中山大学贝锦新等研究人员合作发现，一种罕见的KLHDC4变异Glu510Lys与鼻咽癌的遗传易感性相关并促进肿瘤转移。相关论文于2024年12月18日在线发表在《遗传学报》上。

研究人员整合了3925例鼻咽癌（NPC）患者和15048例健康对照的基因分型数据，发现一个罕见单核苷酸多态性（SNP）（rs141121474）导致KLHDC4基因中的Glu510Lys突变，与NPC风险增加相关。随后的分析揭示KLHDC4在NPC中高表达，并与较差的预后相关。

功能特征表明，KLHDC4在NPC细胞中作为致癌基因发挥作用，增强了其迁移和转移能力，而Glu510Lys突变进一步增强了这些效应。

在机制上，Glu510Lys突变与波形蛋白的相互作用较野生型KLHDC4（KLHDC4-WT）更强，导致波形蛋白稳定性升高并调节上皮-间充质转化过程，从而促进肿瘤转移。此外，波形蛋白敲低显著减轻了KLHDC4-WT和Glu510Lys变异过表达所诱导的致癌效应。

综上所述，这些研究结果强调了罕见KLHDC4变异rs141121474在NPC进展中的关键作用，并提出其作为NPC患者诊断和治疗靶点的潜力。

据悉，多项遗传关联研究已鉴定出与NPC风险相关的多个SNP。然而，这些研究主要集中于常见变异，导致罕见变异对“缺失遗传力”的贡献尚未得到充分探索。

附：英文原文

Title: A rare KLHDC4 variant Glu510Lys is associated with genetic susceptibility and promotes tumor metastasis in nasopharyngeal carcinoma

Author: Chun-Ling Luo a b, Jin-Xin Bei a b f g

Issue&Volume: 2024/12/18

Abstract: Various genetic association studies have identified numerous single nucleotide polymorphisms (SNPs) associated with nasopharyngeal carcinoma (NPC) risk. However, these studies have predominantly focused on common variants, leaving the contribution of rare variants to the "missing heritability" largely unexplored. Here, we integrate genotyping data from 3,925 NPC cases and 15,048 healthy controls to identify a rare SNP, rs141121474, resulting in a Glu510Lys mutation in KLHDC4 gene linked to increased NPC risk. Subsequent analyses reveal that KLHDC4 is highly expressed in NPC and correlates with poorer prognosis. Functional characterizations demonstrate that KLHDC4 acts as an oncogene in NPC cells, enhancing their migratory and metastatic capabilities, with these effects being further augmented by the Glu510Lys mutation. Mechanistically, the Glu510Lys mutant exhibits increased interaction with Vimentin compared to the wild-type KLHDC4 (KLHDC4-WT), leading to elevated Vimentin protein stability and modulation of the epithelial-mesenchymal transition process, thereby promoting tumor metastasis. Moreover, Vimentin knockdown significantly mitigates the oncogenic effects induced by overexpression of both KLHDC4-WT and the Glu510Lys variant. Collectively, our findings highlight the critical role of the rare KLHDC4 variant rs141121474 in NPC progression and propose its potential as a diagnostic and therapeutic target for NPC patients.

DOI: 10.1016/j.jgg.2024.12.008

Source: https://www.sciencedirect.com/science/article/pii/S1673852724003606