文章：

基于细胞起源、体细胞突变和药物使用特征对淋巴瘤进行聚类分析：一项多性状全基因组关联研究

Clustering of lymphoid neoplasms by cell of origin, somatic mutation and drug usage profiles: a multi-trait genome-wide association study

原文发布日期：2025-08-29

DOI: 10.1038/s41408-025-01351-4

类型: Article

开放获取: 是

英文摘要：

Lymphoid neoplasms (LNs) are heterogeneous malignancies arising from lymphoid cells, displaying diverse clinical and molecular features. Although LNs are collectively frequent, individual subtypes are rare, posing challenges for genetic association studies. Indeed, genome-wide association studies (GWAS) explained only a fraction of the heritability. Shared genetic susceptibility and overlapping risk factors suggest a partially common etiology across subtypes. We employed a multi-trait GWAS strategy to improve discovery power by leveraging pleiotropy among LN subtypes. We defined LN phenoclusters based on cell of origin, somatic mutation profiles, and approved therapeutic agents. Using data from three large cohorts—the UK Biobank, Million Veteran Program, and FinnGen—we analyzed 31,937 LN cases and 1.2 million controls across 8 individual subtypes and 7 phenoclusters. We replicated the novel associations in two independent cohorts (All of Us and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial) with 2892 LN cases and 165,791 controls. We identified 76 genome-wide significant loci for individual subtypes or subtype clusters, including 20 novel associations. We identified the subtypes contributing to each locus, putative candidate causal variants, and genes underlying the associations, and found enrichment of specific cell types, biological processes, and drugs associated with LN risk genes. Overall, this study identified new LN genetic risk loci and candidate genes, providing insights that may inform novel therapeutic approaches.
 

摘要翻译： 

淋巴肿瘤（LNs）是一类起源于淋巴细胞的异质性恶性肿瘤，具有多样化的临床和分子特征。尽管淋巴肿瘤总体发病率较高，但各亚型均较为罕见，这为遗传关联研究带来了挑战。事实上，全基因组关联研究（GWAS）仅能解释部分遗传率。共享的遗传易感性和重叠的风险因素提示各亚型之间存在部分共同的病因学基础。我们采用多性状GWAS策略，通过利用淋巴肿瘤亚型间的多效性来提高发现能力。我们依据细胞起源、体细胞突变谱和已批准的治疗药物定义了淋巴肿瘤表型簇。利用英国生物样本库、百万退伍军人计划和FinnGen三大队列的数据，我们分析了8个独立亚型和7个表型簇，共包含31,937例淋巴肿瘤病例和120万例对照。我们在两个独立队列（"全民健康计划"及前列腺、肺、结直肠和卵巢癌筛查试验）中复制了新发现的关联，该验证集包含2,892例淋巴肿瘤病例和165,791例对照。我们共鉴定出76个针对独立亚型或亚型簇的全基因组显著位点，其中包括20个新关联位点。我们明确了各基因位点所对应的淋巴肿瘤亚型、推定的候选致病变异及关联背后的基因基础，并发现特定细胞类型、生物学过程和与淋巴肿瘤风险基因相关的药物存在富集现象。总体而言，本研究识别出新的淋巴肿瘤遗传风险位点和候选基因，为探索新型治疗方法提供了重要线索。

原文链接：

Clustering of lymphoid neoplasms by cell of origin, somatic mutation and drug usage profiles: a multi-trait genome-wide association study