Mittal Pooja, Battaglin Francesca, Yang Yan, Soni Shivani, Stintzing Sebastian, Parikh Aparna R, Ashouri Karam, Algaze Sandra, Jayachandran Priya, Torres-Gonzalez Lesly, Zhang Wu, Cremolini Chiara, Heinemann Volker, Millstein Joshua, Singh Indrakant K, Lenz Heinz-Josef
Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
Department of Zoology, Deshbandhu College, University of Delhi, New Delhi 110019, India.
Int J Mol Sci. 2025 Mar 12;26(6):2556. doi: 10.3390/ijms26062556.
The immune system is alerted for virally infected cells in the body by the antigen presentation pathway, which is in turn mediated by the major histocompatibility complex (MHC) class I and II molecules. Cancer cells overcome immune evasion as a major hallmark by downregulation of the antigen presentation pathway. Therefore, the present study aimed to explore the effect of genetic variants in genes involved in MHC class I and II pathways in patients treated with first-line chemotherapy in combination with targeted antibodies in metastatic colorectal cancer (mCRC) patients. Genomic DNA from the blood samples of 775 patients enrolled in three independent, randomized, first-line trials, namely TRIBE (FOLFIRI-bevacizumab, N = 215), FIRE-3 (FOLFIRI-bevacizumab, N = 107; FOLFIRI-cetuximab, N = 129), and MAVERICC (FOLFIRI-bevacizumab, N = 163; FOLFOX6-bevacizumab, N = 161), was genotyped through OncoArray, a custom array manufactured by Illumina including approximately 530K SNP markers. The impact on the outcome of 40 selected SNPs in 22 genes of MHC class I and II pathways was analyzed. We identified several SNPs in multiple genes associated with targeted treatment benefits across different treatment arms in our study population ( < 0.05). Treatment-SNP interaction analyses confirmed a significant treatment interaction with the targeted agents (bevacizumab vs. cetuximab) and the chemotherapy backbone (FOLFIRI vs. FOLFOX) in certain selected SNPs. Our results highlight a potential role for MHC SNPs as prognostic and predictive biomarkers for first-line treatment in mCRC, with differential effects based on the biologic agent and chemotherapy backbone. These biomarkers, when further validated, may contribute to personalized treatment strategies for mCRC patients.
免疫系统通过抗原呈递途径对体内受病毒感染的细胞发出警报，而该途径又由主要组织相容性复合体（MHC）I类和II类分子介导。癌细胞通过下调抗原呈递途径克服免疫逃逸这一主要特征。因此，本研究旨在探讨参与MHC I类和II类途径的基因中的遗传变异对接受一线化疗联合靶向抗体治疗的转移性结直肠癌（mCRC）患者的影响。对参加三项独立、随机一线试验的775例患者血样中的基因组DNA进行基因分型，这三项试验分别是TRIBE（FOLFIRI-贝伐单抗，N = 215）、FIRE-3（FOLFIRI-贝伐单抗，N = 107；FOLFIRI-西妥昔单抗，N = 129）和MAVERICC（FOLFIRI-贝伐单抗，N = 163；FOLFOX6-贝伐单抗，N = 161），通过OncoArray进行基因分型，OncoArray是Illumina制造的定制芯片，包含约53万个单核苷酸多态性（SNP）标记。分析了MHC I类和II类途径的22个基因中40个选定SNP对治疗结果的影响。我们在研究人群的不同治疗组中鉴定出多个基因中的几个SNP与靶向治疗益处相关（P<0.05）。治疗-SNP相互作用分析证实，在某些选定的SNP中，与靶向药物（贝伐单抗与西妥昔单抗）和化疗主干（FOLFIRI与FOLFOX）存在显著的治疗相互作用。我们的结果突出了MHC SNP作为mCRC一线治疗的预后和预测生物标志物的潜在作用，其效果因生物制剂和化疗主干而异。这些生物标志物经过进一步验证后，可能有助于制定mCRC患者的个性化治疗策略。
