The pan-cancer analysis of whole genomes The expansion of whole-genome sequencing studies from individual ICGC and TCGA working groups presented the opportunity to undertake a meta-analysis of genomic features across tumour types. To achieve this, the PCAWG Consortium was established. A Technical Working Group implemented the informatics analyses by aggregating the raw sequencing data from different working groups that studied individual tumour types, aligning the sequences to the human genome and delivering a set of high-quality somatic mutation calls for downstream analysis (Extended Data Fig. 1). Given the recent meta-analysis

downstream of the source element, in a process called 3′ transduction 7-9. L1 retrotransposons can also promote the somatic transmobilization of Alu elements, SINE-VNTR-Alu (SVA) elements and processed pseudogenes, which are copies of mRNAs that have been reverse transcribed into DNA and inserted into the genome with the machinery of active L1 elements 10-12. Approximately 50% of human tumors contain somatic retrotranspositions of L1 elements 7,13-15. Previous analyses indicate that although a fraction of somatically acquired L1 insertions in cancer may influence gene function, the majority of retrotransposon integrations in a single tumor represent passenger mutations with little or no effect on cancer development 7,13. Nonetheless, L1 elements are capable of promoting other types of genomic structural alterations in the germline and somatically, in addition to canonical L1 insertion events 16-18 ; the effect of these alterations remains largely unexplored in the context of human cancer 19,20 .

Cancers require telomere maintenance mechanisms for unlimited replicative potential. They achieve this through TERT activation or alternative telomere lengthening associated with ATRX or DAXX loss. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, we dissect whole-genome sequencing data of over 2500 matched tumor-control samples from 36 different tumor types aggregated within the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium to characterize the genomic footprints of these mechanisms. While the telomere content of tumors with ATRX or DAXX mutations (ATRX/DAXX trunc) is increased, tumors with TERT modifications show a moderate decrease of telomere content. One quarter of all tumor samples contain somatic integrations of telomeric sequences into non-telomeric DNA. This fraction is increased to 80% prevalence in ATRX/DAXX trunc tumors, which carry an aberrant telomere variant repeat (TVR) distribution as another genomic marker. The latter feature includes enrichment or depletion of the previously undescribed singleton TVRs TTCGGG and TTTGGG, respectively. Our systematic analysis provides new insight into the recurrent genomic alterations associated with telomere maintenance mechanisms in cancer.

Many primary tumours have low levels of molecular oxygen (hypoxia), and hypoxic tumours respond poorly to therapy. Pan-cancer molecular hallmarks of tumour hypoxia remain poorly understood, with limited comprehension of its associations with specific mutational processes, non-coding driver genes and evolutionary features. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2658 cancers across 38 tumour types, we quantify hypoxia in 1188 tumours spanning 27 cancer types. Elevated hypoxia associates with increased mutational load across cancer types, irrespective of underlying mutational class. The proportion of mutations attributed to several mutational signatures of unknown aetiology directly associates with the level of hypoxia, suggesting underlying mutational processes for these signatures. At the gene level, driver mutations in TP53, MYC and PTEN are enriched in hypoxic tumours, and mutations in PTEN interact with hypoxia to direct tumour evolutionary trajectories. Overall, hypoxia plays a critical role in shaping the genomic and evolutionary landscapes of cancer.

About half of all cancers have somatic integrations of retrotransposons. To characterize their role in oncogenesis, we analyzed the patterns and mechanisms of somatic retrotransposition in 2,954 cancer genomes from 37 histological cancer subtypes. We identified 19,166 somatically acquired retrotransposition events, affecting 35% of samples, and spanning a range of event types. L1 insertions emerged as the first most frequent type of somatic structural variation in esophageal adenocarcinoma, and the second most frequent in head-and-neck and colorectal cancers. Aberrant L1 integrations can delete megabase-scale regions of a chromosome, sometimes removing tumour suppressor genes, as well as inducing complex translocations and large-scale duplications. Somatic retrotranspositions can also initiate breakage-fusion-bridge cycles, leading to high-level amplification of oncogenes. These observations illuminate a relevant role of L1 retrotransposition in remodeling the cancer genome, with potential implications in the development of human tumours.Long interspersed nuclear element (LINE)-1 (L1) retrotransposons are widespread repetitive elements in the human genome, representing 17% of the entire DNA content 1,2 . Using a combination of cellular enzymes and self-encoded proteins with endonuclease and reverse transcriptase activity, L1 elements copy and insert themselves at new genomic sites, a process called retrotransposition. Most of the ~500,000 L1 copies in the human reference genome are truncated, inactive elements not able to retrotranspose. A small subset of them, maybe 100-150 L1 loci, remain active in the average human genome, acting as source elements, of which a small number are highly active copies termed hot-L1s 3-5 . These L1 source elements are usually transcriptionally repressed, but epigenetic changes occurring in tumours may promote their expression and allow them to retrotranspose 6,7 . Somatic L1 retrotransposition most often introduces a new copy of the 3' end of the L1 sequence, and can also mobilize unique DNA sequences located immediately downstream of the source element, a process called 3' transduction 7-9 . L1 retrotransposons can also promote the somatic trans-mobilization of Alu, SVA and processed pseudogenes, which are copies of messenger RNAs that have been reverse transcribed into DNA and inserted into the genome using the machinery of active L1 elements 10-12 .6 Approximately 50% of human tumours have somatic retrotransposition of L1 elements 7,13-15 .Previous analyses indicate that although a fraction of somatically acquired L1 insertions in cancer may influence gene function, the majority of retrotransposon integrations in a single tumour represent passenger mutations with little or no effect on cancer development 7,13 .Nonetheless, L1 insertions are capable of promoting other types of genomic structural alterations in the germline and somatically, apart from canonical L1 insertion events [16][17][18] , which remain largely unexplored in human cancer 19,20 .To further understand the roles...