De Re Valli, Caggiari Laura, De Zorzi Mariangela, Talamini Renato, Racanelli Vito, D' Andrea Mario, Buonadonna Angela, Zagonel Vittorina, Cecchin Erika, Innocenti Federico, Toffoli Giuseppe
Translational Research, CRO National Cancer Institute, IRCCS, Aviano, Pordenone, Italy.
Epidemiology and Biostatistics, CRO National Cancer Institute, IRCCS, Aviano, Pordenone, Italy.
PLoS One. 2014 Jan 31;9(1):e84940. doi: 10.1371/journal.pone.0084940. eCollection 2014.
To explore genes of the killer-cell immunoglobulin-like receptor (KIR) and of the HLA ligand and their relationship with the outcome of metastatic colorectal cancer (mCRC) patients treated with first-line 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI).
A total of 224 mCRC patients were screened for KIR/HLA typing. The determination of the KIR/HLA combinations was based upon the gene content and variants. Genetic associations with complete response (CR), time to progression (TTP) and overall survival (OS) were evaluated by calculating odds and hazard ratios. Multivariate modeling with prognostic covariates was also performed.
For CR, the presence of KIR2DL5A, 2DS5, 2DS1, 3DS1, and KIR3DS1/HLA-Bw4-I80 was associated with increased CR rates, with median ORs ranging from 2.1 to 4.3, while the absence of KIR2DS4 and 3DL1 was associated with increased CR rates (OR 3.1). After univariate analysis, patients that underwent resective surgery of tumor, absence of KIR2DS5, and presence of KIR3DL1/HLA-Bw4-I80 showed a significant better OS (HR 1.5 to 2.8). Multivariate analysis identified as parameters independently related to OS the type of treatment (surgery; HR 2.0) and KIR3DL1/HLA-Bw4-I80 genotype (HR for T-I80 2.7 and for no functional KIR/HLA interaction 1.8). For TTP, no association with KIR/HLA genes was observed.
This study, for the first time, evidences that the genotyping for KIR-HLA pairs are found predictive markers associated with complete response and improves overall survival prediction of FOLFIRI treatment response in metastatic colorectal cancer. These results suggest a role of the KIR/HLA system in patient outcome, and guide new research on the immunogenetics of mCRC through mechanistic studies and clinical validation.
探讨杀伤细胞免疫球蛋白样受体（KIR）基因和HLA配体基因及其与接受一线氟尿嘧啶、亚叶酸钙和伊立替康（FOLFIRI）治疗的转移性结直肠癌（mCRC）患者预后的关系。
对224例mCRC患者进行KIR/HLA分型筛查。KIR/HLA组合的确定基于基因含量和变异。通过计算比值比和风险比评估与完全缓解（CR）、疾病进展时间（TTP）和总生存期（OS）的遗传关联。还进行了带有预后协变量的多变量建模。
对于CR，KIR2DL5A、2DS5、2DS1、3DS1以及KIR3DS1/HLA - Bw4 - I80的存在与CR率增加相关，中位数比值比范围为2.1至4.3，而KIR2DS4和3DL1的缺失与CR率增加相关（比值比3.1）。单因素分析后，接受肿瘤切除手术、不存在KIR2DS5以及存在KIR3DL1/HLA - Bw4 - I80的患者显示出显著更好的总生存期（风险比1.5至2.8）。多变量分析确定与总生存期独立相关的参数为治疗类型（手术；风险比2.0）和KIR3DL1/HLA - Bw4 - I80基因型（T - I80的风险比2.7，无功能性KIR/HLA相互作用的风险比1.8）。对于TTP，未观察到与KIR/HLA基因的关联。
本研究首次证明，KIR - HLA对的基因分型是与完全缓解相关的预测标志物，并改善了转移性结直肠癌中FOLFIRI治疗反应的总生存期预测。这些结果表明KIR/HLA系统在患者预后中起作用，并通过机制研究和临床验证指导mCRC免疫遗传学的新研究。
