DLBCL is the most common lymphoma representing approximately one third of all non-Hodgkin lymphomas and about 40% of patients do not benefit of the standard first-line immune-chemotherapeutic treatment (i.e., R-CHOP - rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) that is administered as upfront therapy to substantially all patients independently from the stage of disease and other prognostic parameters. The administration of other pharmacological treatments is in fact limited to selected patients, unfitting for R-CHOP.

Although clinical prognostic scores, i.e. International Prognostic Index (IPI), and molecular classifiers based on the cell of origin are available, at present no biomarkers predictive of R-CHOP response has been identified and validated. Constitutional polymorphisms of genes involved in the mechanism of action of drugs included in R-CHOP have been suggested by many authors to play a role in the efficacy and in some case in the toxicity of this treatment. Thus, it is conceivable that in the future, after proper validation, some polymorphisms can be used as pharmacogenetic biomarkers of therapeutic outcome in this disease setting.

This review discusses the status of the art on molecular biomarkers predictive of DLBCL prognosis and deals with the relevant issue of the variability in response to DLBCL drug treatment. Overall, this review focuses on single nucleotide polymorphisms (SNPs) that, based on a candidate gene approach or on a GWAS analysis, have been suggested to play a role in response to R-CHOP. In particular, SNPs discovered by a candidate gene approach are related to gene involved in drug transport (i.e. ATP-binding cassette transporters), drug metabolism, drug detoxification enzymes, oxidative stress, apoptosis, DNA repair, immunity and angiogenesis.

Data from a GWAS analysis performed in DLBCL patients treated with R-CHOP, identified two SNPs associated with clinical outcomes related to genes involved in pivotal cellular processes and in transcriptional regulation and cell cycle progression, respectively.

Ongoing prospective pharmacogenetic clinical trials, including a GWAS study we performed, have also been discussed.

DLBCL 是最常见的淋巴瘤，约占所有非霍奇金淋巴瘤的三分之一，约 40% 的患者无法从标准的一线免疫化疗治疗（即 R-CHOP - 利妥昔单抗、环磷酰胺、多柔比星、长春新碱、和泼尼松）作为前期治疗给予基本上所有患者，独立于疾病阶段和其他预后参数。其他药物治疗的施用实际上仅限于选定的患者，不适合 R-CHOP。

尽管可以获得临床预后评分，即国际预后指数 (IPI)，以及基于细胞来源的分子分类器，但目前还没有发现和验证预测 R-CHOP 反应的生物标志物。许多作者提出，涉及 R-CHOP 中药物作用机制的基因的组成性多态性在这种治疗的疗效和某些情况下的毒性中发挥作用。因此，可以想象，在未来，经过适当的验证，一些多态性可以用作这种疾病环境中治疗结果的药物遗传学生物标志物。

本综述讨论了预测 DLBCL 预后的分子生物标志物的技术现状，并处理了对 DLBCL 药物治疗反应的变异性的相关问题。总体而言，本综述侧重于单核苷酸多态性 (SNP)，基于候选基因方法或 GWAS 分析，已建议在 R-CHOP 响应中发挥作用。具体而言，通过候选基因方法发现的SNP与参与药物转运（即ATP结合盒转运蛋白）、药物代谢、药物解毒酶、氧化应激、细胞凋亡、DNA修复、免疫和血管生成的基因有关。

在接受 R-CHOP 治疗的 DLBCL 患者中进行的 GWAS 分析数据确定了两个与临床结果相关的 SNP，这些 SNP 分别与参与关键细胞过程和转录调控和细胞周期进程的基因相关。

还讨论了正在进行的前瞻性药物遗传学临床试验，包括我们进行的一项 GWAS 研究。