A compendium of mutational cancer driver genes

A fundamental goal in cancer research is to understand the mechanisms of cell transformation. This is key to developing more efficient cancer detection methods and therapeutic approaches. One milestone towards this objective is the identification of all the genes with mutations capable of driving tumours. Since the 1970s, the list of cancer genes has been growing steadily. Because cancer driver genes are under positive selection in tumorigenesis, their observed patterns of somatic mutations across tumours in a cohort deviate from those expected from neutral mutagenesis. These deviations, which constitute signals of positive selection, may be detected by carefully designed bioinformatics methods, which have become the state of the art in the identification of driver genes. A systematic approach combining several of these signals could lead to a compendium of mutational cancer genes. In this Review, we present the Integrative OncoGenomics (IntOGen) pipeline, an implementation of such an approach to obtain the compendium of mutational cancer drivers. Its application to somatic mutations of more than 28,000 tumours of 66 cancer types reveals 568 cancer genes and points towards their mechanisms of tumorigenesis. The application of this approach to the ever-growing datasets of somatic tumour mutations will support the continuous refinement of our knowledge of the genetic basis of cancer

Pervasive lesion segregation shapes cancer genome evolution

Cancers arise through the acquisition of oncogenic mutations and grow through clonal expansion. Here we reveal that most mutagenic DNA lesions are not resolved as mutations within a single cell-cycle. Instead, DNA lesions segregate unrepaired into daughter cells for multiple cell generations, resulting in the chromosome-scale phasing of subsequent mutations. We characterise this process in mutagen-induced mouse liver tumours and show that DNA replication across persisting lesions can produce multiple alternative alleles in successive cell divisions, thereby generating both multi-allelic and combinatorial genetic diversity. The phasing of lesions enables the accurate measurement of strand biased repair processes, quantification of oncogenic selection, and fine mapping of sister chromatid exchange events. Finally, we demonstrate that lesion segregation is a unifying property of exogenous mutagens, including UV light and chemotherapy agents in human cells and tumours, which has profound implications for the evolution and adaptation of cancer genomes.This work was supported by: Cancer Research UK (20412, 22398), the European Research Council (615584, 682398), the Wellcome Trust (WT108749/Z/15/Z, WT106563/Z/14/A, WT202878/B/16/Z), the European Molecular Biology Laboratory, the MRC Human Genetics Unit core funding programme grants (MC_UU_00007/11, MC_UU_00007/16), and the ERDF/Spanish Ministry of Science, Innovation and Universities-Spanish State Research Agency/DamReMap Project (RTI2018-094095-B-I00)

The Evolution of T-cell acute lymphoblastic leukemia in adult patients under treatment

Acute lymphoblastic leukemia (ALL) is a blood cancer characterized by a high proliferation and maturation arrest of the lymphoid precursors which can either be from B or T-cell lineage. In adult patients, this type of cancer is considered a rare disease and the outcome is worse than children, especially for those presenting the T-Cell ALL (T-ALL) type. In order to get insights on the evolution of adult T-ALL under therapy, we have whole genome sequenced leukemic samples at diagnosis and relapse of 19 adult patients with T-ALL who relapsed after standard treatment. We report the somatic driver alterations and active mutational process and compared them to other ALL cohorts. We pinpoint candidates of therapy resistance by looking at relapse-enriched alterations (e.g. genes NT5C2, ABCB1 and SMARCA4). In most cases, the relapse clone is estimated to diverge from the primary the previous year to the diagnosis, by which time, the relapse-fated subpopulation size ranges from few to millions of cells. We have also simulated different scenarios of primary and relapse leukemias and concluded that the relapsed leukemias of the sequenced cohort are driven by genetic resistance. In this project we provide an integrated vision of the mutational evolution of T-ALL adult cases and highlight the relevance of finding cancer driver genes of resistance. In line with that, we have also generated a compendium of mutational cancer driver genes across different cancer types through the analysis of thousands of tumors with a whole new framework for driver gene discovery (IntOGen).La leucèmia limfoblàstica aguda (LLA) és un càncer de sang que es caracteritza per una altra proliferació i arrest en la maduració dels precursors limfoblàstics que poden ser del llinatge B o T. En pacients adults, aquest tipus de càncer és considerat una malaltia rara i presenten pitjor pronòstic que els pacients pediàtrics en especial en aquells adults del tipus T-LLA. Per tal de conèixer millor l'evolució de la T-LLA en adults en tractament, hem seqüenciat el genoma sencer de mostres a diagnòstic i recaiguda de 19 pacients adults amb T-LLA que van recaure després de rebre el tractament estàndard. Reportem les alteracions somàtiques driver i els processos mutationals actius en comparació amb d’altres cohorts de LLA. També assenyalem candidats de resistència al tractament tot mirant les alteracions abundants en recaiguda (per exemple als gens NT5C2, ABCB1 i SMARCA4). En la majoria dels casos, el clon de recaiguda s’estima que va divergir del clon primari l’any previ a la diagnosi, moment pel qual, les cèl·lules destinades a fer la recurrència constitueixen una subpoblació cel·lular que va de poques a milions de cèl·lules. Mitjançant simulacions de diferents escenaris de leucèmies primàries i de recaiguda, concloem que les leucèmies de recaiguda d’aquesta cohort seqüenciada es deuen a una resistència genètica. En aquest projecte donem una visió integrada de l’ evolució mutacional de les T-LLA en casos adults i resaltem la rellevància de trobar gens driver de resistència. En aquesta línia, també hem generat un compendi de gens driver mutacionals de diferents tipus càncer a través de l'anàlisi de milers de tumors amb una nova plataforma de detecció de gens driver (IntOGen)

Great apes and children infer causal relations from patterns of variation and covariation

We investigated whether nonhuman great apes (N=23), 2.5-year-old (N=20), and 3-year-old children (N=40) infer causal relations from patterns of variation and covariation by adapting the blicket detector paradigm for apes. We presented chimpanzees (Pan troglodytes), bonobos (Pan paniscus), orangutans (Pongo abelii), gorillas (Gorilla gorilla), and children (Homo sapiens) with a novel reward dispenser, the blicket detector. The detector was activated by inserting specific (yet randomly determined) objects, the so-called blickets. Once activated a reward was released, accompanied by lights and a short tone. Participants were shown different patterns of variation and covariation between two different objects and the activation of the detector. When subsequently choosing between one of the two objects to activate the detector on their own all species, except gorillas (who failed the training), took these patterns of correlation into account. In particular, apes and 2.5-year-old children ignored objects whose effect on the detector completely depended on the presence of another object. Follow-up experiments explored whether the apes and children were also able to re-evaluate evidence retrospectively. Only children (3-year-olds in particular) were able to make such retrospective inferences about causal structures from observing the effects of the experimenter’s actions. Apes succeeded here only when they observed the effects of their own interventions. Together, this study provides evidence that apes, like young children, accurately infer causal structures from patterns of (co)variation and that they use this information to inform their own interventions

β-Catenin activity induces an RNA biosynthesis program promoting therapy resistance in T-cell acute lymphoblastic leukemia

Understanding the molecular mechanisms that contribute to the appearance of chemotherapy resistant cell populations is necessary to improve cancer treatment. We have now investigated the role of β-catenin/CTNNB1 in the evolution of T-cell Acute Lymphoblastic Leukemia (T-ALL) patients and its involvement in therapy resistance. We have identified a specific gene signature that is directly regulated by β-catenin, TCF/LEF factors and ZBTB33/Kaiso in T-ALL cell lines, which is highly and significantly represented in five out of six refractory patients from a cohort of 40 children with T-ALL. By subsequent refinement of this gene signature, we found that a subset of β-catenin target genes involved with RNA-processing function are sufficient to segregate T-ALL refractory patients in three independent cohorts. We demonstrate the implication of β-catenin in RNA and protein synthesis in T-ALL and provide in vitro and in vivo experimental evidence that β-catenin is crucial for the cellular response to chemotherapy, mainly in the cellular recovery phase after treatment. We propose that combination treatments involving chemotherapy plus β-catenin inhibitors will enhance chemotherapy response and prevent disease relapse in T-ALL patients.This work has been funded by Agencia Estatal de Investigación (SAF2016-75613-R and PID2019-104695RB-I00), Fundación AECC (GC16173697BIGA) and WCR (13-0064). VGH, DA and TL are recipients of Sara Borrell fellowship from ISCIII co-funded by the ESF+ (CD21/00145), FPI (BES-2017-080880) and AECC fellowship (POSTD21975LOBO), respectively