The ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium analyzed 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types, revealing that cancer genomes on average contain 4–5 driver mutations, though 5% of cases had no identified drivers. Chromothripsis, a catastrophic event causing multiple structural variants, is common in early tumour evolution, particularly in acral melanoma. Cancers with abnormal telomere maintenance often originate from low-replicative tissues and use mechanisms to prevent telomere attrition. Common and rare germline variants influence somatic mutation patterns, including point mutations, structural variants, and retrotransposition. The study identified non-coding mutations beyond TERT promoter, new mutational signatures, and diverse transcriptional consequences of somatic mutations. Cancer is a heterogeneous disease driven by multiple genetic abnormalities, with driver mutations providing a selective advantage to cancer clones. The study used cloud computing and standardized pipelines to process data, achieving high-quality variant calls. Benchmarking showed high sensitivity and precision in detecting somatic mutations. The analysis revealed that 91% of tumours had at least one driver mutation, with an average of 4.6 per tumour. Non-coding driver mutations were less frequent than coding ones, though the TERT promoter was frequently affected. Driver mutations in tumour-suppressor genes were often two-hit inactivation events. Some tumours lacked identified drivers, possibly due to technical or biological factors. The study identified recurrent CNAs and SVs, including SETD2 mutations in medulloblastomas. Chromothripsis, a catastrophic event causing multiple DNA breaks, was common in several cancers, often associated with driver mutations. The timing of clustered mutations suggested early occurrence in some cancers, such as melanomas. Germline variants influenced somatic mutation patterns, with APOBEC3B-like mutagenesis linked to specific genetic loci. Telomere maintenance mechanisms varied across tumour types, with some cancers using alternative lengthening of telomeres. The study provided insights into the genetic basis of cancer, highlighting the importance of driver mutations and the complexity of tumour evolution. The findings contribute to understanding cancer biology and inform potential therapeutic strategies.The ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium analyzed 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types, revealing that cancer genomes on average contain 4–5 driver mutations, though 5% of cases had no identified drivers. Chromothripsis, a catastrophic event causing multiple structural variants, is common in early tumour evolution, particularly in acral melanoma. Cancers with abnormal telomere maintenance often originate from low-replicative tissues and use mechanisms to prevent telomere attrition. Common and rare germline variants influence somatic mutation patterns, including point mutations, structural variants, and retrotransposition. The study identified non-coding mutations beyond TERT promoter, new mutational signatures, and diverse transcriptional consequences of somatic mutations. Cancer is a heterogeneous disease driven by multiple genetic abnormalities, with driver mutations providing a selective advantage to cancer clones. The study used cloud computing and standardized pipelines to process data, achieving high-quality variant calls. Benchmarking showed high sensitivity and precision in detecting somatic mutations. The analysis revealed that 91% of tumours had at least one driver mutation, with an average of 4.6 per tumour. Non-coding driver mutations were less frequent than coding ones, though the TERT promoter was frequently affected. Driver mutations in tumour-suppressor genes were often two-hit inactivation events. Some tumours lacked identified drivers, possibly due to technical or biological factors. The study identified recurrent CNAs and SVs, including SETD2 mutations in medulloblastomas. Chromothripsis, a catastrophic event causing multiple DNA breaks, was common in several cancers, often associated with driver mutations. The timing of clustered mutations suggested early occurrence in some cancers, such as melanomas. Germline variants influenced somatic mutation patterns, with APOBEC3B-like mutagenesis linked to specific genetic loci. Telomere maintenance mechanisms varied across tumour types, with some cancers using alternative lengthening of telomeres. The study provided insights into the genetic basis of cancer, highlighting the importance of driver mutations and the complexity of tumour evolution. The findings contribute to understanding cancer biology and inform potential therapeutic strategies.