Although treatment options for B-cell malignancies have expanded, many patients continue to face limited response rates, highlighting an urgent need for new therapeutic targets. To prioritize candidate drug targets for B-cell malignancies, we employed Mendelian Randomization to estimate potentially causal relationships between 445 immune cell traits and six B-cell cancers: follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), Hodgkin lymphoma (HL), marginal zone lymphoma (MZL), chronic lymphocytic leukemia (CLL), and multiple myeloma (MM), totaling 22,922 cases and 394,204 controls. 163 traits showed a suggestive association with at least one B-cell malignancy (P < 0.05), with 34 traits being significant after correction for multiple testing (P < 2 × 10−4). By integrating findings with observational data and clinical trial evidence to support drug target candidacy, 24 cell surface markers were identified as druggable targets. In addition to established therapeutic targets such as CD3, CD20 and CD38, our analysis highlights BAFF-R and CD39 in HL, CD25 in MM, CD27 in CLL, CD80/86 in DLBCL, and CCR2 in FL and MZL as promising candidates for therapeutic inhibition. Our findings provide further support for the potential of human genetics to guide the identification of drug targets and address a productivity-limiting step.
尽管B细胞恶性肿瘤的治疗选择已有所扩展，但许多患者的反应率仍然有限，这凸显了对新治疗靶点的迫切需求。为了筛选B细胞恶性肿瘤的候选药物靶点，我们采用孟德尔随机化方法，评估了445种免疫细胞特征与六种B细胞癌症之间的潜在因果关系：滤泡性淋巴瘤（FL）、弥漫性大B细胞淋巴瘤（DLBCL）、霍奇金淋巴瘤（HL）、边缘区淋巴瘤（MZL）、慢性淋巴细胞白血病（CLL）和多发性骨髓瘤（MM），共涉及22,922例病例和394,204例对照。163项特征显示与至少一种B细胞恶性肿瘤存在提示性关联（P < 0.05），其中34项特征在多重检验校正后仍具有显著性（P < 2 × 10−4）。通过整合观察性数据和临床试验证据以支持药物靶点的候选性，我们确定了24个细胞表面标志物可作为可成药靶点。除已确立的治疗靶点如CD3、CD20和CD38外，我们的分析还突出了HL中的BAFF-R和CD39、MM中的CD25、CLL中的CD27、DLBCL中的CD80/86以及FL和MZL中的CCR2作为有潜力的治疗抑制靶点。这些发现进一步支持了人类遗传学在指导药物靶点识别及解决生产力限制环节方面的潜力。
肿瘤(癌症)患者之家