结直肠癌单纯肺转移和单纯肝转移的基因特征分析

Genetic characteristics of isolated lung metastasis and isolated liver metastasis from colorectal cancer

目的探讨结直肠癌肺转移和肝转移的基因特征。方法从本中心1996年1月至2018年12月结直肠癌数据库选取19例单纯肺转移(LuM组)、19例单纯肝转移(LiM组)和12例局部进展期结直肠癌(对照组)的原发灶和转移灶,使用二代测序技术进行测序,分析其单核苷酸变异(SNV)和拷贝数变化(CNV)。经质控后纳入最终分析的样本量为LuM组原发灶17例、转移灶16例,LiM组原发灶17例、转移灶19例,对照组原发灶12例。结果LuM组、LiM组和对照组间SNV的差异无统计学意义(P>0.05)。原发灶CNV对比显示,在转移组(LuM+LiM)中,ZFHX4(91.2%vs.8.3%)、FAM131B(32.4%vs.0.0%)、GATA2(32.4%vs.0.0%)和FOXL2(32.4%vs.0.0%)的扩增频率高于对照组(P<0.05),而RECQL4扩增(8.8%vs.75.0%)和CYP2A6缺失(2.9%vs.33.3%)频率低于对照组(P<0.05)。在转移组内部,LuM组的HNF4A(41.2%vs.0.0%)、BRD4(47.1%vs.5.9%)和U2AF1(35.3%vs.0.0%)的扩增频率高于LiM组(P<0.05)。转移灶CNV对比显示,LuM组MET扩增(25.0%vs.0.0%)、SDHC扩增(25.0%vs.0.0%)和RTK/RAS通路改变(100.0%vs.73.7%)频率高于LiM组,而ZFHX4(50.0%vs.89.5%)和FOXL2(18.8%vs.68.4%)的扩增频率低于LiM组(P<0.05)。结论原发灶的CNV特征与不同的转移风险有关,可以据此筛选根治术后潜在的转移人群及改善围手术期的精准治疗。肺转移灶更易出现MET和SDHC扩增及RTK/RAS通路的激活。

Objective To explore the genetic characteristics of lung metastases and liver metastases from colorectal cancer(CRC).Methods Tissue samples of the primary tumors and metastatic lesions from 19 CRC patients with isolated lung metastases(LuM Cohort),19 with isolated liver metastases(LiM Cohort),and 12 without metastases(Control Cohort)were chosen from the CRC Database(1996-2018)and sequenced by the next generation sequencing.Single nucleotide variations(SNVs)and copy number variations(CNVs)were analyzed.After the quality control,the sample sizes involved in the final analysis were 17 primary tumors and 16 metastatic lesions in the LuM Cohort,17 primary tumors and 19 metastatic lesions in the LiM Cohort,and 12 primary tumors in the Control Cohort.Results No SNV differences were observed among LuM,LiM and Control Cohorts.For primary tumors,ZFHX4(91.2%vs.8.3%),FAM131 B(32.4%vs.0.0%),GATA2(32.4%vs.0.0%)and FOXL2(32.4%vs.0.0%)were amplified significantly more frequently in the Metastatic Cohorts than the Control Cohort,while RECQL4 amplification(8.8%vs.75.0%)and CYP2 A6 loss(2.9%vs.33.3%)were more in the Control Cohort.Frequencies of amplification of HNF4 A(41.2%vs.0.0%),BRD4(47.1%vs.5.9%)and U2 AF1(35.3%vs.0.0%)were significantly higher in the LuM Cohort than the LiM Cohort.For metastatic lesions,amplification of MET(25.0%vs.0.0%),SDHC(25.0%vs.0.0%)and genetic alterations in the RTK/RAS pathway(100.0%vs.73.7%)were more frequent in the LuM Cohort than the LiM Cohort,while frequencies of ZFHX4(50.0%vs.89.5%,P=0.022)and FOXL2(18.8%vs.68.4%)were more in the LiM Cohort.Conclusion CNV features of the primary tumors were associated with different potential of metastases,based on which we could identify patients at high risk of metastases and optimize periopertive strategies.MET and SDHC amplification as well as RTK/RAS pathway activation were more frequently in lung metastases.