Suchergebnisse

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). ; Peer Reviewed ; Postprint (published version)

PI13-00285 PI11-01439 ; Germline mutations in UNC5C have been suggested to increase colorectal cancer (CRC) risk, thus causing hereditary CRC. However, the evidence gathered thus far is insufficient to include the study of the UNC5C gene in the routine genetic testing of familial CRC. Here we aim at providing a more conclusive answer about the contribution of germline UNC5C mutations to genetically unexplained hereditary CRC and/or polyposis cases. To achieve this goal we sequenced the coding region and exon-intron boundaries of UNC5C in 544 familial CRC or polyposis patients (529 families), using a technique that combines pooled DNA amplification and massively parallel sequencing. A total of eight novel or rare variants, all missense, were identified in eight families. Co-segregation data in the families and association results in case-control series are not consistent with a causal effect for 7 of the 8 identified variants, including c.1882_1883delinsAA (p.A628K), previously described as a disease-causing mutation. One variant, c.2210G > A (p.S737N), remained unclassified. In conclusion, our results suggest that the contribution of germline mutations in UNC5C to hereditary colorectal cancer and to polyposis cases is negligible. ; This work was funded by the Spanish Ministry of Economy and Competitiveness and co-funded by FEDER funds -a way to build Europe- [SAF2012-38885 (LV), SAF2013-45836-R (XSP), SAF2012-33636 (GC)]; Carlos III Health Institute [PI13-00285 (CL), PI11-01439 (VM)]; Red Tematica de Investigacion Cooperativa en Cancer [RTICC RD12/0036/0031, RD12/0036/0008, RD12/0036/0067], the Government of Catalonia [2014SGR338, 2014SGR647], and the Scientific Foundation Asociacion Espanola Contra el Cancer. We thank Tirso Pons from the Spanish National Cancer Research Center (CNIO) for his assistance. We are grateful to the researchers of the MCC-Spain study for providing the data to assess the identified UNC5C rare variants in the general population. ; Sí

Analysis of mutational signatures is becoming routine in cancer genomics, with implications for pathogenesis, classification, prognosis, and even treatment decisions. However, the field lacks a consensus on analysis and result interpretation. Using whole-genome sequencing of multiple myeloma (MM), chronic lymphocytic leukemia (CLL) and acute myeloid leukemia, we compare the performance of public signature analysis tools. We describe caveats and pitfalls of de novo signature extraction and fitting approaches, reporting on common inaccuracies: erroneous signature assignment, identification of localized hyper-mutational processes, overcalling of signatures. We provide reproducible solutions to solve these issues and use orthogonal approaches to validate our results. We show how a comprehensive mutational signature analysis may provide relevant biological insights, reporting evidence of c-AID activity among unmutated CLL cases or the absence of BRCA1/BRCA2-mediated homologous recombination deficiency in a MM cohort. Finally, we propose a general analysis framework to ensure production of accurate and reproducible mutational signature data. ; F.M. is supported by A.I.L. (Associazione Italiana Contro le Leucemie-Linfomi e Mieloma ONLUS), by S.I.E.S. (Società Italiana di Ematologia Sperimentale) and by the Memorial Sloan Kettering Cancer Center NCI Core Grant (P30 CA 008748). N.B. is funded by the University of Milan (project 22597-PSR2017_DIP_032) and by the European Research Council under the European Union's Horizon 2020 research and innovation program (grant agreement no. 817997). X.S.P. is supported by thr Ministerio de Economía y Competitividad Grant No. SAF2017–87811-R. F.N. is supported by a pre-doctoral fellowship of the MINECO (BES-2016–076372). This work was supported by the Instituto de Salud Carlos III (project PMP15/00007, F.N., E.C.), the "la Caixa" Foundation Grant No HR17-00221 (Health Research 2017 Program, F.N., E.C.), the Ministerio de Economía y Competitividad (MINECO) SAF2013-45836-R (E.C.) from. Plan Nacional de I + D + I, Generalitat de Catalunya Suport Grups de Recerca AGAUR 2017-SGR-1142 (E.C.) and the European Regional Development Fund "Una manera de hacer Europa". E.C. is supported by ICREA under the ICREA Academia program. A.D. is funded by a CRUK Pioneer Award C60100/A23433. S.N.Z. is funded by a CRUK Advanced Clinician Scientist Award (C60100/A23916) and a CRUK Grand Challenge Award (C60100/A25274). This work was supported by: Department of Veterans Affairs Merit Review Award I01BX001584-01 (N.C.M.), NIH grants P01-155258 (N.C.M., H.A.L., M.F., P.J.C., K.C.A.) and 5P50CA100707-13 (N.C.M., H.A.L., K.C.A).

Analysis of mutational signatures is becoming routine in cancer genomics, with implications for pathogenesis, classification, prognosis, and even treatment decisions. However, the field lacks a consensus on analysis and result interpretation. Using whole-genome sequencing of multiple myeloma (MM), chronic lymphocytic leukemia (CLL) and acute myeloid leukemia, we compare the performance of public signature analysis tools. We describe caveats and pitfalls of de novo signature extraction and fitting approaches, reporting on common inaccuracies: erroneous signature assignment, identification of localized hyper-mutational processes, overcalling of signatures. We provide reproducible solutions to solve these issues and use orthogonal approaches to validate our results. We show how a comprehensive mutational signature analysis may provide relevant biological insights, reporting evidence of c-AID activity among unmutated CLL cases or the absence of BRCA1/BRCA2-mediated homologous recombination deficiency in a MM cohort. Finally, we propose a general analysis framework to ensure production of accurate and reproducible mutational signature data. ; F.M. is supported by A.I.L. (Associazione Italiana Contro le Leucemie-Linfomi e Mieloma ONLUS), by S.I.E.S. (Società Italiana di Ematologia Sperimentale) and by the Memorial Sloan Kettering Cancer Center NCI Core Grant (P30 CA 008748). N.B. is funded by the University of Milan (project 22597-PSR2017_DIP_032) and by the European Research Council under the European Union's Horizon 2020 research and innovation program (grant agreement no. 817997). X.S.P. is supported by thr Ministerio de Economía y Competitividad Grant No. SAF2017–87811-R. F.N. is supported by a pre-doctoral fellowship of the MINECO (BES-2016–076372). This work was supported by the Instituto de Salud Carlos III (project PMP15/00007, F.N., E.C.), the "la Caixa" Foundation Grant No HR17-00221 (Health Research 2017 Program, F.N., E.C.), the Ministerio de Economía y Competitividad (MINECO) SAF2013-45836-R (E.C.) from. Plan Nacional de I + D + I, Generalitat de Catalunya Suport Grups de Recerca AGAUR 2017-SGR-1142 (E.C.) and the European Regional Development Fund "Una manera de hacer Europa". E.C. is supported by ICREA under the ICREA Academia program. A.D. is funded by a CRUK Pioneer Award C60100/A23433. S.N.Z. is funded by a CRUK Advanced Clinician Scientist Award (C60100/A23916) and a CRUK Grand Challenge Award (C60100/A25274). This work was supported by: Department of Veterans Affairs Merit Review Award I01BX001584-01 (N.C.M.), NIH grants P01-155258 (N.C.M., H.A.L., M.F., P.J.C., K.C.A.) and 5P50CA100707-13 (N.C.M., H.A.L., K.C.A). We thank Michael R. Stratton for discussions and help in data interpretation. ; Peer Reviewed ; Postprint (author's final draft)

Analysis of mutational signatures is becoming routine in cancer genomics, with implications for pathogenesis, classification, prognosis, and even treatment decisions. However, the field lacks a consensus on analysis and result interpretation. Using whole-genome sequencing of multiple myeloma (MM), chronic lymphocytic leukemia (CLL) and acute myeloid leukemia, we compare the performance of public signature analysis tools. We describe caveats and pitfalls of de novo signature extraction and fitting approaches, reporting on common inaccuracies: erroneous signature assignment, identification of localized hyper-mutational processes, overcalling of signatures. We provide reproducible solutions to solve these issues and use orthogonal approaches to validate our results. We show how a comprehensive mutational signature analysis may provide relevant biological insights, reporting evidence of c-AID activity among unmutated CLL cases or the absence of BRCA1/BRCA2-mediated homologous recombination deficiency in a MM cohort. Finally, we propose a general analysis framework to ensure production of accurate and reproducible mutational signature data. ; F.M. is supported by A.I.L. (Associazione Italiana Contro le Leucemie-Linfomi e Mieloma ONLUS), by S.I.E.S. (Società Italiana di Ematologia Sperimentale) and by the Memorial Sloan Kettering Cancer Center NCI Core Grant (P30 CA 008748). N.B. is funded by the University of Milan (project 22597-PSR2017_DIP_032) and by the European Research Council under the European Union's Horizon 2020 research and innovation program (grant agreement no. 817997). X.S.P. is supported by thr Ministerio de Economía y Competitividad Grant No. SAF2017–87811-R. F.N. is supported by a pre-doctoral fellowship of the MINECO (BES-2016–076372). This work was supported by the Instituto de Salud Carlos III (project PMP15/00007, F.N., E.C.), the "la Caixa" Foundation Grant No HR17-00221 (Health Research 2017 Program, F.N., E.C.), the Ministerio de Economía y Competitividad (MINECO) SAF2013-45836-R (E.C.) from. Plan Nacional de I + D + I, Generalitat de Catalunya Suport Grups de Recerca AGAUR 2017-SGR-1142 (E.C.) and the European Regional Development Fund "Una manera de hacer Europa". E.C. is supported by ICREA under the ICREA Academia program. A.D. is funded by a CRUK Pioneer Award C60100/A23433. S.N.Z. is funded by a CRUK Advanced Clinician Scientist Award (C60100/A23916) and a CRUK Grand Challenge Award (C60100/A25274). This work was supported by: Department of Veterans Affairs Merit Review Award I01BX001584-01 (N.C.M.), NIH grants P01-155258 (N.C.M., H.A.L., M.F., P.J.C., K.C.A.) and 5P50CA100707-13 (N.C.M., H.A.L., K.C.A). We thank Michael R. Stratton for discussions and help in data interpretation. ; Peer Reviewed ; Postprint (author's final draft)

Germline mutations in BUB1 and BUB3 have been reported to increase the risk of developing colorectal cancer (CRC) at young age, in presence of variegated aneuploidy and reminiscent dysmorphic traits of mosaic variegated aneuploidy syndrome. We performed a mutational analysis of BUB1 and BUB3 in 456 uncharacterized mismatch repair-proficient hereditary non-polyposis CRC families and 88 polyposis cases. Four novel or rare germline variants, one splice-site and three missense, were identified in four families. Neither variegated aneuploidy nor dysmorphic traits were observed in carriers. Evident functional effects in the heterozygous form were observed for c.1965-1G>A, but not for c.2296G>A (p.E766K), in spite of the positive co-segregation in the family. BUB1 c.2473C>T (p.P825S) and BUB3 c.77C>T (p.T26I) remained as variants of uncertain significance. As of today, the rarity of functionally relevant mutations identified in familial and/or early onset series does not support the inclusion of BUB1 and BUB3 testing in routine genetic diagnostics of familial CRC. ; his work was supported by the Spanish Ministry of Economy and Competitiveness, co-funded by FEDER funds – a way to build Europe – (grants SAF2016 – 80888-R to LValle, SAF2015 – 68016-R to GC and MP, and SAF2013 – 45836-R to XSP]; Carlos III National Health Institute [PI16/00563 to CL and CIBER- ONC]; the Government of Catalonia [ Pla estratègic de recerca i innovació en salut (PERIS) and 2014SGR338]; the Scientific Foundation Asociación Española Contra el Cáncer ; and EU COST Action BM1206. PM holds a Juan de la Cierva postdoc- toral fellowship from the Spanish Ministry of Economy and Competitiveness, and RMdV, a Dutch Cancer Society (KWF) Fellowship (KUN14–666 ; Sí

As whole-genome sequencing for cancer genome analysis becomes a clinical tool, a full understanding of the variables affecting sequencing analysis output is required. Here using tumour-normal sample pairs from two different types of cancer, chronic lymphocytic leukaemia and medulloblastoma, we conduct a benchmarking exercise within the context of the International Cancer Genome Consortium. We compare sequencing methods, analysis pipelines and validation methods. We show that using PCR-free methods and increasing sequencing depth to ∼ 100 × shows benefits, as long as the tumour:control coverage ratio remains balanced. We observe widely varying mutation call rates and low concordance among analysis pipelines, reflecting the artefact-prone nature of the raw data and lack of standards for dealing with the artefacts. However, we show that, using the benchmark mutation set we have created, many issues are in fact easy to remedy and have an immediate positive impact on mutation detection accuracy. ; We thank the DKFZ Genomics and Proteomics Core Facility and the OICR Genome Technologies Platform for provision of sequencing services. Financial support was provided by the consortium projects READNA under grant agreement FP7 Health-F4-2008-201418, ESGI under grant agreement 262055, GEUVADIS under grant agreement 261123 of the European Commission Framework Programme 7, ICGC-CLL through the Spanish Ministry of Science and Innovation (MICINN), the Instituto de Salud Carlos III (ISCIII) and the Generalitat de Catalunya. Additional financial support was provided by the PedBrain Tumor Project contributing to the International Cancer Genome Consortium, funded by German Cancer Aid (109252) and by the German Federal Ministry of Education and Research (BMBF, grants #01KU1201A, MedSys #0315416C and NGFNplus #01GS0883; the Ontario Institute for Cancer Research to PCB and JDM through funding provided by the Government of Ontario, Ministry of Research and Innovation; Genome Canada; the Canada Foundation for Innovation and Prostate Cancer Canada with funding from the Movember Foundation (PCB). PCB was also supported by a Terry Fox Research Institute New Investigator Award, a CIHR New Investigator Award and a Genome Canada Large-Scale Applied Project Contract. The Synergie Lyon Cancer platform has received support from the French National Institute of Cancer (INCa) and from the ABS4NGS ANR project (ANR-11-BINF-0001-06). The ICGC RIKEN study was supported partially by RIKEN President's Fund 2011, and the supercomputing resource for the RIKEN study was provided by the Human Genome Center, University of Tokyo. MDE, LB, AGL and CLA were supported by Cancer Research UK, the University of Cambridge and Hutchison-Whampoa Limited. SD is supported by the Torres Quevedo subprogram (MI CINN) under grant agreement PTQ-12-05391. EH is supported by the Research Council of Norway under grant agreements 221580 and 218241 and by the Norwegian Cancer Society under grant agreement 71220-PR-2006-0433. Very special thanks go to Jennifer Jennings for administrating the activity of the ICGC Verification Working Group and Anna Borrell for administrative support. ; This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/ncomms10001