Deleterious Effect of RAS and Evolutionary High-risk TP53 Double Mutation in Colorectal Liver Metastases.
Deleterious Effect of RAS and Evolutionary High-risk TP53 Double Mutation in Colorectal Liver Metastases.
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DOI：
10.1097/sla.0000000000002450
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发表时间：
2019-05
影响因子：
9
通讯作者：
Vauthey JN
中科院分区：
文献类型：
--
作者：
Chun YS;Passot G;Yamashita S;Nusrat M;Katsonis P;Loree JM;Conrad C;Tzeng CD;Xiao L;Aloia TA;Eng C;Kopetz SE;Lichtarge O;Vauthey JN
评估体细胞基因突变对结直肠癌肝转移切除术（CLM）患者生存率的影响。接受CLM切除术的患者具有异质性结局，准确的风险分层对于优化手术患者的选择是必要的。对401名接受CLM切除术的患者的原发性肿瘤和/或肝转移瘤进行了50种癌症相关基因的下一代测序。错义TP 53突变通过进化行动评分（EAp 53）进行分类，这是一种将突变分为低风险或高风险的新方法。最常见的体细胞基因突变是TP 53（65.6%），其次是KRAS（48.1%）和APC（47.4%）。RAS/TP 53双突变，确定在31.4%的患者，与原发肿瘤的位置在右结肠（P = 0.006）。在多变量分析中，RAS/TP 53双突变是总生存期较短的独立预测因子（风险比，2.62; 95%可信区间1.41 - 4.87; P = 0.002）。在RAS共突变患者中，EAp 53高风险突变与较短的5年总生存率（12.2%）相关，而TP 53野生型为55.7%（P < 0.001）。RAS和TP 53突变的负面预后影响仅限于两种基因均携带突变的肿瘤。伴随RAS和TP 53突变与CLM切除术后生存率降低相关。高EAp 53预测预后较差的患者子集。这些初步分析表明，肝转移瘤的手术切除应仔细考虑在这一子集的患者。
To assess the impact of somatic gene mutations on survival among patients undergoing resection of colorectal liver metastases (CLM). Patients undergoing CLM resection have heterogeneous outcomes, and accurate risk stratification is necessary to optimize patient selection for surgery. Next-generation sequencing of 50 cancer-related genes was performed from primary tumors and/or liver metastases in 401 patients undergoing CLM resection. Missense TP53 mutations were classified by the Evolutionary Action Score (EAp53), a novel approach that dichotomizes mutations as low or high risk. The most frequent somatic gene mutations were TP53 (65.6%), followed by KRAS (48.1%) and APC (47.4%). Double mutation in RAS/TP53, identified in 31.4% of patients, was correlated with primary tumor location in the right colon (P = 0.006). On multivariable analysis, RAS/TP53 double mutation was an independent predictor of shorter overall survival (hazard ratio, 2.62; 95% confidence interval 1.41 to 4.87; P = 0.002). In patients with co-mutated RAS, EAp53 high risk mutations were associated with shorter 5-year overall survival of 12.2%, compared with 55.7% for TP53 wild-type (P < 0.001). The negative prognostic effects of RAS and TP53 mutations were limited to tumors harboring mutations in both genes. Concomitant RAS and TP53 mutations are associated with decreased survival after CLM resection. A high EAp53 predicts a subset of patients with worse prognosis. These preliminary analyses suggest that surgical resection of liver metastases should be carefully considered in this subset of patients.