DPYD、ABCB1、GSTP1、ERCC1基因多态性与晚期结肠癌临床特征、不良反应、预后的关系

Study of relationship between polymorphisms of DPYD, ABCB1, GSTP1, ERCC1 genes and clinical features, adverse reactions and prognosis of advanced colonic cancer

目的检测晚期肠癌患者药物基因多态性,分析其与临床特征、以奥沙利铂或氟尿嘧啶为主化疗方案不良反应和预后的关系。方法收集2016年3月至2018年5月在中国解放军总医院肿瘤内科住院治疗的108例晚期结肠癌患者的外周血,以Life平台检测对DPYD、ABCB1、GSTP1、ERCC1基因进行单核苷酸多态性(SNP)分型,比较不同基因型与患者KRAS状态、肿瘤部位(左右)、不良反应和中位无进展生存时间(PFS)的差异。结果纳入晚期肠癌患者108例,DPYD 4个位点(rs3918290、rs55886062、rs67376798、rs2297595)均为野生型,ERCC1(rs11615)GG纯合型基因52例(48.1%),AG杂合型基因50例(46.3%),AA野生型基因6例(5.6%)。GSTP1(rs1695)AG杂合型突变36例(33.3%),AA野生型66例(66.1%),GG纯和突变型6例(5.6%)。ABCB1(rs1045642)AG杂合型基因58例(53.7%),GG纯合型基因42例(38.9%),AA野生型8例(7.4%)。肿瘤位于左右半结肠与ERCC1基因分布频率有关(χ~2=4.802,P=0.028),与GSTP1,ABCB1基因分布频率无关。KRAS突变患者ABCB1杂合突变率42.9%,未见突变患者为72.7%,两者差异具有统计学意义(χ~2=3.939,P=0.047)。GSTP1 AG型和GG型较AA型易产生2～3级全身不良反应高(77.8%vs. 45.5%,χ~2=5.193;P=0.023)。ABCB1 GG型和AA型患者发生3～4级不良反应率为32.9%,对比AG型患者发生不良反应率为62.1%,差异具有统计学意义(χ~2=4.862,P=0.027)。中位疾病进展时间PFS与ABCB1和GSTP1基因多态性无关,与不同ERCC1基因型有关,ERRC1杂合型突变(AG型)患者较纯和型(GG型+AA型)具有较短PFS(5.6 m vs. 8.0 m,P=0.029)。结论检测基因多态性具有临床价值,对晚期肠癌化疗的不良反应、预后及为患者调整化疗方案具有有效的指导作用。

Objective Detecting the polymorphism of drug genes in patients with advanced colorectal cancer, and analyze its relationship with clinical features, adverse reactions and prognosis of oxaliplatin and fluorouracil based chemotherapy. Methods Peripheral blood of 108 patients with advanced colorectal cancer who were hospitalized in our department from March 2016 to May 2018 was collected. Single-nucleotide polymorphisms (SNP) were performed on the DPYD, ABCB1, GSTP1, and ERCC1 genes by Life platform assay to compare the differences between different genotypes and patients′ KRAS status, tumor location (left and right), adverse reactions, and median disease progression time (PFS). Results 108 patients with advanced colorectal cancer were included, four sites of DPYD (rs3918290, rs55886062, rs67376798, rs2297595) were wild type, fifty-two cases (48.1%) were ERCC1 (rs11615) GG gene, 50 (46.3%) were AG gene, 6 (5.6%) were AA wild type gene, 36 cases (33.3%) of GSTP1 (rs1695) were AG heterozygous mutation, sixty-six cases (66.1%) of AA wild type, six cases of GG pure and mutant type (5.6%). Fifty-eight cases (53.7%) of ABCB1 (rs1045642) were AG heterozygous gene, fourty-two cases (38.9%) were GG type gene, eight cases (7.4%) of AA wild type. Tumors located in the left and right colon and ERCC1 gene distribution was related (χ^2=4.802, P=0.028) and was not related to the frequency of GSTP1 and ABCB1 gene distribution. The ABCB1 AG type rate was 42.9% in KRAS mutation patients and 72.7% in wild type patients, which were statistically different (χ^2=3.939, P=0.047). GSTP1 AG type and GG type are more likely to produce 2~3 grade systemic adverse reactions than AA type (77.8% vs. 45.5%,χ^2=5.193;P=0.023). The grade 3~4 adverse reaction rate of patients of ABCB1 GG type and AA type was 32.9%, compared with the adverse reaction rate of 62.1% for patients with type AG (χ^2=4.8.62, P=0.027). The median disease progression time (PFS) was not associated with ABCB1 and GSTP1 gene polymorphisms, and was associated with different ERCC1 genotypes. The ERRC1 heterozygous mutation (AG type) patients has a shorter PFS than GG and AA type (5.6 m vs. 8.0 m, P=0.029). Conclusions The detection of gene polymorphism has clinical value, suggesting adverse reactions and prognosis for advanced colorectal cancer chemotherapy, and providing effective guidance for patients to adjust chemotherapy.