美国斯坦福大学医学院Paul A. Khavari研究组报道了癌症相关种系风险变异的功能分析。相关论文发表在2025年2月17日出版的《自然—遗传学》杂志上。

调控DNA中的单核苷酸变异（SNVs）与遗传性癌症风险有关。在相关的原代人类细胞类型中，对与13种肿瘤相关的4041个SNVs进行了大规模平行报告基因分析，其中包括90%的人类恶性肿瘤，然后结合匹配的染色质可及性、DNA环和表达定量性状位点数据，提名了380个潜在的调节SNVs及其假定的靶基因。后者强调了终生癌症风险中的特定蛋白质网络，包括线粒体翻译、DNA损伤修复和Rho GTPase活性。

CRISPR敲除筛选表明，生殖系推定风险基因的一个子集也能促进已建立的癌症的生长。编辑SNV rs10411210表明，其风险等位基因增加了rhiphin RHPN2的表达，并刺激它们响应的RhoA激活，表明单个SNVs可能上调癌症相关途径。这些功能数据是对变异优先排序的努力和对癌症遗传风险潜在机制的进一步调查的阻力。

附：英文原文

Title: Functional analysis of cancer-associated germline risk variants

Author: Kellman, Laura N., Neela, Poornima H., Srinivasan, Suhas, Siprashvili, Zurab, Shanderson, Ronald L., Hong, Audrey W., Rao, Deepti, Porter, Douglas F., Reynolds, David L., Meyers, Robin M., Guo, Margaret G., Yang, Xue, Zhao, Yang, Wozniak, Glenn G., Donohue, Laura K. H., Shenoy, Rajani, Ko, Lisa A., Nguyen, Duy T., Mondal, Smarajit, Garcia, Omar S., Elcavage, Lara E., Elfaki, Ibtihal, Abell, Nathan S., Tao, Shiying, Lopez, Christopher M., Montgomery, Stephen B., Khavari, Paul A.

Issue&Volume: 2025-02-17

Abstract: Single-nucleotide variants (SNVs) in regulatory DNA are linked to inherited cancer risk. Massively parallel reporter assays of 4,041 SNVs linked to 13 neoplasms comprising >90% of human malignancies were performed in pertinent primary human cell types and then integrated with matching chromatin accessibility, DNA looping and expression quantitative trait loci data to nominate 380 potentially regulatory SNVs and their putative target genes. The latter highlighted specific protein networks in lifetime cancer risk, including mitochondrial translation, DNA damage repair and Rho GTPase activity. A CRISPR knockout screen demonstrated that a subset of germline putative risk genes also enables the growth of established cancers. Editing one SNV, rs10411210, showed that its risk allele increases rhophilin RHPN2 expression and stimulus-responsive RhoA activation, indicating that individual SNVs may upregulate cancer-linked pathways. These functional data are a resource for variant prioritization efforts and further interrogation of the mechanisms underlying inherited risk for cancer.

DOI: 10.1038/s41588-024-02070-5

Source: https://www.nature.com/articles/s41588-024-02070-5