Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 17 de 17
Filtrar
1.
Hum Mol Genet ; 31(20): 3558-3565, 2022 10 10.
Artículo en Inglés | MEDLINE | ID: mdl-35717579

RESUMEN

Although multiple common susceptibility loci for lung cancer (LC) have been identified by genome-wide association studies, they can explain only a small portion of heritability. The etiological contribution of rare deleterious variants (RDVs) to LC risk is not fully characterized and may account for part of the missing heritability. Here, we sequenced the whole exomes of 2777 participants from the Environment and Genetics in Lung cancer Etiology study, a homogenous population including 1461 LC cases and 1316 controls. In single-variant analyses, we identified a new RDV, rs77187983 [EHBP1, odds ratio (OR) = 3.13, 95% confidence interval (CI) = 1.34-7.30, P = 0.008] and replicated two previously reported RDVs, rs11571833 (BRCA2, OR = 2.18; 95% CI = 1.25-3.81, P = 0.006) and rs752672077 (MPZL2, OR = 3.70, 95% CI = 1.04-13.15, P = 0.044). In gene-based analyses, we confirmed BRCA2 (P = 0.007) and ATM (P = 0.014) associations with LC risk and identified TRIB3 (P = 0.009), involved in maintaining genome stability and DNA repair, as a new candidate susceptibility gene. Furthermore, cases were enriched with RDVs in homologous recombination repair [carrier frequency (CF) = 22.9% versus 19.5%, P = 0.017] and Fanconi anemia (CF = 12.5% versus 10.2%, P = 0.036) pathways. Our results were not significant after multiple testing corrections but were enriched in cases versus controls from large scale public biobank resources, including The Cancer Genome Atlas, FinnGen and UK Biobank. Our study identifies novel candidate genes and highlights the importance of RDVs in DNA repair-related genes for LC susceptibility. These findings improve our understanding of LC heritability and may contribute to the development of risk stratification and prevention strategies.


Asunto(s)
Estudio de Asociación del Genoma Completo , Neoplasias Pulmonares , Reparación del ADN/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo/métodos , Células Germinativas , Humanos , Neoplasias Pulmonares/genética
4.
medRxiv ; 2024 May 17.
Artículo en Inglés | MEDLINE | ID: mdl-38798417

RESUMEN

Lung cancer in never smokers (LCINS) accounts for up to 25% of all lung cancers and has been associated with exposure to secondhand tobacco smoke and air pollution in observational studies. Here, we evaluate the mutagenic exposures in LCINS by examining deep whole-genome sequencing data from a large international cohort of 871 treatment-naïve LCINS recruited from 28 geographical locations within the Sherlock-Lung study. KRAS mutations were 3.8-fold more common in adenocarcinomas of never smokers from North America and Europe, while a 1.6-fold higher prevalence of EGFR and TP53 mutations was observed in adenocarcinomas from East Asia. Signature SBS40a, with unknown cause, was found in most samples and accounted for the largest proportion of single base substitutions in adenocarcinomas, being enriched in EGFR-mutated cases. Conversely, the aristolochic acid signature SBS22a was almost exclusively observed in patients from Taipei. Even though LCINS exposed to secondhand smoke had an 8.3% higher mutational burden and 5.4% shorter telomeres, passive smoking was not associated with driver mutations in cancer driver genes or the activities of individual mutational signatures. In contrast, patients from regions with high levels of air pollution were more likely to have TP53 mutations while exhibiting shorter telomeres and an increase in most types of somatic mutations, including a 3.9-fold elevation of signature SBS4 (q-value=3.1 × 10-5), previously linked mainly to tobacco smoking, and a 76% increase of clock-like signature SBS5 (q-value=5.0 × 10-5). A positive dose-response effect was observed with air pollution levels, which correlated with both a decrease in telomere length and an elevation in somatic mutations, notably attributed to signatures SBS4 and SBS5. Our results elucidate the diversity of mutational processes shaping the genomic landscape of lung cancer in never smokers.

5.
bioRxiv ; 2024 Apr 03.
Artículo en Inglés | MEDLINE | ID: mdl-38617360

RESUMEN

APOBEC enzymes are part of the innate immunity and are responsible for restricting viruses and retroelements by deaminating cytosine residues1,2. Most solid tumors harbor different levels of somatic mutations attributed to the off-target activities of APOBEC3A (A3A) and/or APOBEC3B (A3B)3-6. However, how APOBEC3A/B enzymes shape the tumor evolution in the presence of exogenous mutagenic processes is largely unknown. Here, by combining deep whole-genome sequencing with multi-omics profiling of 309 lung cancers from smokers with detailed tobacco smoking information, we identify two subtypes defined by low (LAS) and high (HAS) APOBEC mutagenesis. LAS are enriched for A3B-like mutagenesis and KRAS mutations, whereas HAS for A3A-like mutagenesis and TP53 mutations. Unlike APOBEC3A, APOBEC3B expression is strongly associated with an upregulation of the base excision repair pathway. Hypermutation by unrepaired A3A and tobacco smoking mutagenesis combined with TP53-induced genomic instability can trigger senescence7, apoptosis8, and cell regeneration9, as indicated by high expression of pulmonary healing signaling pathway, stemness markers and distal cell-of-origin in HAS. The expected association of tobacco smoking variables (e.g., time to first cigarette) with genomic/epigenomic changes are not observed in HAS, a plausible consequence of frequent cell senescence or apoptosis. HAS have more neoantigens, slower clonal expansion, and older age at onset compared to LAS, particularly in heavy smokers, consistent with high proportions of newly generated, unmutated cells and frequent immuno-editing. These findings show how heterogeneity in mutational burden across co-occurring mutational processes and cell types contributes to tumor development, with important clinical implications.

6.
Cancers (Basel) ; 14(4)2022 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-35205708

RESUMEN

Lung cancer is the major leading cause of cancer-related mortality worldwide. Multiple epigenetic factors-in particular, DNA methylation-have been associated with the development of lung cancer. In this review, we summarize the current knowledge on DNA methylation alterations in lung tumorigenesis, as well as their associations with different histological subtypes, common cancer driver gene mutations (e.g., KRAS, EGFR, and TP53), and major epidemiological risk factors (e.g., sex, smoking status, race/ethnicity). Understanding the mechanisms of DNA methylation regulation and their associations with various risk factors can provide further insights into carcinogenesis, and create future avenues for prevention and personalized treatments. In addition, we also highlight outstanding questions regarding DNA methylation in lung cancer to be elucidated in future studies.

7.
Sci Rep ; 12(1): 12696, 2022 07 26.
Artículo en Inglés | MEDLINE | ID: mdl-35882937

RESUMEN

Despite recent advances in therapy, multiple myeloma essentially remains an incurable malignancy. Targeting tumour-specific essential genes, which constitute a druggable dependency, potentially offers a strategy for developing new therapeutic agents to treat MM and overcome drug resistance. To explore this possibility, we analysed DepMap project data identifying 23 MM essential genes and examined the relationship between their expression and patient outcome in three independent series totalling 1503 cases. The expression of TCF3 and FLVCR1 were both significantly associated with progression-free survival. IKBKB is already a drug target in other diseases, offering the prospect of repurposing to treat MM, while PIM2 is currently being investigated as a treatment for the disease. Our analysis supports the rationale of using large-scale genetic perturbation screens to guide the development of new therapeutic agents for MM.


Asunto(s)
Antineoplásicos , Mieloma Múltiple , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Desarrollo de Medicamentos , Humanos , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/genética , Mieloma Múltiple/patología
8.
Blood Cancer J ; 11(11): 177, 2021 11 09.
Artículo en Inglés | MEDLINE | ID: mdl-34753926

RESUMEN

To obtain a comprehensive picture of composite genetic driver events and clonal dynamics in subtypes of paediatric acute lymphoblastic leukaemia (ALL) we analysed tumour-normal whole genome sequencing and expression data from 361 newly diagnosed patients. We report the identification of both structural drivers, as well as recurrent non-coding variation in promoters. Additionally we found the transcriptional profile of histone gene cluster 1 and CTCF altered tumours shared hallmarks of hyperdiploid ALL suggesting a 'hyperdiploid like' subtype. ALL subtypes are driven by distinct mutational processes with AID mutagenesis being confined to ETV6-RUNX1 tumours. Subclonality is a ubiquitous feature of ALL, consistent with Darwinian evolution driving selection and expansion of tumours. Driver mutations in B-cell developmental genes (IKZF1, PAX5, ZEB2) tend to be clonal and RAS/RTK mutations subclonal. In addition to identifying new avenues for therapeutic exploitation, this analysis highlights that targeted therapies should take into account composite mutational profile and clonality.


Asunto(s)
Familia de Multigenes , Mutación , Proteínas de Neoplasias/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Masculino
9.
Nat Genet ; 53(9): 1348-1359, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34493867

RESUMEN

Lung cancer in never smokers (LCINS) is a common cause of cancer mortality but its genomic landscape is poorly characterized. Here high-coverage whole-genome sequencing of 232 LCINS showed 3 subtypes defined by copy number aberrations. The dominant subtype (piano), which is rare in lung cancer in smokers, features somatic UBA1 mutations, germline AR variants and stem cell-like properties, including low mutational burden, high intratumor heterogeneity, long telomeres, frequent KRAS mutations and slow growth, as suggested by the occurrence of cancer drivers' progenitor cells many years before tumor diagnosis. The other subtypes are characterized by specific amplifications and EGFR mutations (mezzo-forte) and whole-genome doubling (forte). No strong tobacco smoking signatures were detected, even in cases with exposure to secondhand tobacco smoke. Genes within the receptor tyrosine kinase-Ras pathway had distinct impacts on survival; five genomic alterations independently doubled mortality. These findings create avenues for personalized treatment in LCINS.


Asunto(s)
Variaciones en el Número de Copia de ADN/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , No Fumadores/estadística & datos numéricos , Adulto , Anciano , Anciano de 80 o más Años , Receptores ErbB/genética , Femenino , Genoma/genética , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Persona de Mediana Edad , Células Madre Neoplásicas/patología , Proteínas Proto-Oncogénicas p21(ras)/genética , Receptores Androgénicos/genética , Factores de Riesgo , Fumar/genética , Enzimas Activadoras de Ubiquitina/genética , Secuenciación Completa del Genoma , Adulto Joven
10.
Blood Cancer J ; 10(10): 101, 2020 10 14.
Artículo en Inglés | MEDLINE | ID: mdl-33057009

RESUMEN

Most patients with multiple myeloma (MM) die from progressive disease after relapse. To advance our understanding of MM evolution mechanisms, we performed whole-genome sequencing of 80 IGH-translocated tumour-normal newly diagnosed pairs and 24 matched relapsed tumours from the Myeloma XI trial. We identify multiple events as potentially important for survival and therapy-resistance at relapse including driver point mutations (e.g., TET2), translocations (MAP3K14), lengthened telomeres, and increased genomic instability (e.g., 17p deletions). Despite heterogeneous mutational processes contributing to relapsed mutations across MM subtypes, increased AID/APOBEC activity is particularly associated with shorter progression time to relapse, and contributes to higher mutational burden at relapse. In addition, we identify three enhanced major clonal evolution patterns of MM relapse, independent of treatment strategies and molecular karyotypes, questioning the viability of "evolutionary herding" approach in treating drug-resistant MM. Our data show that MM relapse is associated with acquisition of new mutations and clonal selection, and suggest APOBEC enzymes among potential targets for therapy-resistant MM.


Asunto(s)
Deleción Cromosómica , Cromosomas Humanos Par 17/genética , Modelos Genéticos , Mieloma Múltiple/genética , Proteínas de Neoplasias/genética , Mutación Puntual , Translocación Genética , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Recurrencia
11.
Blood Cancer J ; 9(8): 60, 2019 08 06.
Artículo en Inglés | MEDLINE | ID: mdl-31387987

RESUMEN

To gain insight into multiple myeloma (MM) tumorigenesis, we analyzed the mutational signatures in 874 whole-exome and 850 whole-genome data from the CoMMpass Study. We identified that coding and non-coding regions are differentially dominated by distinct single-nucleotide variant (SNV) mutational signatures, as well as five de novo structural rearrangement signatures. Mutational signatures reflective of different principle mutational processes-aging, defective DNA repair, and apolipoprotein B editing complex (APOBEC)/activation-induced deaminase activity-characterize MM. These mutational signatures show evidence of subgroup specificity-APOBEC-attributed signatures associated with MAF translocation t(14;16) and t(14;20) MM; potentially DNA repair deficiency with t(11;14) and t(4;14); and aging with hyperdiploidy. Mutational signatures beyond that associated with APOBEC are independent of established prognostic markers and appear to have relevance to predicting high-risk MM.


Asunto(s)
Mieloma Múltiple/genética , Mutación , Desaminasas APOBEC/genética , Análisis Mutacional de ADN , Humanos , Mieloma Múltiple/metabolismo , Mieloma Múltiple/patología , Pronóstico , Proteínas Proto-Oncogénicas c-maf/genética , Tasa de Supervivencia , Transcriptoma , Translocación Genética , Secuenciación del Exoma/métodos , Secuenciación Completa del Genoma/métodos
12.
Blood Adv ; 3(1): 21-32, 2019 01 08.
Artículo en Inglés | MEDLINE | ID: mdl-30606723

RESUMEN

The identification of driver mutations is fundamental to understanding oncogenesis. Although genes frequently mutated in B-cell lymphoma have been identified, the search for driver mutations has largely focused on the coding genome. Here we report an analysis of the noncoding genome using whole-genome sequencing data from 117 patients with B-cell lymphoma. Using promoter capture Hi-C data in naive B cells, we define cis-regulatory elements, which represent an enriched subset of the noncoding genome in which to search for driver mutations. Regulatory regions were identified whose mutation significantly alters gene expression, including copy number variation at cis-regulatory elements targeting CD69, IGLL5, and MMP14, and single nucleotide variants in a cis-regulatory element for TPRG1 We also show the commonality of pathways targeted by coding and noncoding mutations, exemplified by MMP14, which regulates Notch signaling, a pathway important in lymphomagenesis and whose expression is associated with patient survival. This study provides an enhanced understanding of lymphomagenesis and describes the advantages of using chromosome conformation capture to decipher noncoding mutations relevant to cancer biology.


Asunto(s)
Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Linfoma de Células B/genética , Mutación , ARN no Traducido/genética , Biología Computacional/métodos , Variaciones en el Número de Copia de ADN , Bases de Datos Genéticas , Amplificación de Genes , Regulación Neoplásica de la Expresión Génica , Estudios de Asociación Genética/métodos , Humanos , Linfoma de Células B/mortalidad , Linfoma de Células B/patología , Sistemas de Lectura Abierta , Regiones Promotoras Genéticas , Secuenciación Completa del Genoma
14.
Leukemia ; 32(11): 2459-2470, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-29654271

RESUMEN

Multiple myeloma (MM) is a biologically heterogeneous malignancy, however, the mechanisms underlying this complexity are incompletely understood. We report an analysis of the whole-genome sequencing of 765 MM patients from CoMMpass. By employing promoter capture Hi-C in naïve B-cells, we identify cis-regulatory elements (CREs) that represent a highly enriched subset of the non-coding genome in which to search for driver mutations. We identify regulatory regions whose mutation significantly alters the expression of genes as candidate non-coding drivers, including copy number variation (CNV) at CREs of MYC and single-nucleotide variants (SNVs) in a PAX5 enhancer. To better inform the interplay between non-coding driver mutations with other driver mechanisms, and their respective roles in oncogenic pathways, we extended our analysis identifying coding drivers in 40 genes, including 11 novel candidates. We demonstrate the same pathways can be targeted by coding and non-coding mutations; exemplified by IRF4 and PRDM1, along with BCL6 and PAX5, genes that are central to plasma cell differentiation. This study reveals new insights into the complex genetic alterations driving MM development and an enhanced understanding of oncogenic pathways.


Asunto(s)
Mieloma Múltiple/genética , Oncogenes/genética , Adulto , Anciano , Anciano de 80 o más Años , Carcinogénesis/genética , Diferenciación Celular/genética , Variaciones en el Número de Copia de ADN/genética , Femenino , Genoma Humano/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Masculino , Persona de Mediana Edad , Mutación/genética , Polimorfismo de Nucleótido Simple/genética , Regiones Promotoras Genéticas/genética , Secuencias Reguladoras de Ácidos Nucleicos/genética , Secuenciación Completa del Genoma/métodos
15.
Cell Rep ; 20(11): 2556-2564, 2017 Sep 12.
Artículo en Inglés | MEDLINE | ID: mdl-28903037

RESUMEN

Multiple myeloma (MM) is a malignancy of plasma cells. Genome-wide association studies have shown that variation at 5q15 influences MM risk. Here, we have sought to decipher the causal variant at 5q15 and the mechanism by which it influences tumorigenesis. We show that rs6877329 G > C resides in a predicted enhancer element that physically interacts with the transcription start site of ELL2. The rs6877329-C risk allele is associated with reduced enhancer activity and lowered ELL2 expression. Since ELL2 is critical to the B cell differentiation process, reduced ELL2 expression is consistent with inherited genetic variation contributing to arrest of plasma cell development, facilitating MM clonal expansion. These data provide evidence for a biological mechanism underlying a hereditary risk of MM at 5q15.


Asunto(s)
Cromosomas Humanos Par 5/genética , Elementos de Facilitación Genéticos , Predisposición Genética a la Enfermedad , Mieloma Múltiple/genética , Polimorfismo de Nucleótido Simple/genética , Factores de Elongación Transcripcional/genética , Alelos , Diploidia , Epigénesis Genética , Epigenómica , Sitios Genéticos , Humanos , Proteínas Nucleares/metabolismo , Mapeo Físico de Cromosoma , Pronóstico , Unión Proteica , Factores de Riesgo , Elongación de la Transcripción Genética , Respuesta de Proteína Desplegada/genética
17.
Oncotarget ; 9(88): 35801-35802, 2018 Nov 09.
Artículo en Inglés | MEDLINE | ID: mdl-30533192
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA