Zheng Ming
Beijing Institute of Basic Medical Sciences, Beijing, China
Academy of Military Medical Sciences, Beijing, China.
J Immunother Cancer. 2025 May 30;13(5):e010486. doi: 10.1136/jitc-2024-010486.
The somatic mutation theory predicts that cancer risk should scale proportionally with lifetime cell divisions; yet large-bodied and long-lived species exhibit lower-than-expected cancer incidence-a long-standing contradiction termed Peto's paradox. Resolving this paradox and clarifying how tumor mutational burden (TMB) shapes treatment response to immune-checkpoint inhibitor (ICI) therapy remain unmet needs in precision oncology.
This study analyzed three data streams: (1) human cancer incidence data from North American registries; (2) cancer mortality records for 110,148 mammals (191 species) linked to body mass, life expectancy, and cancer risk, and (3) >30,000 tumors profiled in three independent pan-cancer cohorts and clinical outcomes in >2,700 ICI-treated patients. A digital-medicine approach using 1,000 bootstraps was employed to generate digital randomized cohorts for internal validation, with clinicogenomic covariates matched to mirror real-world clinical features.
(1) Both cancer incidence and mutational accumulation are age-coupled in humans (<0.001), sharply rising after age 40. (2) Across species, cancer risk correlates strongly with somatic mutation rate and lifetime mutational burden (rho>0.6), but not with body size or life expectancy (rho<0.2), quantitatively resolving Peto's paradox. (3) TMB coherently increases with patients' age across The Cancer Genome Atlas, OrigiMed, and Memorial Sloan Kettering (MSK) cohorts, independent of TMB-detection assays (all <0.001). (4) In ICI-treated patients, higher TMB confers dose-dependent improvement in overall and progression-free survival and objective response rate. A "super-high" TMB threshold (>25 mut/Mb via MSK-Integrated Mutation Profiling of Actionable Cancer Targets or FoundationOne test) markedly enriched complete remissions (~8-fold increase), validated consistently in both real-world independent cohorts and digital randomized cohorts.
Somatic mutational accumulation emerges as a unifying determinant of cancer risk in human and non-human species, resolving Peto's paradox and redefining TMB as a clinically actionable cancer hallmark. Quantifying TMB stratifies immunotherapy efficacy dose-dependently, with super-high TMB predicting durable tumor eradication; thus, therapeutically boosting neoantigen load in low-TMB tumors may convert ICI non-responders to responders. By proposing a universal framework-"cancer disease continuum"-unified by mutational burden as a shared hallmark across tumor initiation, progression, and immunogenicity, this study recasts mutational burden as both a biological price of longevity and an Achilles' heel exploitable for durable, complete tumor remission in personalized medicine.
体细胞突变理论预测癌症风险应与终生细胞分裂成比例增加；然而，体型大且寿命长的物种癌症发病率低于预期——这一长期存在的矛盾被称为佩托悖论。解决这一悖论并阐明肿瘤突变负担（TMB）如何影响免疫检查点抑制剂（ICI）治疗的反应，仍然是精准肿瘤学中尚未满足的需求。
本研究分析了三个数据流：（1）来自北美登记处的人类癌症发病率数据；（2）110148只哺乳动物（191个物种）的癌症死亡率记录，这些记录与体重、预期寿命和癌症风险相关；（3）三个独立泛癌队列中>30000个肿瘤的特征分析以及>2700例接受ICI治疗患者的临床结局。采用一种使用1000次自抽样的数字医学方法来生成数字随机队列进行内部验证，使临床基因组协变量相匹配以反映真实世界的临床特征。
（1）人类的癌症发病率和突变积累均与年龄相关（<0.001），40岁后急剧上升。（2）在不同物种中，癌症风险与体细胞突变率和终生突变负担密切相关（相关系数>0.6），但与体型或预期寿命无关（相关系数<0.2），从定量角度解决了佩托悖论。（3）在癌症基因组图谱、OrigiMed和纪念斯隆凯特琳癌症中心（MSK）队列中，TMB随患者年龄一致增加，与TMB检测方法无关（均<0.001）。（4）在接受ICI治疗的患者中，较高的TMB可使总生存期、无进展生存期和客观缓解率呈剂量依赖性改善。一个“超高”TMB阈值（通过MSK可操作癌症靶点综合突变分析或FoundationOne检测>25个突变/Mb）显著富集完全缓解（增加约8倍），在真实世界独立队列和数字随机队列中均得到一致验证。
体细胞突变积累成为人类和非人类物种癌症风险的统一决定因素，解决了佩托悖论，并将TMB重新定义为一个临床可操作的癌症标志。量化TMB可剂量依赖性地分层免疫治疗疗效，超高TMB预示着持久的肿瘤根除；因此，在低TMB肿瘤中治疗性增加新抗原负荷可能会将ICI无反应者转变为有反应者。通过提出一个由突变负担统一的通用框架——“癌症疾病连续体”，作为肿瘤发生、进展和免疫原性的共同标志，本研究将突变负担重塑为长寿的生物学代价以及个性化医学中实现持久、完全肿瘤缓解可利用的致命弱点。
