While recent studies have identified higher than anticipated heterogeneity of mutation rate across genomic regions, mutations in exons and introns are assumed to be generated at the same rate. Here we find fewer somatic mutations in exons than expected from their sequence content and demonstrate that this is not due to purifying selection. Instead, we show that it is caused by higher mismatch-repair activity in exonic than in intronic regions. Our findings have important implications for understanding of mutational and DNA repair processes and knowledge of the evolution of eukaryotic genes, and they have practical ramifications for the study of evolution of both tumors and species. ; We acknowledge funding from Spanish Ministry of Economy and Competitiveness (SAF2015-66084-R, MINECO/FEDER, UE), La Fundació la Marató de TV3, EU H2020 Programme 2014-2020 under grant agreements no. 634143 (MedBioinformatics) and by the European Research Council (Consolidator Grant 682398). IRB Barcelona is a recipient of a Severo Ochoa Centre of Excellence Award from the Spanish Ministry of Economy and Competitiveness (MINECO; Government of Spain) and is supported by CERCA (Generalitat de Catalunya). R. Sabarinathan is supported by an EMBO Long-Term Fellowship (ALTF 568-2014) co-funded by the European Commission (EMBOCOFUND2012, GA-2012-600394) support from Marie Curie Actions. A.Gonzalez-Perez is supported by a Ramón y Cajal contract
Background: Adult T cell acute lymphoblastic leukemia (T-ALL) is a rare disease that affects less than 10 individuals in one million. It has been less studied than its cognate pediatric malignancy, which is more prevalent. A higher percentage of the adult patients relapse, compared to children. It is thus essential to study the mechanisms of relapse of adult T-ALL cases. Results: We profile whole-genome somatic mutations of 19 primary T-ALLs from adult patients and the corresponding relapse malignancies and analyze their evolution upon treatment in comparison with 238 pediatric and young adult ALL cases. We compare the mutational processes and driver mutations active in primary and relapse adult T-ALLs with those of pediatric patients. A precise estimation of clock-like mutations in leukemic cells shows that the emergence of the relapse clone occurs several months before the diagnosis of the primary T-ALL. Specifically, through the doubling time of the leukemic population, we find that in at least 14 out of the 19 patients, the population of relapse leukemia present at the moment of diagnosis comprises more than one but fewer than 108 blasts. Using simulations, we show that in all patients the relapse appears to be driven by genetic mutations. Conclusions: The early appearance of a population of leukemic cells with genetic mechanisms of resistance across adult T-ALL cases constitutes a challenge for treatment. Improving early detection of the malignancy is thus key to prevent its relapse. ; The authors would like to thank the Asociación Española Contra el Cáncer (AECC) for financially supporting this project (GC16173697BIGA). N.L.-B. acknowledges funding from the European Research Council (consolidator grant 682398) and the ERDF/Spanish Ministry of Science, Innovation and Universities–Spanish State Research Agency/DamReMap Project (RTI2018-094095-B-I00). S. G work is supported by the European Union's Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No. 754510. I. S is supported by FPI fellowship from Spanish Ministry of Economy and Competitiveness (project reference SAF2015-66084-R). V.G-H. is supported by the AECC (project reference GC16173697BIGA-9). IRB Barcelona is a recipient of a Severo Ochoa Centre of Excellence Award from the Spanish Ministry of Economy and Competitiveness (MINECO; Government of Spain) and is supported by CERCA (Generalitat de Catalunya).
The catalog of cancer driver mutations in protein-coding genes has greatly expanded in the past decade. However, non-coding cancer driver mutations are less well-characterized and only a handful of recurrent non-coding mutations, most notably TERT promoter mutations, have been reported. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2658 cancer across 38 tumor types, we perform multi-faceted pathway and network analyses of non-coding mutations across 2583 whole cancer genomes from 27 tumor types compiled by the ICGC/TCGA PCAWG project that was motivated by the success of pathway and network analyses in prioritizing rare mutations in protein-coding genes. While few non-coding genomic elements are recurrently mutated in this cohort, we identify 93 genes harboring non-coding mutations that cluster into several modules of interacting proteins. Among these are promoter mutations associated with reduced mRNA expression in TP53, TLE4, and TCF4. We find that biological processes had variable proportions of coding and non-coding mutations, with chromatin remodeling and proliferation pathways altered primarily by coding mutations, while developmental pathways, including Wnt and Notch, altered by both coding and non-coding mutations. RNA splicing is primarily altered by non-coding mutations in this cohort, and samples containing non-coding mutations in well-known RNA splicing factors exhibit similar gene expression signatures as samples with coding mutations in these genes. These analyses contribute a new repertoire of possible cancer genes and mechanisms that are altered by non-coding mutations and offer insights into additional cancer vulnerabilities that can be investigated for potential therapeutic treatments. ; B.J.R. received funding from NIH grants U24CA211000 and R01HG007069. J.M.S. received funding from NIH grants U24CA143858, R01CA180778, and U24CA210990. J.R. received funding from the Ontario Institute for Cancer Research (OICR) Investigator Award provided by the Government of Ontario, Operating Grant from Cancer Research Society (CRS) (#21089), the Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery Grant (#RGPIN-2016-06485), and the Canadian Institutes of Health Research (CIHR) Project Grant. K.M. received funding from IWT/SBO NEMOA and FWO 3G046318 and G.0371.06 grants. J.M.G.I. received funding from the Novo Nordisk Foundation (NNF17OC0027594 and NNF14CC0001) and the Innovation Fund Denmark (5184-00102B). S.B. received funding from the Novo Nordisk Foundation (NNF17OC0027594 and NNF14CC0001). J.B. received funding from the BioTalent Canada Student Internship Program. A.V. and M.V. received funding from the Joint BSC-IRB-CRG Program in Computational Biology and the Severo Ochoa Award (SEV 2015-0493). M.A.R. was supported in part by the National Cancer Institute of the NIH (Cancer Target Discovery and Development Network grant U01CA217875)
Sex differences have been observed in multiple facets of cancer epidemiology, treatment and biology, and in most cancers outside the sex organs. Efforts to link these clinical differences to specific molecular features have focused on somatic mutations within the coding regions of the genome. Here we report a pan-cancer analysis of sex differences in whole genomes of 1983 tumours of 28 subtypes as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. We both confirm the results of exome studies, and also uncover previously undescribed sex differences. These include sex-biases in coding and non-coding cancer drivers, mutation prevalence and strikingly, in mutational signatures related to underlying mutational processes. These results underline the pervasiveness of molecular sex differences and strengthen the call for increased consideration of sex in molecular cancer research. ; This study was conducted with the support of the Ontario Institute for Cancer Research to P.C.B. through funding provided by the Government of Ontario. This work was supported by the Discovery Frontiers: Advancing Big Data Science in Genomics Research program, which is jointly funded by the Natural Sciences and Engineering Research Council (NSERC) of Canada, the Canadian Institutes of Health Research (CIHR), Genome Canada and the Canada Foundation for Innovation (CFI). P.C.B. was supported by a Terry Fox Research Institute New Investigator Award and a CIHR New Investigator Award. This work was supported by an NSERC Discovery grant and by Canadian Institutes of Health Research, grant #SVB-145586, to P.C.B. This work was supported by the NIH/NCI under award number P30CA016042 and an operating grant from the National Cancer Institute Early Detection Research Network (1U01CA214194-01)
