Minimal spatial heterogeneity in chronic lymphocytic leukemia at diagnosis

Acknowledgements This study was supported by the Instituto de Salud Carlos III and the European Regional Development Fund “Una manera de hacer Europa” (grant PMP15/00007), and the “la Caixa” Foundation (grant CLLEvolution-HR17-00221). EC is an Academia Researcher of the ‘Institució Catalana de Recerca i Estudis Avançats’ (ICREA) of the Generalitat de Catalunya. FN is supported by a predoctoral fellowship of the Ministerio de Economía y Competitividad (BES-2016-076372). FM is supported by the Memorial Sloan Kettering Cancer Center NCI Core Grant (P30 CA 008748).Peer ReviewedPostprint (author's final draft

Comparative analysis of cancer genes in the human and chimpanzee genomes

Background: Cancer is a major medical problem in modern societies. However, the incidence of this disease in non-human primates is very low. To study whether genetic differences between human and chimpanzee could contribute to their distinct cancer susceptibility, we have examined in the chimpanzee genome the orthologous genes of a set of 333 human cancer genes. Results: This analysis has revealed that all examined human cancer genes are present in chimpanzee, contain intact open reading frames and show a high degree of conservation between both species. However, detailed analysis of this set of genes has shown some differences in genes of special relevance for human cancer. Thus, the chimpanzee gene encoding p53 contains a Pro residue at codon 72, while this codon is polymorphic in humans and can code for Arg or Pro, generating isoforms with different ability to induce apoptosis or interact with p73. Moreover, sequencing of the BRCA1 gene has shown an 8 Kb deletion in the chimpanzee sequence that prematurely truncates the co-regulated NBR2 gene. Conclusion: These data suggest that small differences in cancer genes, as those found in tumor suppressor genes, might influence the differences in cancer susceptibility between human and chimpanzee. Nevertheless, further analysis will be required to determine the exact contribution of the genetic changes identified in this study to the different cancer incidence in non-human primates

ATM germline variants in a young adult with chronic lymphocytic leukemia: 8 years of genomic evolution

The authors thank the Hematopathology Collection registered at the Biobank of Hospital Clínic—Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) as well as Sílvia Martín for the technical support. This study was supported by the “la Caixa” Foundation (CLLEvolution-LCF/PR/HR17/52150017, Health Research 2017 Program HR17-00221, to EC), the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (810287, BCLLatlas, to EC, and HH), CERCA Program/Generalitat de Catalunya, Generalitat de Catalunya Suport Grups de Recerca AGAUR 2017-SGR-1142 (to EC), CIBERONC (CB16/12/00225 to EC), Ministerio de Ciencia e Innovación PID2020-117185RB-I00 (to XSP), FEDER: European Regional Development Fund “Una manera de hacer Europa”, and Fundación Asociación Española Contra el Cáncer FUNCAR-PRYGN211258SUÁR (to XSP). The authors thankfully acknowledge the computer resources at MareNostrum4 and the technical support provided by Barcelona Supercomputing Center (RES activity BCV-2018-3-0001). FN acknowledge research support from the American Association for Cancer Research (2021 AACR-Amgen Fellowship in Clinical/Translational Cancer Research, Grant Number 21-40-11-NADE), the European Hematology Association (EHA Junior Research Grant 2021, Grant Number RG-202012-00245), and the Lady Tata Memorial Trust (International Award for Research in Leukemia 2021–2022, Grant Number LADY_TATA_21_3223). EC is an Academia Researcher of the “Institució Catalana de Recerca i Estudis Avançats” (ICREA) of the Generalitat de Catalunya. This work was partially developed at the Centre Esther Koplowitz (CEK, Barcelona, Spain)

Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia

Chronic lymphocytic leukaemia (CLL), the most frequent leukaemia in adults in Western countries, is a heterogeneous disease with variable clinical presentation and evolution. Two major molecular subtypes can be distinguished, characterized respectively by a high or low number of somatic hypermutations in the variable region of immunoglobulin genes. The molecular changes leading to the pathogenesis of the disease are still poorly understood. Here we performed whole-genome sequencing of four cases of CLL and identified 46 somatic mutations that potentially affect gene function. Further analysis of these mutations in 363 patients with CLL identified four genes that are recurrently mutated: notch 1 (NOTCH1), exportin 1 (XPO1), myeloid differentiation primary response gene 88 (MYD88) and kelch-like 6 (KLHL6). Mutations in MYD88 and KLHL6 are predominant in cases of CLL with mutated immunoglobulin genes, whereas NOTCH1 and XPO1 mutations are mainly detected in patients with unmutated immunoglobulins. The patterns of somatic mutation, supported by functional and clinical analyses, strongly indicate that the recurrent NOTCH1, MYD88 and XPO1 mutations are oncogenic changes that contribute to the clinical evolution of the disease. To our knowledge, this is the first comprehensive analysis of CLL combining whole-genome sequencing with clinical characteristics and clinical outcomes. It highlights the usefulness of this approach for the identification of clinically relevant mutations in cancer

Cryptic insertions of the immunoglobulin light chain enhancer region near CCND1 in t(11;14)-negative mantle cell lymphoma

This work was supported by research funding from Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III PI17/01061 (SB), Ministerio de Ciencia y Innovación RTI2018-094274-B-I00 (EC), SAF2017-87811-R (XSP) from Plan Nacional de I+D+I, the NIH grant number 1 P01CA229100 (EC), Generalitat de Catalunya Suport Grups de Recerca 2017-SGR-709 (SB), 2017-SGR-1142 (EC), and the European Regional Development Fund “Una manera de fer Europa”, CERCA Programme/Generalitat de Catalunya. EC is an Academia Researcher of the “Institució Catalana de Recerca i Estudis Avançats” of the Generalitat de Catalunya. Miriam Prieto is supported by “Acció instrumental d’incorporació de científics i tecnòlegs PERIS 2016” (SLT002/16/00347) from Generalitat de Catalunya. Alfredo Rivas-Delgado is supported by “Josep Font” grant from Hospital Clínic de Barcelona. Information on authorship, contributions, and financial & other disclosures was provided by the authors and is available with the online version of this article at www.haematologica.org