探讨YTHDF1单核苷酸多态性(SNP)在符合杭州标准肝移植受者术后肝癌复发中的预测价值。

回顾性分析2015年1月1日至2019年5月31日在浙江大学医学院附属第一医院接受肝癌肝移植并符合杭州标准的139例受者临床资料，中位年龄54岁(30～73岁)，其中男性120例，女性19例。在1 000 Genmoes Project数据库中，设定人群为汉族、最小等位基因频率>5%及r²>0.8，利用Haploview软件筛选出标签单核苷酸多态性(tagSNP)。采用配对样本Wilcoxon检验比较YTHDF1在肝癌及癌旁组织中的表达差异，采用Kaplan-Meier方法绘制rs68041888 G携带型和非携带型肝癌肝移植受者术后无复发生存曲线并比较无复发生存时间，采用Cox比例风险回归模型进行肝癌肝移植术后肿瘤复发影响因素分析，采用卡方检验或Fisher确切概率法比较肿瘤复发与未复发组受者YTHDF1 tagSNP基因型分布。P<0.05为差异有统计学意义。

随访至2020年5月31日，139例肝癌肝移植受者平均无复发生存时间为(43.9±2.0)个月(1～56个月)，其中28例肝癌复发。YTHDF1在肝癌组织中的表达水平高于癌旁组织，评分中位数分别为6分(4～9分)和3分(1～6分)，差异有统计学意义(Z＝4.087，P<0.05)。28例复发组受者rs68041888位点的G/A型、G/G型和A/A型分别为8、13和7例，111例未复发组受者中则分别为42、61和8例，两组基因型分布差异有统计学意义(χ²＝0.025，P<0.05)。其余tagSNP基因型分布差异均无统计学意义(P均>0.05)。rs68041888 G非携带型(位点为A/A型)受者肝癌复发比例高于携带型(位点为G/A型、G/G型)，分别为46.7%(7/15)和16.9%(21/124)，差异有统计学意义(P＝0.018)。rs68041888 G携带型与非携带型受者术后1年无复发生存比例分别为87.1%(108/124)和66.7%(10/15)，无复发生存时间分别为(45.6±2.1)和(27.9±5.2)个月，差异有统计学意义(χ²＝5.980，P＝0.014)。复发组术前AFP≤400 μg/L和rs68041888 G携带型受者比例分别为71.4%(20/28)、75.0%(21/28)，均低于未复发组受者[91.0%(101/111)、92.8(103/111)]，差异均有统计学意义(χ²＝5.955和5.621，P均<0.05) 。其余指标差异均无统计学有意义(P均>0.05)。将单因素分析中P<0.10的变量纳入Cox比例风险回归模型进行多因素分析。结果显示，术前AFP、肿瘤数量、组织学分级和rs68041888 G携带与否与肿瘤复发有关(RR＝5.024、2.352、2.523和3.693，P均<0.05)。

在符合杭州标准的肝癌肝移植受者中，rs68041888 G非携带型受者肿瘤复发风险较高。rs68041888基因型对肝移植术后肝癌复发的预测具有潜在价值。

To investigate the predictive value of YTHDF1 single nucleotide polymorphism (SNP) in the hepatocellular carcinoma recurrence of liver transplant recipients within Hangzhou criteria.

We retrospectively analyzed the clinical data of 139 recipients who received liver transplantation from the First Affiliated Hospital of Zhejiang University and met Hangzhou criteria from January 1, 2015 to May 31, 2019, with a median age of 54 years (30-73 years), including 120 males and 19 females. The tag SNPs (Han population, minor allele frequency>5% and r²>0.8) were obtained from 1 000 Genmoes Project database with Haploview. Paired-sample Wilcoxon test was used to compare the expression differences of YTHDF1 in liver cancer and adjacent tissues. Kaplan-Meier method was used to draw recurrence-free survival curves of rs68041888 G-carrying and non-carrying liver recipients and to compare recurrence-free survival time. Cox proportional hazards regression model was used to analyze the factors affecting tumor recurrence after liver transplantation. The Chi-square test or Fisher′s exact probability method was used to compare the YTHDF1 tagSNP genotype distribution of the tumor recurrence and non-recurrence groups. A P<0.05 was considered statistically significant.

Follow-up to May 31, 2020, the average recurrence-free survival time of 139 liver transplant recipients was (43.9±2.0) months (1 to 56 months). Among 139 liver recipients, 28 had recurrence. The expression level of YTHDF1 in liver cancer tissues is higher than that in adjacent tissues (6 points vs. 3 points, Z=4.087, P<0.05). There were 8, 13 and 7 cases of G/A, G/G and A/A at rs68041888 locus among 28 recipients in recurrence group, respectively. Among the 111 recipients in the non-recurrence group, they were 42, 61, and 8, respectively. The difference in genotype distribution between the two groups was statistically significant (χ²=0.025, P<0.05). There was no statistically significant difference in the distribution of other tagSNP genotypes (all P>0.05). rs68041888 G non-carrying type (locus type A/A) recipients of liver cancer recurrence rate (46.7%, 7/15) is higher than that of carrier type (locating type G/A, G/G type) (16.9%, 21/124) (P=0.018). The 1-year recurrence-free survival rates of rs68041888 G-carrying and non-carrying recipients were 87.1% (108/124) and 66.7% (10/15), respectively, and the recurrence-free survival time was (45.6±2.1) and (27.9±5.2) months (χ²=5.980, P=0.014). The proportions of recipients with preoperative AFP≤400 μg/L and rs68041888 G-carrying type in the recurrence group were 71.4% (20/28) and 75.0% (21/28), respectively, which were lower than those in the non-recurrence group [91.0% (101/111), 92.8% (103/111)] (χ²=5.955 and 5.621, both P<0.05). The differences in other indicators were not statistically significant (all P>0.05). The variables with P<0.10 in the univariate analysis were incorporated into the Cox proportional hazards regression model for multivariate analysis. The results showed that preoperative AFP, tumor number, histological grade and rs68041888 G carrying or not were related to tumor recurrence (RR=5.024, 2.352, 2.523, 3.693, P all<0.05).

The liver recipients who met Hangzhou criteria without rs68041888 G type have a higher risk of recurrence. The rs68041888 genotype has potential value in predicting the recurrence of HCC after liver transplantation.