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Article ; Online: Copy number footprints of platinum-based anticancer therapies.

Gonzalez, Santiago / Lopez-Bigas, Nuria / Gonzalez-Perez, Abel

2023 Volume 19, Issue 2, Page(s) e1010634

Abstract: Recently, distinct mutational footprints observed in metastatic tumors, secondary malignancies and normal human tissues have been demonstrated to be caused by the exposure to several chemotherapeutic drugs. These characteristic mutations originate from ... ...

Abstract	Recently, distinct mutational footprints observed in metastatic tumors, secondary malignancies and normal human tissues have been demonstrated to be caused by the exposure to several chemotherapeutic drugs. These characteristic mutations originate from specific lesions caused by these chemicals to the DNA of exposed cells. However, it is unknown whether the exposure to these chemotherapies leads to a specific footprint of larger chromosomal aberrations. Here, we address this question exploiting whole genome sequencing data of metastatic tumors obtained from patients exposed to different chemotherapeutic drugs. As a result, we discovered a specific copy number footprint across tumors from patients previously exposed to platinum-based therapies. This footprint is characterized by a significant increase in the number of chromosomal fragments of copy number 1-4 and size smaller than 10 Mb in exposed tumors with respect to their unexposed counterparts (median 14-387% greater across tumor types). The number of chromosomal fragments characteristic of the platinum-associated CN footprint increases significantly with the activity of the well known platinum-related footprint of single nucleotide variants across exposed tumors.
MeSH term(s)	Humans ; Chromosome Aberrations ; DNA Copy Number Variations ; Mutation ; Neoplasms/genetics ; Antineoplastic Agents/pharmacology ; Platinum/pharmacology
Chemical Substances	Antineoplastic Agents ; Platinum (49DFR088MY)
Language	English
Publishing date	2023-02-13
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2186725-2
ISSN	1553-7404 ; 1553-7390
ISSN (online)	1553-7404
ISSN	1553-7390
DOI	10.1371/journal.pgen.1010634
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Hotspot propensity across mutational processes.

Arnedo-Pac, Claudia / Muiños, Ferran / Gonzalez-Perez, Abel / Lopez-Bigas, Nuria

Molecular systems biology

2023 Volume 20, Issue 1, Page(s) 6–27

Abstract: The sparsity of mutations observed across tumours hinders our ability to study mutation rate variability at nucleotide resolution. To circumvent this, here we investigated the propensity of mutational processes to form mutational hotspots as a readout of ...

Abstract	The sparsity of mutations observed across tumours hinders our ability to study mutation rate variability at nucleotide resolution. To circumvent this, here we investigated the propensity of mutational processes to form mutational hotspots as a readout of their mutation rate variability at single base resolution. Mutational signatures 1 and 17 have the highest hotspot propensity (5-78 times higher than other processes). After accounting for trinucleotide mutational probabilities, sequence composition and mutational heterogeneity at 10 Kbp, most (94-95%) signature 17 hotspots remain unexplained, suggesting a significant role of local genomic features. For signature 1, the inclusion of genome-wide distribution of methylated CpG sites into models can explain most (80-100%) of the hotspot propensity. There is an increased hotspot propensity of signature 1 in normal tissues and de novo germline mutations. We demonstrate that hotspot propensity is a useful readout to assess the accuracy of mutation rate models at nucleotide resolution. This new approach and the findings derived from it open up new avenues for a range of somatic and germline studies investigating and modelling mutagenesis.
MeSH term(s)	Humans ; Mutation ; Mutation Rate ; Neoplasms/genetics ; Base Sequence ; Nucleotides
Chemical Substances	Nucleotides
Language	English
Publishing date	2023-12-20
Publishing country	England
Document type	Journal Article
ZDB-ID	2193510-5
ISSN	1744-4292 ; 1744-4292
ISSN (online)	1744-4292
ISSN	1744-4292
DOI	10.1038/s44320-023-00001-w
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Article ; Online: Genomic deletions explain the generation of alternative BRAF isoforms conferring resistance to MAPK inhibitors in melanoma.

Aya, Francisco / Lanuza-Gracia, Pablo / González-Pérez, Abel / Bonnal, Sophie / Mancini, Estefania / López-Bigas, Nuria / Arance, Ana / Valcárcel, Juan

Cell reports

2024 Volume 43, Issue 4, Page(s) 114048

Abstract: Resistance to MAPK inhibitors (MAPKi), the main cause of relapse in BRAF-mutant melanoma, is associated with the production of alternative BRAF mRNA isoforms (altBRAFs) in up to 30% of patients receiving BRAF inhibitor monotherapy. These altBRAFs have ... ...

Abstract	Resistance to MAPK inhibitors (MAPKi), the main cause of relapse in BRAF-mutant melanoma, is associated with the production of alternative BRAF mRNA isoforms (altBRAFs) in up to 30% of patients receiving BRAF inhibitor monotherapy. These altBRAFs have been described as being generated by alternative pre-mRNA splicing, and splicing modulation has been proposed as a therapeutic strategy to overcome resistance. In contrast, we report that altBRAFs are generated through genomic deletions. Using different in vitro models of altBRAF-mediated melanoma resistance, we demonstrate the production of altBRAFs exclusively from the BRAF V600E allele, correlating with corresponding genomic deletions. Genomic deletions are also detected in tumor samples from melanoma and breast cancer patients expressing altBRAFs. Along with the identification of altBRAFs in BRAF wild-type and in MAPKi-naive melanoma samples, our results represent a major shift in our understanding of mechanisms leading to the generation of BRAF transcripts variants associated with resistance in melanoma.
MeSH term(s)	Proto-Oncogene Proteins B-raf/genetics ; Proto-Oncogene Proteins B-raf/antagonists & inhibitors ; Proto-Oncogene Proteins B-raf/metabolism ; Melanoma/genetics ; Melanoma/drug therapy ; Melanoma/pathology ; Humans ; Drug Resistance, Neoplasm/genetics ; Protein Kinase Inhibitors/pharmacology ; Cell Line, Tumor ; Protein Isoforms/metabolism ; Protein Isoforms/genetics ; Alternative Splicing/genetics ; Female ; Gene Deletion
Chemical Substances	Proto-Oncogene Proteins B-raf (EC 2.7.11.1) ; Protein Kinase Inhibitors ; BRAF protein, human (EC 2.7.11.1) ; Protein Isoforms
Language	English
Publishing date	2024-04-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2024.114048
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Article ; Online: Identification of Clonal Hematopoiesis Driver Mutations through In Silico Saturation Mutagenesis.

Demajo, Santiago / Ramis-Zaldivar, Joan Enric / Muinos, Ferran / Grau, Miguel L / Andrianova, Maria / Lopez-Bigas, Nuria / Gonzalez-Perez, Abel

Cancer discovery

2024

Abstract: Clonal hematopoiesis (CH) is a phenomenon of clonal expansion of hematopoietic stem cells driven by somatic mutations affecting certain genes. Recently, CH has been linked to the development of hematologic malignancies, cardiovascular diseases, and other ...

Abstract	Clonal hematopoiesis (CH) is a phenomenon of clonal expansion of hematopoietic stem cells driven by somatic mutations affecting certain genes. Recently, CH has been linked to the development of hematologic malignancies, cardiovascular diseases, and other conditions. Although the most frequently mutated CH driver genes have been identified, a systematic landscape of the mutations capable of initiating this phenomenon is still lacking. Here, we trained machine-learning models for 12 of the most recurrent CH genes to identify their driver mutations. These models outperform expert-curated rules based on prior knowledge of the function of these genes. Moreover, their application to identify CH driver mutations across almost half a million donors of the UK Biobank reproduces known associations between CH driver mutations and age, and the prevalence of several diseases and conditions. We thus propose that these models support the accurate identification of CH across healthy individuals.
Language	English
Publishing date	2024-05-09
Publishing country	United States
Document type	Journal Article
ZDB-ID	2625242-9
ISSN	2159-8290 ; 2159-8274
ISSN (online)	2159-8290
ISSN	2159-8274
DOI	10.1158/2159-8290.CD-23-1416
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Article ; Online: Predicting disease variants using biodiversity and machine learning.

Arnedo-Pac, Claudia / Lopez-Bigas, Nuria / Muiños, Ferran

Nature biotechnology

2021 Volume 40, Issue 1, Page(s) 27–28

MeSH term(s)	Biodiversity ; Machine Learning
Language	English
Publishing date	2021-12-23
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	1311932-1
ISSN	1546-1696 ; 1087-0156
ISSN (online)	1546-1696
ISSN	1087-0156
DOI	10.1038/s41587-021-01187-w
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Zs.A 2167: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 137: Show issues
Zs.MG 43: Show issues

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Article ; Online: Are carcinogens direct mutagens?

Lopez-Bigas, Nuria / Gonzalez-Perez, Abel

Nature genetics

2020 Volume 52, Issue 11, Page(s) 1137–1138

MeSH term(s)	Animals ; Carcinogens/toxicity ; Humans ; Mice ; Mutagens/toxicity ; Mutation
Chemical Substances	Carcinogens ; Mutagens
Language	English
Publishing date	2020-08-17
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	1108734-1
ISSN	1546-1718 ; 1061-4036
ISSN (online)	1546-1718
ISSN	1061-4036
DOI	10.1038/s41588-020-00730-w
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Zs.A 3613: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 46: Show issues

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Article ; Online: Variable interplay of UV-induced DNA damage and repair at transcription factor binding sites.

Frigola, Joan / Sabarinathan, Radhakrishnan / Gonzalez-Perez, Abel / Lopez-Bigas, Nuria

Nucleic acids research

2021 Volume 49, Issue 2, Page(s) 891–901

Abstract: An abnormally high rate of UV-light related mutations appears at transcription factor binding sites (TFBS) across melanomas. The binding of transcription factors (TFs) to the DNA impairs the repair of UV-induced lesions and certain TFs have been shown to ...

Abstract	An abnormally high rate of UV-light related mutations appears at transcription factor binding sites (TFBS) across melanomas. The binding of transcription factors (TFs) to the DNA impairs the repair of UV-induced lesions and certain TFs have been shown to increase the rate of generation of these lesions at their binding sites. However, the precise contribution of these two elements to the increase in mutation rate at TFBS in these malignant cells is not understood. Here, exploiting nucleotide-resolution data, we computed the rate of formation and repair of UV-lesions within the binding sites of TFs of different families. We observed, at certain dipyrimidine positions within the binding site of TFs in the Tryptophan Cluster family, an increased rate of formation of UV-induced lesions, corroborating previous studies. Nevertheless, across most families of TFs, the observed increased mutation rate within the entire DNA region covered by the protein results from the decreased repair efficiency. While the rate of mutations across all TFBS does not agree with the amount of UV-induced lesions observed immediately after UV exposure, it strongly agrees with that observed after 48 h. This corroborates the determinant role of the impaired repair in the observed increase of mutation rate.
MeSH term(s)	Binding Sites ; Chromosome Mapping ; DNA Damage ; DNA Repair ; DNA, Neoplasm/genetics ; DNA, Neoplasm/radiation effects ; Humans ; Melanoma/genetics ; Mutagenesis ; Mutation ; Pyrimidine Dimers/genetics ; Pyrimidine Dimers/metabolism ; Skin Neoplasms/genetics ; Transcription Factors/metabolism ; Ultraviolet Rays/adverse effects ; Whole Genome Sequencing
Chemical Substances	DNA, Neoplasm ; Pyrimidine Dimers ; Transcription Factors
Language	English
Publishing date	2021-01-07
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	186809-3
ISSN	1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
ISSN (online)	1362-4962 ; 1362-4954
ISSN	0301-5610 ; 0305-1048
DOI	10.1093/nar/gkaa1219
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Zs.A 1067: Show issues

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Article ; Online: Ten simple rules for a successful international consortium in big data omics.

Stobbe, Miranda D / Gonzalez-Perez, Abel / Lopez-Bigas, Nuria / Gut, Ivo Glynne

PLoS computational biology

2022 Volume 18, Issue 10, Page(s) e1010546

MeSH term(s)	Big Data
Language	English
Publishing date	2022-10-20
Publishing country	United States
Document type	Editorial ; Research Support, Non-U.S. Gov't
ZDB-ID	2193340-6
ISSN	1553-7358 ; 1553-734X
ISSN (online)	1553-7358
ISSN	1553-734X
DOI	10.1371/journal.pcbi.1010546
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Article ; Online: Discovering the drivers of clonal hematopoiesis.

Pich, Oriol / Reyes-Salazar, Iker / Gonzalez-Perez, Abel / Lopez-Bigas, Nuria

Nature communications

2022 Volume 13, Issue 1, Page(s) 4267

Abstract: Mutations in genes that confer a selective advantage to hematopoietic stem cells (HSCs) drive clonal hematopoiesis (CH). While some CH drivers have been identified, the compendium of all genes able to drive CH upon mutations in HSCs remains incomplete. ... ...

Abstract	Mutations in genes that confer a selective advantage to hematopoietic stem cells (HSCs) drive clonal hematopoiesis (CH). While some CH drivers have been identified, the compendium of all genes able to drive CH upon mutations in HSCs remains incomplete. Exploiting signals of positive selection in blood somatic mutations may be an effective way to identify CH driver genes, analogously to cancer. Using the tumor sample in blood/tumor pairs as reference, we identify blood somatic mutations across more than 12,000 donors from two large cancer genomics cohorts. The application of IntOGen, a driver discovery pipeline, to both cohorts, and more than 24,000 targeted sequenced samples yields a list of close to 70 genes with signals of positive selection in CH, available at http://www.intogen.org/ch . This approach recovers known CH genes, and discovers other candidates.
MeSH term(s)	Clonal Hematopoiesis/genetics ; Hematopoiesis/genetics ; Hematopoietic Stem Cells ; Humans ; Mutation ; Neoplasms/genetics
Language	English
Publishing date	2022-07-23
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-022-31878-0
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Article: Identification of Clonal Hematopoiesis Driver Mutations through In Silico Saturation Mutagenesis.

Demajo, Santiago / Ramis-Zaldivar, Joan Enric / Muiños, Ferran / Grau, Miguel L / Andrianova, Maria / López-Bigas, Núria / González-Pérez, Abel

medRxiv : the preprint server for health sciences

2023

Abstract: Clonal hematopoiesis (CH) is a phenomenon of clonal expansion of hematopoietic stem cells driven by somatic mutations affecting certain genes. Recently, CH has been linked to the development of a number of hematologic malignancies, cardiovascular ... ...

Abstract	Clonal hematopoiesis (CH) is a phenomenon of clonal expansion of hematopoietic stem cells driven by somatic mutations affecting certain genes. Recently, CH has been linked to the development of a number of hematologic malignancies, cardiovascular diseases and other conditions. Although the most frequently mutated CH driver genes have been identified, a systematic landscape of the mutations capable of initiating this phenomenon is still lacking. Here, we train high-quality machine-learning models for 12 of the most recurrent CH driver genes to identify their driver mutations. These models outperform an experimental base-editing approach and expert-curated rules based on prior knowledge of the function of these genes. Moreover, their application to identify CH driver mutations across almost half a million donors of the UK Biobank reproduces known associations between CH driver mutations and age, and the prevalence of several diseases and conditions. We thus propose that these models support the accurate identification of CH across healthy individuals.
Language	English
Publishing date	2023-12-14
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.12.13.23299893
Database	MEDical Literature Analysis and Retrieval System OnLINE

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