Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8520, Japan.
Department of Surgery, Niigata Cancer Centre Hospital, Niigata 951-8566, Japan.
Oncol Rep. 2020 Jun;43(6):1853-1862. doi: 10.3892/or.2020.7561. Epub 2020 Mar 23.
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 mutant-type were analyzed. Moreover, RNF43 mutant-type was classified according to primary tumor sidedness, i.e., right-sided 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 mutant-type. 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.
右侧结直肠癌（RCRC）的生存结果比左侧结直肠癌（LCRC）差。最近，在锯齿状肿瘤发生途径中，RNF43 突变和 BRAF V600E 突变的重要性已被报道，该途径是 RCRC 的癌前病变之一。据推测，RNF43 突变的临床意义因原发肿瘤侧别而异。为了验证这一假说，研究了 RCRC 和 LCRC 中 RNF43 突变患者的临床病理特征和生存结果。分析了 201 例 I-IV 期 CRC 患者。采用 415 基因panel 检测 RNF43 等遗传改变。分析 RNF43 野生型和 RNF43 突变型之间的临床病理特征。此外，根据原发肿瘤侧别，将 RNF43 突变型分为右侧 RNF43 突变型或左侧 RNF43 突变型，并比较两组之间的临床病理特征。比较了我们的队列和 TCGA 样本中 RNF43 突变的流行率、谱和频率。在 201 例患者中有 27 例（13%）观察到 RNF43 突变。多变量分析显示，年龄（≥65 岁）、无静脉侵犯和 BRAF V600E 突变与 RNF43 突变独立相关。在 27 例 RNF43 突变患者中，12 例为右侧 RNF43 突变型，15 例为左侧 RNF43 突变型。与左侧 RNF43 突变型相比，右侧 RNF43 突变型与组织学分级 3、存在淋巴管浸润、APC 野生型、BRAF V600E 突变、微卫星不稳定高（MSI-H）和 RNF43 无义/移码突变显著相关。同样，在 TCGA 队列中，与 LCRC 相比，RCRC 中更频繁地观察到 RNF43 无义/移码突变（P=0.042）。在 IV 期疾病中，右侧 RNF43 突变型的总生存明显劣于 RNF43 野生型和左侧 RNF43 突变型（P=0.001 和 P=0.023）。RNF43 突变可能是一种独特的分子亚型，与 BRAF V600E 突变一起与 RCRC 中的侵袭性肿瘤生物学相关。
