Ian Tomlinson

Ian Tomlinson is a world-leading human geneticist and cancer biologist who has made transformative contributions to understanding the inherited and somatic genetic basis of colorectal cancer. Based at the University of Edinburgh (and formerly at the University of Oxford, where he led the Colon Cancer Genetics Group for many years), his research has encompassed genome-wide association studies (GWAS) for CRC susceptibility, characterization of novel cancer predisposition syndromes, and fundamental analysis of mutational processes in colorectal tumors. Tomlinson has been one of the principal architects of large-scale GWAS analyses for colorectal cancer, contributing to consortia — including the COGENT and GECCO studies — that have collectively identified more than 130 common genetic variants associated with CRC risk. These GWAS discoveries have provided insight into biological pathways underlying CRC predisposition (including Wnt signaling, BMP signaling, and cell cycle regulation) and have been used to construct polygenic risk scores (PRS) with potential clinical utility for population-based risk stratification and targeted screening programs. A landmark contribution from Tomlinson's laboratory is the discovery of POLE and POLD1 exonuclease domain mutations as causes of hereditary CRC predisposition. In 2012–2013, his group identified that germline mutations in the proofreading exonuclease domains of DNA polymerases epsilon (POLE) and delta (POLD1) cause a cancer predisposition syndrome characterized by an extremely high tumor mutational burden — sometimes exceeding 100 mutations per megabase — and an "ultramutator" phenotype. This discovery defined a new hereditary CRC syndrome, now called polymerase proofreading-associated polyposis (PPAP), and revealed that POLE/POLD1 exonuclease-mutant tumors are highly responsive to immune checkpoint inhibitors due to their massive neoantigen load, with important therapeutic implications. Tomlinson's research has also addressed mutational signatures in CRC, contributing to analyses demonstrating how different mutagenic processes — including MMR deficiency, oxidative damage, and POLE ultramutation — leave distinct genomic fingerprints that can be used to classify tumors, predict prognosis, and select therapies. He is a Fellow of the Academy of Medical Sciences and has served on numerous national and international scientific advisory panels.

Ian Tomlinson 是世界领先的人类遗传学家和癌症生物学家，在理解结直肠癌的遗传和体细胞遗传基础方面做出了变革性贡献。他是大规模CRC全基因组关联研究（GWAS）的主要架构师之一，与COGENT和GECCO等联盟合作鉴定了130余个CRC风险相关常见遗传变异。 Tomlinson 实验室的里程碑贡献是发现POLE和POLD1核酸外切酶结构域的胚系突变导致遗传性CRC易感综合征——聚合酶校对相关息肉病（PPAP）——其特征是极高的肿瘤突变负荷。这一发现揭示了POLE/POLD1超突变肿瘤对免疫检查点抑制剂高度敏感，具有重要的治疗意义。