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1.
Clin Epigenetics ; 15(1): 7, 2023 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-36639817

RESUMO

BACKGROUND: Accurate regulation of DNA methylation is necessary for normal cells to differentiate, develop and function. TET2 catalyzes stepwise DNA demethylation in hematopoietic cells. Mutations in the TET2 gene predispose to hematological malignancies by causing DNA methylation overload and aberrant epigenomic landscape. Studies on mice and cell lines show that the function of TET2 is boosted by vitamin C. Thus, by strengthening the demethylation activity of TET2, vitamin C could play a role in the prevention of hematological malignancies in individuals with TET2 dysfunction. We recently identified a family with lymphoma predisposition where a heterozygous truncating germline mutation in TET2 segregated with nodular lymphocyte-predominant Hodgkin lymphoma. The mutation carriers displayed a hypermethylation pattern that was absent in the family members without the mutation. METHODS: In a clinical trial of 1 year, we investigated the effects of oral 1 g/day vitamin C supplementation on DNA methylation by analyzing genome-wide DNA methylation and gene expression patterns from the family members. RESULTS: We show that vitamin C reinforces the DNA demethylation cascade, reduces the proportion of hypermethylated loci and diminishes gene expression differences between TET2 mutation carriers and control individuals. CONCLUSIONS: These results suggest that vitamin C supplementation increases DNA methylation turnover and provide a basis for further work to examine the potential benefits of vitamin C supplementation in individuals with germline and somatic TET2 mutations. TRIAL REGISTRATION: This trial was registered at EudraCT with reference number of 2018-000155-41 (01.04.2019).


Assuntos
Ácido Ascórbico , Proteínas de Ligação a DNA , Dioxigenases , Neoplasias Hematológicas , Ácido Ascórbico/uso terapêutico , Dioxigenases/genética , Desmetilação do DNA , Metilação de DNA , Proteínas de Ligação a DNA/genética , Mutação em Linhagem Germinativa , Neoplasias Hematológicas/genética , Mutação , Vitaminas/uso terapêutico , Humanos
2.
Hum Mol Genet ; 32(7): 1063-1071, 2023 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-36048862

RESUMO

Precision medicine carries great potential for management of all tumor types. The aim of this retrospective study was to investigate if the two most common genetically distinct uterine fibroid subclasses, driven by aberrations in MED12 and HMGA2 genes, respectively, influence response to treatment with the progesterone receptor modulator ulipristal acetate. Changes in diameter and mutation status were derived for 101 uterine fibroids surgically removed after ulipristal acetate treatment. A significant difference in treatment response between the two major subclasses was detected. MED12 mutant fibroids had 4.4 times higher odds of shrinking in response to ulipristal acetate treatment as compared to HMGA2 driven fibroids (95% confidence interval 1.37-13.9; P = 0.013), and in a multivariate analysis molecular subclassification was an independent predictive factor. Compatible with this finding, gene expression and DNA methylation analyses revealed subclass specific differences in progesterone receptor signaling. The work provides a proof-of-principle that uterine fibroid treatment response is influenced by molecular subclass and that the genetic subclasses should be taken into account when evaluating current and future uterine fibroid therapies.


Assuntos
Leiomioma , Neoplasias Uterinas , Feminino , Humanos , Neoplasias Uterinas/tratamento farmacológico , Neoplasias Uterinas/genética , Neoplasias Uterinas/patologia , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismo , Estudos Retrospectivos , Leiomioma/tratamento farmacológico , Leiomioma/genética , Leiomioma/patologia , Fatores de Transcrição
3.
Nat Genet ; 54(3): 283-294, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35190730

RESUMO

DNA can determine where and when genes are expressed, but the full set of sequence determinants that control gene expression is unknown. Here, we measured the transcriptional activity of DNA sequences that represent an ~100 times larger sequence space than the human genome using massively parallel reporter assays (MPRAs). Machine learning models revealed that transcription factors (TFs) generally act in an additive manner with weak grammar and that most enhancers increase expression from a promoter by a mechanism that does not appear to involve specific TF-TF interactions. The enhancers themselves can be classified into three types: classical, closed chromatin and chromatin dependent. We also show that few TFs are strongly active in a cell, with most activities being similar between cell types. Individual TFs can have multiple gene regulatory activities, including chromatin opening and enhancing, promoting and determining transcription start site (TSS) activity, consistent with the view that the TF binding motif is the key atomic unit of gene expression.


Assuntos
Sequências Reguladoras de Ácido Nucleico , Fatores de Transcrição , Sítios de Ligação/genética , Genoma Humano/genética , Humanos , Ligação Proteica , Sequências Reguladoras de Ácido Nucleico/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
4.
J Med Genet ; 59(7): 644-651, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-34281993

RESUMO

BACKGROUND: Genes involved in epigenetic regulation are central for chromatin structure and gene expression. Specific mutations in these might promote carcinogenesis in several tissue types. METHODS: We used exome, whole-genome and Sanger sequencing to detect rare variants shared by seven affected individuals in a striking early-onset multi-cancer family. The only variant that segregated with malignancy resided in a histone demethylase KDM4C. Consequently, we went on to study the epigenetic landscape of the mutation carriers with ATAC, ChIP (chromatin immunoprecipitation) and RNA-sequencing from lymphoblastoid cell lines to identify possible pathogenic effects. RESULTS: A novel variant in KDM4C, encoding a H3K9me3 histone demethylase and transcription regulator, was found to segregate with malignancy in the family. Based on Roadmap Epigenomics Project data, differentially accessible chromatin regions between the variant carriers and controls enrich to normally H3K9me3-marked chromatin. We could not detect a difference in global H3K9 trimethylation levels. However, carriers of the variant seemed to have more trimethylated H3K9 at transcription start sites. Pathway analyses of ChIP-seq and differential gene expression data suggested that genes regulated through KDM4C interaction partner EZH2 and its interaction partner PLZF are aberrantly expressed in mutation carriers. CONCLUSIONS: The apparent dysregulation of H3K9 trimethylation and KDM4C-associated genes in lymphoblastoid cells supports the hypothesis that the KDM4C variant is causative of the multi-cancer susceptibility in the family. As the variant is ultrarare, located in the conserved catalytic JmjC domain and predicted pathogenic by the majority of available in silico tools, further studies on the role of KDM4C in cancer predisposition are warranted.


Assuntos
Histona Desmetilases , Histona Desmetilases com o Domínio Jumonji , Neoplasias , Cromatina/genética , Epigênese Genética , Células Germinativas/metabolismo , Células Germinativas/patologia , Histona Desmetilases/genética , Histonas/genética , Histonas/metabolismo , Humanos , Histona Desmetilases com o Domínio Jumonji/química , Histona Desmetilases com o Domínio Jumonji/genética , Histona Desmetilases com o Domínio Jumonji/metabolismo , Neoplasias/genética , Fenótipo
5.
Nat Commun ; 12(1): 5448, 2021 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-34521855

RESUMO

Mechanical forces in a constrained cellular environment were recently established as a facilitator of chromosomal damage. Whether this could contribute to tumorigenesis is not known. Uterine leiomyomas are common neoplasms that display relatively few chromosomal aberrations. We hypothesized that if mechanical forces contribute to chromosomal damage, signs of this could be seen in uterine leiomyomas from parous women. We examined the karyotypes of 1946 tumors, and found a striking overrepresentation of chromosomal damage associated with parity. We then subjected myometrial cells to physiological forces similar to those encountered during pregnancy, and found this to cause DNA breaks and a DNA repair response. While mechanical forces acting in constrained cellular environments may thus contribute to neoplastic degeneration, and genesis of uterine leiomyoma, further studies are needed to prove possible causality of the observed association. No evidence for progression to malignancy was found.


Assuntos
Aberrações Cromossômicas , Reparo do DNA , Leiomioma/genética , Complexo Mediador/genética , Paridade , Neoplasias Uterinas/genética , Adulto , Fenômenos Biomecânicos , Quebras de DNA de Cadeia Dupla , Feminino , Expressão Gênica , Humanos , Histerectomia , Cariótipo , Leiomioma/etiologia , Leiomioma/patologia , Leiomioma/cirurgia , Mutação , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Miométrio/metabolismo , Miométrio/patologia , Gravidez , Cultura Primária de Células , Estudos Prospectivos , Neoplasias Uterinas/etiologia , Neoplasias Uterinas/patologia , Neoplasias Uterinas/cirurgia
6.
Nature ; 596(7872): 398-403, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34349258

RESUMO

One in four women suffers from uterine leiomyomas (ULs)-benign tumours of the uterine wall, also known as uterine fibroids-at some point in premenopausal life. ULs can cause excessive bleeding, pain and infertility1, and are a common cause of hysterectomy2. They emerge through at least three distinct genetic drivers: mutations in MED12 or FH, or genomic rearrangement of HMGA23. Here we created genome-wide datasets, using DNA, RNA, assay for transposase-accessible chromatin (ATAC), chromatin immunoprecipitation (ChIP) and HiC chromatin immunoprecipitation (HiChIP) sequencing of primary tissues to profoundly understand the genesis of UL. We identified somatic mutations in genes encoding six members of the SRCAP histone-loading complex4, and found that germline mutations in the SRCAP members YEATS4 and ZNHIT1 predispose women to UL. Tumours bearing these mutations showed defective deposition of the histone variant H2A.Z. In ULs, H2A.Z occupancy correlated positively with chromatin accessibility and gene expression, and negatively with DNA methylation, but these correlations were weak in tumours bearing SRCAP complex mutations. In these tumours, open chromatin emerged at transcription start sites where H2A.Z was lost, which was associated with upregulation of genes. Furthermore, YEATS4 defects were associated with abnormal upregulation of bivalent embryonic stem cell genes, as previously shown in mice5. Our work describes a potential mechanism of tumorigenesis-epigenetic instability caused by deficient H2A.Z deposition-and suggests that ULs arise through an aberrant differentiation program driven by deranged chromatin, emanating from a small number of mutually exclusive driver mutations.


Assuntos
Montagem e Desmontagem da Cromatina , Cromatina/genética , Cromatina/metabolismo , Histonas/deficiência , Leiomioma/genética , Mutação , Neoplasias Uterinas/genética , Carcinogênese/genética , Linhagem Celular , Cromatina/química , Células-Tronco Embrionárias/metabolismo , Epigênese Genética , Feminino , Regulação Neoplásica da Expressão Gênica , Histonas/genética , Histonas/metabolismo , Humanos , Leiomioma/metabolismo , Leiomioma/patologia , Ligases/genética , Complexo Repressor Polycomb 1/genética , Proteínas do Grupo Polycomb/genética , Fatores de Transcrição/genética , Neoplasias Uterinas/metabolismo , Neoplasias Uterinas/patologia
7.
Hum Mol Genet ; 30(24): 2429-2440, 2021 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-34274970

RESUMO

Many hereditary cancer syndromes are associated with an increased risk of small and large intestinal adenocarcinomas. However, conditions bearing a high risk to both adenocarcinomas and neuroendocrine tumors are yet to be described. We studied a family with 16 individuals in four generations affected by a wide spectrum of intestinal tumors, including hyperplastic polyps, adenomas, small intestinal neuroendocrine tumors, and colorectal and small intestinal adenocarcinomas. To assess the genetic susceptibility and understand the novel phenotype, we utilized multiple molecular methods, including whole genome sequencing, RNA sequencing, single cell sequencing, RNA in situ hybridization and organoid culture. We detected a heterozygous deletion at the cystic fibrosis locus (7q31.2) perfectly segregating with the intestinal tumor predisposition in the family. The deletion removes a topologically associating domain border between CFTR and WNT2, aberrantly activating WNT2 in the intestinal epithelium. These consequences suggest that the deletion predisposes to small intestinal neuroendocrine tumors and small and large intestinal adenocarcinomas, and reveals the broad tumorigenic effects of aberrant WNT activation in the human intestine.


Assuntos
Adenocarcinoma , Adenoma , Neoplasias Colorretais , Tumores Neuroendócrinos , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adenoma/genética , Adenoma/patologia , Neoplasias Colorretais/genética , Humanos , Mucosa Intestinal/patologia , Tumores Neuroendócrinos/genética , Tumores Neuroendócrinos/patologia , Proteína Wnt2
8.
Nat Commun ; 10(1): 4022, 2019 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-31492840

RESUMO

Genomic instability pathways in colorectal cancer (CRC) have been extensively studied, but the role of retrotransposition in colorectal carcinogenesis remains poorly understood. Although retrotransposons are usually repressed, they become active in several human cancers, in particular those of the gastrointestinal tract. Here we characterize retrotransposon insertions in 202 colorectal tumor whole genomes and investigate their associations with molecular and clinical characteristics. We find highly variable retrotransposon activity among tumors and identify recurrent insertions in 15 known cancer genes. In approximately 1% of the cases we identify insertions in APC, likely to be tumor-initiating events. Insertions are positively associated with the CpG island methylator phenotype and the genomic fraction of allelic imbalance. Clinically, high number of insertions is independently associated with poor disease-specific survival.


Assuntos
Neoplasias Colorretais/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Elementos Nucleotídeos Longos e Dispersos/genética , Mutagênese Insercional , Idoso , Células CACO-2 , Carcinogênese/genética , Linhagem Celular Tumoral , Neoplasias Colorretais/patologia , Ilhas de CpG/genética , Metilação de DNA , Feminino , Instabilidade Genômica , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade
9.
Nat Commun ; 10(1): 2154, 2019 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-31089142

RESUMO

Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide, and has a strong heritable basis. We report a genome-wide association analysis of 34,627 CRC cases and 71,379 controls of European ancestry that identifies SNPs at 31 new CRC risk loci. We also identify eight independent risk SNPs at the new and previously reported European CRC loci, and a further nine CRC SNPs at loci previously only identified in Asian populations. We use in situ promoter capture Hi-C (CHi-C), gene expression, and in silico annotation methods to identify likely target genes of CRC SNPs. Whilst these new SNP associations implicate target genes that are enriched for known CRC pathways such as Wnt and BMP, they also highlight novel pathways with no prior links to colorectal tumourigenesis. These findings provide further insight into CRC susceptibility and enhance the prospects of applying genetic risk scores to personalised screening and prevention.


Assuntos
Neoplasias Colorretais/genética , Loci Gênicos , Predisposição Genética para Doença , Povo Asiático/genética , Estudos de Casos e Controles , Neoplasias Colorretais/patologia , Conjuntos de Dados como Assunto , Feminino , Estudo de Associação Genômica Ampla , Humanos , Padrões de Herança , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco , População Branca/genética
10.
Nat Commun ; 10(1): 1252, 2019 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-30890702

RESUMO

Clonal hematopoiesis driven by somatic heterozygous TET2 loss is linked to malignant degeneration via consequent aberrant DNA methylation, and possibly to cardiovascular disease via increased cytokine and chemokine expression as reported in mice. Here, we discover a germline TET2 mutation in a lymphoma family. We observe neither unusual predisposition to atherosclerosis nor abnormal pro-inflammatory cytokine or chemokine expression. The latter finding is confirmed in cells from three additional unrelated TET2 germline mutation carriers. The TET2 defect elevates blood DNA methylation levels, especially at active enhancers and cell-type specific regulatory regions with binding sequences of master transcription factors involved in hematopoiesis. The regions display reduced methylation relative to all open chromatin regions in four DNMT3A germline mutation carriers, potentially due to TET2-mediated oxidation. Our findings provide insight into the interplay between epigenetic modulators and transcription factor activity in hematological neoplasia, but do not confirm the putative role of TET2 in atherosclerosis.


Assuntos
Aterosclerose/genética , Metilação de DNA/genética , Proteínas de Ligação a DNA/genética , Haploinsuficiência , Doença de Hodgkin/genética , Proteínas Proto-Oncogênicas/genética , Adulto , Aterosclerose/patologia , Células Cultivadas , DNA (Citosina-5-)-Metiltransferases/genética , DNA (Citosina-5-)-Metiltransferases/metabolismo , DNA Metiltransferase 3A , Proteínas de Ligação a DNA/metabolismo , Dioxigenases , Epigênese Genética , Feminino , Finlândia , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Hematopoese/genética , Doença de Hodgkin/sangue , Doença de Hodgkin/patologia , Humanos , Masculino , Fenótipo , Cultura Primária de Células , Proteínas Proto-Oncogênicas/metabolismo , RNA Interferente Pequeno/metabolismo , Sequenciamento Completo do Genoma
11.
Fam Cancer ; 18(1): 113-119, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30097855

RESUMO

Angioimmunoblastic T-cell lymphoma (AITL) is a subtype of peripheral T-cell lymphoma with a poor prognosis: the 5-year survival rate is approximately 30%. Somatic driver mutations have been found in TET2, IDH2, DNMT3A, RHOA, FYN, PLCG1, and CD28, whereas germline susceptibility to AITL has to our knowledge not been studied. The homogenous Finnish population is well suited for studies on genetic predisposition. Here, we performed an exome-wide rare variant analysis in 23 AITL patients. No germline mutations were found in the driver genes, implying that they are not frequently involved in genetic AITL predisposition. Potentially pathogenic variants present in at least two patients and showing significant (p < 0.01) enrichment in our sample set were found in ten genes: POLK, PRKCB, ZNF676, PRRC2B, PCDHGB6, GNL3L, TTC36, OTOG, OSGEPL1, and RASSF9. The most significantly enriched variants, causing p.Lys469Ter in a splice variant of POLK and p.Pro588His in PRKCB, are intriguing candidates as Polk deficient mice display a spontaneous mutator phenotype, whereas PRKCB was recently shown to be somatically mutated in 33% of another peripheral T-cell lymphoma, adult T-cell lymphoma. If validated, our findings would provide new insight into the pathogenesis of AITL, as well as tools for early detection in susceptible individuals.


Assuntos
Análise Mutacional de DNA , Predisposição Genética para Doença , Linfoma de Células T Periférico/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Mutação em Linhagem Germinativa , Humanos , Linfoma de Células T Periférico/mortalidade , Masculino , Pessoa de Meia-Idade , Sequenciamento do Exoma
12.
Nat Protoc ; 13(11): 2580-2600, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30323186

RESUMO

Next-generation sequencing (NGS) is routinely applied in life sciences and clinical practice, but interpretation of the massive quantities of genomic data produced has become a critical challenge. The genome-wide mutation analyses enabled by NGS have had a revolutionary impact in revealing the predisposing and driving DNA alterations behind a multitude of disorders. The workflow to identify causative mutations from NGS data, for example in cancer and rare diseases, commonly involves phases such as quality filtering, case-control comparison, genome annotation, and visual validation, which require multiple processing steps and usage of various tools and scripts. To this end, we have introduced an interactive and user-friendly multi-platform-compatible software, BasePlayer, which allows scientists, regardless of bioinformatics training, to carry out variant analysis in disease genetics settings. A genome-wide scan of regulatory regions for mutation clusters can be carried out with a desktop computer in ~10 min with a dataset of 3 million somatic variants in 200 whole-genome-sequenced (WGS) cancers.


Assuntos
Análise Mutacional de DNA/métodos , DNA de Neoplasias/genética , Genoma Humano , Mutação , Neoplasias/genética , Software , Sequência de Bases , Biologia Computacional , DNA Intergênico , Exoma , Genética Médica/métodos , Sequenciamento de Nucleotídeos em Larga Escala/estatística & dados numéricos , Humanos , Neoplasias/diagnóstico , Neoplasias/patologia , Sequenciamento Completo do Genoma
13.
Nat Commun ; 9(1): 3664, 2018 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-30202008

RESUMO

Point mutations in cancer have been extensively studied but chromosomal gains and losses have been more challenging to interpret due to their unspecific nature. Here we examine high-resolution allelic imbalance (AI) landscape in 1699 colorectal cancers, 256 of which have been whole-genome sequenced (WGSed). The imbalances pinpoint 38 genes as plausible AI targets based on previous knowledge. Unbiased CRISPR-Cas9 knockout and activation screens identified in total 79 genes within AI peaks regulating cell growth. Genetic and functional data implicate loss of TP53 as a sufficient driver of AI. The WGS highlights an influence of copy number aberrations on the rate of detected somatic point mutations. Importantly, the data reveal several associations between AI target genes, suggesting a role for a network of lineage-determining transcription factors in colorectal tumorigenesis. Overall, the results unravel the contribution of AI in colorectal cancer and provide a plausible explanation why so few genes are commonly affected by point mutations in cancers.


Assuntos
Desequilíbrio Alélico , Neoplasias Colorretais/genética , Predisposição Genética para Doença , Sistemas CRISPR-Cas , Aberrações Cromossômicas , Cromossomos Humanos Par 8 , Neoplasias Colorretais/patologia , Variações do Número de Cópias de DNA , Dinamarca , Perfilação da Expressão Gênica , Genômica , Genótipo , Humanos , Perda de Heterozigosidade , Repetições de Microssatélites , Fenótipo , Mutação Puntual , Proteínas Proto-Oncogênicas p21(ras)/genética , RNA Interferente Pequeno/genética , Fatores de Transcrição/genética , Proteína Supressora de Tumor p53/genética , Sequenciamento Completo do Genoma
14.
Nature ; 562(7725): 76-81, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30250250

RESUMO

Nucleosomes cover most of the genome and are thought to be displaced by transcription factors in regions that direct gene expression. However, the modes of interaction between transcription factors and nucleosomal DNA remain largely unknown. Here we systematically explore interactions between the nucleosome and 220 transcription factors representing diverse structural families. Consistent with earlier observations, we find that the majority of the studied transcription factors have less access to nucleosomal DNA than to free DNA. The motifs recovered from transcription factors bound to nucleosomal and free DNA are generally similar. However, steric hindrance and scaffolding by the nucleosome result in specific positioning and orientation of the motifs. Many transcription factors preferentially bind close to the end of nucleosomal DNA, or to periodic positions on the solvent-exposed side of the DNA. In addition, several transcription factors usually bind to nucleosomal DNA in a particular orientation. Some transcription factors specifically interact with DNA located at the dyad position at which only one DNA gyre is wound, whereas other transcription factors prefer sites spanning two DNA gyres and bind specifically to each of them. Our work reveals notable differences in the binding of transcription factors to free and nucleosomal DNA, and uncovers a diverse interaction landscape between transcription factors and the nucleosome.


Assuntos
Nucleossomos/metabolismo , Fatores de Transcrição/metabolismo , Animais , Sequência de Bases , DNA/química , DNA/genética , DNA/metabolismo , Humanos , Camundongos , Modelos Moleculares , Nucleossomos/química , Nucleossomos/genética , Motivos de Nucleotídeos , Ligação Proteica , Rotação , Técnica de Seleção de Aptâmeros , Fatores de Transcrição/química , Fatores de Transcrição/classificação
15.
Elife ; 72018 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-30226466

RESUMO

Uterine leiomyomas (ULs) are benign tumors that are a major burden to women's health. A genome-wide association study on 15,453 UL cases and 392,628 controls was performed, followed by replication of the genomic risk in six cohorts. Effects of the risk alleles were evaluated in view of molecular and clinical characteristics. 22 loci displayed a genome-wide significant association. The likely predisposition genes could be grouped to two biological processes. Genes involved in genome stability were represented by TERT, TERC, OBFC1 - highlighting the role of telomere maintenance - TP53 and ATM. Genes involved in genitourinary development, WNT4, WT1, SALL1, MED12, ESR1, GREB1, FOXO1, DMRT1 and uterine stem cell marker antigen CD44, formed another strong subgroup. The combined risk contributed by the 22 loci was associated with MED12 mutation-positive tumors. The findings link genes for uterine development and genetic stability to leiomyomagenesis, and in part explain the more frequent occurrence of UL in women of African origin.


Assuntos
Loci Gênicos , Predisposição Genética para Doença , Instabilidade Genômica , Leiomioma/genética , Neoplasias Uterinas/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Morfogênese , Medição de Risco , Útero/crescimento & desenvolvimento
16.
EMBO Mol Med ; 10(9)2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30108113

RESUMO

Microsatellite instability (MSI) leads to accumulation of an excessive number of mutations in the genome, mostly small insertions and deletions. MSI colorectal cancers (CRCs), however, also contain more point mutations than microsatellite-stable (MSS) tumors, yet they have not been as comprehensively studied. To identify candidate driver genes affected by point mutations in MSI CRC, we ranked genes based on mutation significance while correcting for replication timing and gene expression utilizing an algorithm, MutSigCV Somatic point mutation data from the exome kit-targeted area from 24 exome-sequenced sporadic MSI CRCs and respective normals, and 12 whole-genome-sequenced sporadic MSI CRCs and respective normals were utilized. The top 73 genes were validated in 93 additional MSI CRCs. The MutSigCV ranking identified several well-established MSI CRC driver genes and provided additional evidence for previously proposed CRC candidate genes as well as shortlisted genes that have to our knowledge not been linked to CRC before. Two genes, SMARCB1 and STK38L, were also functionally scrutinized, providing evidence of a tumorigenic role, for SMARCB1 mutations in particular.


Assuntos
Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Instabilidade de Microssatélites , Mutação Puntual , Redes Reguladoras de Genes , Humanos , Anotação de Sequência Molecular , Análise de Sequência de DNA
17.
Br J Cancer ; 117(12): 1855-1864, 2017 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-29073636

RESUMO

BACKGROUND: Uterine leiomyomas can be classified into molecularly distinct subtypes according to their genetic triggers: MED12 mutations, HMGA2 upregulation, or inactivation of FH. The aim of this study was to identify metabolites and metabolic pathways that are dysregulated in different subtypes of leiomyomas. METHODS: We performed global metabolomic profiling of 25 uterine leiomyomas and 17 corresponding myometrium specimens using liquid chromatography-tandem mass spectroscopy. RESULTS: A total of 641 metabolites were detected. All leiomyomas displayed reduced homocarnosine and haeme metabolite levels. We identified a clearly distinct metabolomic profile for leiomyomas of the FH subtype, characterised by metabolic alterations in the tricarboxylic acid cycle and pentose phosphate pathways, and increased levels of multiple lipids and amino acids. Several metabolites were uniquely elevated in leiomyomas of the FH subtype, including N6-succinyladenosine and argininosuccinate, serving as potential biomarkers for FH deficiency. In contrast, leiomyomas of the MED12 subtype displayed reduced levels of vitamin A, multiple membrane lipids and amino acids, and dysregulation of vitamin C metabolism, a finding which was also compatible with gene expression data. CONCLUSIONS: The study reveals the metabolomic heterogeneity of leiomyomas and provides the requisite framework for strategies designed to target metabolic alterations promoting the growth of these prevalent tumours.


Assuntos
Leiomioma/metabolismo , Neoplasias Uterinas/genética , Neoplasias Uterinas/metabolismo , Adenosina/análogos & derivados , Adenosina/metabolismo , Aminoácidos/metabolismo , Ácido Argininossuccínico/metabolismo , Ácido Ascórbico/metabolismo , Ciclo do Ácido Cítrico , Feminino , Fumarato Hidratase/genética , Proteína HMGA2/genética , Humanos , Leiomioma/genética , Metabolismo dos Lipídeos , Complexo Mediador/genética , Redes e Vias Metabólicas , Metaboloma , Via de Pentose Fosfato , Vitamina A/metabolismo
18.
Eur J Cancer ; 84: 228-238, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28829991

RESUMO

BACKGROUND: While dietary fat has been established as a risk factor for colorectal cancer (CRC), associations between fatty acids (FAs) and CRC have been inconsistent. Using Mendelian randomisation (MR), we sought to evaluate associations between polyunsaturated (PUFA), monounsaturated (MUFA) and saturated FAs (SFAs) and CRC risk. METHODS: We analysed genotype data on 9254 CRC cases and 18,386 controls of European ancestry. Externally weighted polygenic risk scores were generated and used to evaluate associations with CRC per one standard deviation increase in genetically defined plasma FA levels. RESULTS: Risk reduction was observed for oleic and palmitoleic MUFAs (OROA = 0.77, 95% CI: 0.65-0.92, P = 3.9 × 10-3; ORPOA = 0.36, 95% CI: 0.15-0.84, P = 0.018). PUFAs linoleic and arachidonic acid had negative and positive associations with CRC respectively (ORLA = 0.95, 95% CI: 0.93-0.98, P = 3.7 × 10-4; ORAA = 1.05, 95% CI: 1.02-1.07, P = 1.7 × 10-4). The SFA stearic acid was associated with increased CRC risk (ORSA = 1.17, 95% CI: 1.01-1.35, P = 0.041). CONCLUSION: Results from our analysis are broadly consistent with a pro-inflammatory FA profile having a detrimental effect in terms of CRC risk.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Dieta/efeitos adversos , Ácidos Graxos/efeitos adversos , Mediadores da Inflamação/efeitos adversos , Polimorfismo de Nucleotídeo Único , Estudos de Casos e Controles , Neoplasias Colorretais/sangue , Neoplasias Colorretais/etnologia , Neoplasias Colorretais/prevenção & controle , Dieta Saudável , Dieta Mediterrânea , Ácidos Graxos/sangue , Interação Gene-Ambiente , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Mediadores da Inflamação/sangue , Análise da Randomização Mendeliana , Razão de Chances , Fenótipo , Fatores de Proteção , Medição de Risco , Fatores de Risco , Comportamento de Redução do Risco , População Branca/genética
19.
Cancer Res ; 77(15): 4078-4088, 2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28611049

RESUMO

Approximately 15% of colorectal cancers exhibit microsatellite instability (MSI), which leads to accumulation of large numbers of small insertions and deletions (indels). Genes that provide growth advantage to cells via loss-of-function mutations in microsatellites are called MSI target genes. Several criteria to define these genes have been suggested, one of them being simple mutation frequency. Microsatellite mutation rate, however, depends on the length and nucleotide context of the microsatellite. Therefore, assessing the general impact of mismatch repair deficiency on the likelihood of mutation events is paramount when following this approach. To identify MSI target genes, we developed a statistical model for the somatic background indel mutation rate of microsatellites to assess mutation significance. Exome sequencing data of 24 MSI colorectal cancers revealed indels at 54 million mononucleotide microsatellites of three or more nucleotides in length. The top 105 microsatellites from 71 genes were further analyzed in 93 additional MSI colorectal cancers. Mutation significance and estimated clonality of mutations determined the most likely MSI target genes to be the aminoadipate-semialdehyde dehydrogenase AASDH and the solute transporter SLC9A8 Our findings offer a systematic profiling of the somatic background mutation rate in protein-coding mononucleotide microsatellites, allowing a full cataloging of the true targets of MSI in colorectal cancer. Cancer Res; 77(15); 4078-88. ©2017 AACR.


Assuntos
Neoplasias Colorretais/genética , Análise Mutacional de DNA/métodos , Instabilidade de Microssatélites , Modelos Estatísticos , Humanos , Mutação
20.
Elife ; 62017 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-28583252

RESUMO

The gene desert upstream of the MYC oncogene on chromosome 8q24 contains susceptibility loci for several major forms of human cancer. The region shows high conservation between human and mouse and contains multiple MYC enhancers that are activated in tumor cells. However, the role of this region in normal development has not been addressed. Here we show that a 538 kb deletion of the entire MYC upstream super-enhancer region in mice results in 50% to 80% decrease in Myc expression in multiple tissues. The mice are viable and show no overt phenotype. However, they are resistant to tumorigenesis, and most normal cells isolated from them grow slowly in culture. These results reveal that only cells whose MYC activity is increased by serum or oncogenic driver mutations depend on the 8q24 super-enhancer region, and indicate that targeting the activity of this element is a promising strategy of cancer chemoprevention and therapy.


Assuntos
Elementos Facilitadores Genéticos , Proteínas Proto-Oncogênicas c-myc/biossíntese , Proteínas Proto-Oncogênicas c-myc/genética , Deleção de Sequência , Animais , Carcinogênese , Expressão Gênica , Camundongos , Camundongos Knockout
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