rates of RNF43 wild-type, right-sided RNF43 mutant-type, and left-sided RNF43 mutant-type were analyzed using log-rank test.
Results:CGS revealed that 8 of 109 patients (7%) had RNF43 mutation. RNF43 mutation was significantly associated with high age (65 or more) (P = 0.020), presence of BRAF mutation (P = 0.005), absence of KRAS and PTEN mutations (P = 0.049 and P = 0.026, respectively). RNF43 mutation was observed in 3 of 33 right-sided CRC (9%) and 5 of 76 left-sided CRC (7%), respectively. Interestingly, RNF43 mutations in right-sided CRC were nonsense mutation (R145X) or frameshift mutation (P192fs, S262fs), while those in left-sided CRC were missense mutations (T58S, W200C, R221W, R519Q, R519Q). All the three right-sided RNF43 mutant-type were high age (65 or more), female, BRAF V600E mutant-type. Right-sided RNF43 mutant-type showed significantly worse OS than RNF43 wild-type and left-sided RNF43 mutant-type (P = 0.007 and P = 0.046, respectively).
Conclusion:Clinicopathological characteristics and survival outcome of patients with RNF43 mutation might differ between right-sided and left-sided CRC. In right-sided CRC, RNF43 mutation is a small, but distinct molecular subtype which is associated with aggressive tumor biology along with BRAF V600E mutation. Future preclinical and clinical studies might have to focus on RNF43 mutation for improving survival outcome in right-sided CRC.
