美国华盛顿大学Rosa Ana Risques团队取得一项新突破。他们的最新研究提出了人类膀胱体细胞突变选择中的性别和吸烟偏见。该项研究成果发表在2025年10月8日出版的《自然》上。

由于肿瘤的发生是由体细胞突变驱动的，课题组人员想知道在正常膀胱中克隆的景观是否因性别和吸烟史而不同。使用超深双工DNA测序（约5000 ×），该课题组人员在45人的79个正常膀胱样本中鉴定了16个基因的克隆驱动突变。男性在RBM10、CDKN1A和ARID1A中的截断驱动突变明显多于女性，尽管非蛋白质影响突变的水平相似。

这一结果表明，在男性尿路上皮中，这些基因的驱动截短突变具有更强的正选择作用。课题组研究人员还发现激活TERT启动子突变在正常膀胱中驱动克隆扩增，这与年龄和吸烟密切相关。这些发现表明膀胱癌的危险因素，如性和吸烟，塑造了正常尿路上皮的克隆景观。通过这种方法发现的大量突变为研究体内突变的功能效应提供了一种新的策略-自然饱和诱变-可以扩展到其他人体组织。

据了解，男性患几种癌症的风险比女性高。膀胱癌的风险要高出10倍，原因尚不清楚。吸烟也是包括膀胱癌在内的几种肿瘤的主要危险因素。

附：英文原文

Title: Sex and smoking bias in the selection of somatic mutations in human bladder

Author: Calvet, Ferriol, Blanco Martinez-Illescas, Raquel, Muios, Ferran, Tretiakova, Maria, Latorre-Esteves, Elena S., Fredrickson, Jeanne, Andrianova, Maria, Pellegrini, Stefano, Huber, Axel Rosendahl, Ramis-Zaldivar, Joan Enric, An, Shuyi Charlotte, Thieme, Elana, Kohrn, Brendan F., Grau, Miguel L., Gonzalez-Perez, Abel, Lopez-Bigas, Nuria, Risques, Rosa Ana

Issue&Volume: 2025-10-08

Abstract: Men are at higher risk of several cancer types than women1. For bladder cancer the risk is four times higher for reasons that are not clear2. Smoking is also a principal risk factor for several tumour types, including bladder cancer3. As tumourigenesis is driven by somatic mutations, we wondered whether the landscape of clones in the normal bladder differs by sex and smoking history. Using ultradeep duplex DNA sequencing (approximately 5,000×), we identified thousands of clonal driver mutations in 16 genes across 79 normal bladder samples from 45 people. Men had significantly more truncating driver mutations in RBM10, CDKN1A and ARID1A than women, despite similar levels of non-protein-affecting mutations. This result indicates stronger positive selection on driver truncating mutations in these genes in the male urothelium. We also found activating TERT promoter mutations driving clonal expansions in the normal bladder that were associated strongly with age and smoking. These findings indicate that bladder cancer risk factors, such as sex and smoking, shape the clonal landscape of the normal urothelium. The high number of mutations identified by this approach offers a new strategy to study the functional effect of thousands of mutations in vivo—natural saturation mutagenesis—that can be extended to other human tissues.

DOI: 10.1038/s41586-025-09521-x

Source: https://www.nature.com/articles/s41586-025-09521-x