RNF43 mutation is associated with aggressive tumor biology along with BRAF V600E mutation in right-sided colorectal cancer

Akio Matsumoto, Yoshifumi Shimada, Mae Nakano, Hidehito Oyanagi, Yosuke Tajima, Masato Nakano, Hitoshi Kameyama, Yuki Hirose, Hiroshi Ichikawa, Masayuki Nagahashi, Hitoshi Nogami, Satoshi Maruyama, Yasumasa Takii, Yiwei Ling, Shujiro Okuda, Toshifumi Wakai

Research output: Contribution to journalArticle

Abstract

Right-sided colorectal cancer (RCRC) demonstrates worse survival outcome compared with left-sided CRC (LCRC). Recently, the importance of RNF43 mutation and BRAF V600E mutation has been reported in the serrated neoplasia pathway, which is one of the precancerous lesions in RCRC. It was hypothesized that the clinical significance of RNF43 mutation differs according to primary tumor sidedness. To test this hypothesis, the clinicopathological characteristics and survival outcome of patients with RNF43 mutation in RCRC and LCRC were investigated. Stage I-IV CRC patients (n=201) were analyzed. Genetic alterations including RNF43 using a 415-gene panel were investigated. Clinicopathological characteristics between RNF43 wild-type and RNF43 mutanttype were analyzed. Moreover, RNF43 mutant-type was classified according to primary tumor sidedness, i.e., rightsided RNF43 mutant-type or left-sided RNF43 mutant-type, and the clinicopathological characteristics between the two groups were compared. RNF43 mutational prevalence, spectrum and frequency between our cohort and TCGA samples were compared. RNF43 mutation was observed in 27 out of 201 patients (13%). Multivariate analysis revealed that age (≥65), absence of venous invasion, and BRAF V600E mutation were independently associated with RNF43 mutation. Among the 27 patients with RNF43 mutation, 12 patients were right-sided RNF43 mutant-type and 15 left-sided RNF43 mutant-type. Right-sided RNF43 mutant-type was significantly associated with histopathological grade 3, presence of lymphatic invasion, APC wild, BRAF V600E mutation, microsatellite instability-high (MSI-H), and RNF43 nonsense/frameshift mutation compared with left-sided RNF43 mutanttype. Similarly, RNF43 nonsense/frameshift mutations were more frequently observed in RCRC compared with LCRC in the TCGA cohort (P=0.042). Right-sided RNF43 mutant-type exhibited significantly worse overall survival than RNF43 wild-type and left-sided RNF43 mutant-type (P=0.001 and P=0.023, respectively) in stage IV disease. RNF43 mutation may be a distinct molecular subtype which is associated with aggressive tumor biology along with BRAF V600E mutation in RCRC.

Original languageEnglish
Pages (from-to)1853-1862
Number of pages10
JournalOncology reports
Volume43
Issue number6
DOIs
Publication statusPublished - 2020

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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  • Cite this

    Matsumoto, A., Shimada, Y., Nakano, M., Oyanagi, H., Tajima, Y., Nakano, M., Kameyama, H., Hirose, Y., Ichikawa, H., Nagahashi, M., Nogami, H., Maruyama, S., Takii, Y., Ling, Y., Okuda, S., & Wakai, T. (2020). RNF43 mutation is associated with aggressive tumor biology along with BRAF V600E mutation in right-sided colorectal cancer. Oncology reports, 43(6), 1853-1862. https://doi.org/10.3892/or.2020.7561