随着越来越多地使用肿瘤突变负荷作为免疫检查点抑制剂的生物标志物，癌症中的体细胞超突变得到了发展。 CpG 二核苷酸处 5-甲基胞嘧啶自发脱氨基为胸腺嘧啶是正常细胞和癌细胞中最普遍的内源突变过程之一。在这里，我们对泛癌水平的体细胞 CpG 超突变进行了系统研究。我们研究了 30,191 名癌症患者和 103 种癌症类型，并开发了一种算法来识别体细胞 CpG 超突变。在各种癌症类型中，我们观察到儿童白血病（3.5%）、儿童高级别神经胶质瘤（1.7%）和结直肠癌（1%）的患病率最高。我们发现错配修复复合体 MutSα (MSH2-MSH6) 中的种系变异和体细胞突变是癌症中体细胞 CpG 超突变的遗传驱动因素，这些突变经常集中在 CpG 位点和 TP53 驱动突变上。我们进一步观察了体细胞 CpG 超突变与免疫检查点抑制剂反应之间的关联。总体而言，我们的研究发现了新的癌症类型，这些类型表现出体细胞 CpG 超突变、与 MutSα 缺乏密切相关，以及在癌症免疫治疗中的潜在用途。© 2024。作者。

Somatic hypermutation in cancer has gained momentum with the increased use of tumour mutation burden as a biomarker for immune checkpoint inhibitors. Spontaneous deamination of 5-methylcytosine to thymine at CpG dinucleotides is one of the most ubiquitous endogenous mutational processes in normal and cancer cells. Here, we performed a systematic investigation of somatic CpG hypermutation at a pan-cancer level. We studied 30,191 cancer patients and 103 cancer types and developed an algorithm to identify somatic CpG hypermutation. Across cancer types, we observed the highest prevalence in paediatric leukaemia (3.5%), paediatric high-grade glioma (1.7%), and colorectal cancer (1%). We discovered germline variants and somatic mutations in the mismatch repair complex MutSα (MSH2-MSH6) as genetic drivers of somatic CpG hypermutation in cancer, which frequently converged on CpG sites and TP53 driver mutations. We further observe an association between somatic CpG hypermutation and response to immune checkpoint inhibitors. Overall, our study identified novel cancer types that display somatic CpG hypermutation, strong association with MutSα-deficiency, and potential utility in cancer immunotherapy.© 2024. The Author(s).