RNF43 mutation is associated with aggressive tumor biology along with BRAF V600E mutation in right-sided colorectal cancer
RNF43 mutation is associated with aggressive tumor biology along with BRAF V600E mutation in right-sided colorectal cancer
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DOI：
10.3892/or.2020.7561
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发表时间：
2020-06-01
期刊：
影响因子：
4.2
通讯作者：
Wakai, Toshifumi
中科院分区：
文献类型：
--
作者：
Matsumoto, Akio;Shimada, Yoshifumi;Wakai, Toshifumi
与左侧结直肠癌（LCRC）相比，右侧结直肠癌（RCRC）的生存结局较差。近年来，RCRC的癌前病变之一--锯齿状瘤形成通路中RNF 43突变和BRAF V600 E突变的重要性被报道。据推测，RNF 43突变的临床意义根据原发肿瘤的侧性而不同。为了验证这一假设，研究了RCRC和LCRC中RNF 43突变患者的临床病理特征和生存结局。分析了I-IV期CRC患者（n=201）。使用415个基因组研究了包括RNF 43在内的遗传改变。分析RNF 43野生型与RNF 43突变型的临床病理特征。此外，RNF 43突变型根据原发性肿瘤侧性进行分类，即，右侧RNF 43突变型或左侧RNF 43突变型，比较两组间的临床病理特征。比较我们的队列和TCGA样本之间的RNF 43突变患病率、谱和频率。201例患者中有27例（13%）观察到RNF 43突变。多变量分析显示年龄（≥ 65岁）、无静脉侵犯和BRAF V600 E突变与RNF 43突变独立相关。在27例RNF 43突变患者中，12例为右侧RNF 43突变型，15例为左侧RNF 43突变型。与左侧RNF 43突变型相比，右侧RNF 43突变型与组织病理学3级、淋巴管浸润、APC野生型、BRAF V600 E突变、微卫星不稳定性高（MSI-H）和RNF 43无义/移码突变显著相关。同样，在TCGA队列中，与LCRC相比，RCRC中观察到的RNF 43无义/移码突变更频繁（P=0.042）。在IV期疾病中，右侧RNF 43突变型的总体存活率显著低于RNF 43野生型和左侧RNF 43突变型（分别为P=0.001和P=0.023）。RNF 43突变可能是RCRC中与BRAF V600 E突变一起沿着与侵袭性肿瘤生物学相关的独特分子亚型。
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.