We analysed whole genome sequences of 560 breast cancers to advance understanding of the driver mutations conferring clonal advantage and the mutational processes generating somatic mutations. 93 protein-coding cancer genes carried likely driver mutations. Some non-coding regions exhibited high mutation frequencies but most have distinctive structural features probably causing elevated mutation rates and do not harbour driver mutations. Mutational signature analysis was extended to genome rearrangements and revealed 12 base substitution and six rearrangement signatures. Three rearrangement signatures, characterised by tandem duplications or deletions, appear associated with defective homologous recombination based DNA repair: one with deficient BRCA1 function; another with deficient BRCA1 or BRCA2 function; the cause of the third is unknown. This analysis of all classes of somatic mutation across exons, introns and intergenic regions highlights the repertoire of cancer genes and mutational processes operative, and progresses towards a comprehensive account of the somatic genetic basis of breast cancer.

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

Approximately 1-5% of breast cancers are attributed to inherited mutations in BRCA1 or BRCA2 and are selectively sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors. Germline and/or somatic mutations in BRCA1/BRCA2 in other cancer types also confer selective sensitivity to PARP inhibitors. Thus, assays to detect BRCA1/BRCA2 deficient tumours have been sought. Recently, somatic substitution, insertion/deletion and rearrangement patterns or mutational signatures were associated with BRCA1/BRCA2 dysfunction. We used a supervised lasso logistic regression model to identify six critically distinguishing mutational signatures predictive of BRCA1/BRCA2 deficiency. A weighted model called HRDetect was developed to accurately detect BRCA1/BRCA2 deficient samples. HRDetect identifies BRCA1/BRCA2 deficient tumours with 98.7% sensitivity (AUC 0.98). Application of this model in a cohort of 560 breast cancer patients with 22 known germline BRCA1/BRCA2 mutation carriers, allowed us to identify an additional 22 somatic BRCA1/BRCA2 null tumours and 47 tumours with functional BRCA1/BRCA2-deficiency where no mutation was detected. We validated HRDetect on independent cohorts of breast, ovarian and pancreatic cancers, and demonstrate efficacy on alternative sequencing strategies. Integrating all classes of mutational signatures thus reveals a larger proportion of breast cancer patients (of up to 22%) than hitherto appreciated (~1-5%) that could have selective therapeutic sensitivity to PARP-inhibition.

Summary Whole-genome-sequencing (WGS) of human tumors has revealed distinct mutation patterns that hint at the causative origins of cancer. We examined mutational signatures in 324 WGS human-induced pluripotent stem cells exposed to 79 known or suspected environmental carcinogens. Forty-one yielded characteristic substitution mutational signatures. Some were similar to signatures found in human tumors. Additionally, six agents produced double-substitution signatures and eight produced indel signatures. Investigating mutation asymmetries across genome topography revealed fully functional mismatch and transcription-coupled repair pathways. DNA damage induced by environmental mutagens can be resolved by disparate repair and/or replicative pathways, resulting in an assortment of signature outcomes even for a single agent. This compendium of experimentally induced mutational signatures permits further exploration of roles of environmental agents in cancer etiology and underscores how human stem cell DNA is directly vulnerable to environmental agents. Video Abstract