RESUMO
Colorectal carcinoma (CRC) is a common cause of mortality1, but a comprehensive description of its genomic landscape is lacking2-9. Here we perform whole-genome sequencing of 2,023 CRC samples from participants in the UK 100,000 Genomes Project, thereby providing a highly detailed somatic mutational landscape of this cancer. Integrated analyses identify more than 250 putative CRC driver genes, many not previously implicated in CRC or other cancers, including several recurrent changes outside the coding genome. We extend the molecular pathways involved in CRC development, define four new common subgroups of microsatellite-stable CRC based on genomic features and show that these groups have independent prognostic associations. We also characterize several rare molecular CRC subgroups, some with potential clinical relevance, including cancers with both microsatellite and chromosomal instability. We demonstrate a spectrum of mutational profiles across the colorectum, which reflect aetiological differences. These include the role of Escherichia colipks+ colibactin in rectal cancers10 and the importance of the SBS93 signature11-13, which suggests that diet or smoking is a risk factor. Immune-escape driver mutations14 are near-ubiquitous in hypermutant tumours and occur in about half of microsatellite-stable CRCs, often in the form of HLA copy number changes. Many driver mutations are actionable, including those associated with rare subgroups (for example, BRCA1 and IDH1), highlighting the role of whole-genome sequencing in optimizing patient care.
Assuntos
Neoplasias Colorretais , Genômica , Mutação , Humanos , Neoplasias Colorretais/genética , Feminino , Masculino , Instabilidade de Microssatélites , Sequenciamento Completo do Genoma , Prognóstico , Reino Unido/epidemiologia , Instabilidade Cromossômica/genética , Genoma Humano/genética , Variações do Número de Cópias de DNA/genética , Antígenos HLA/genéticaRESUMO
BACKGROUND: Although considerable effort has been put into decoding of the osteosarcoma genome, very little is known about germline mutations that underlie this primary malignant tumour of bone. METHODS AND RESULTS: We followed here a coincidental finding in a multiple endocrine neoplasia family in which a 32-year-old patient carrying a germline pathogenic RET mutation developed an osteosarcoma 2 years after the resection of a medullary thyroid carcinoma. Sequencing analysis of additional 336 patients with osteosarcoma led to the identification of germline activating mutations in the RET proto-oncogene in three cases and somatic amplifications of the gene locus in five matched tumours (4%, n=5/124 tumours). Functional analysis of the pathogenic variants together with an integrative analysis of osteosarcoma genomes confirmed that the mutant RET proteins couple functional kinase activity to dysfunctional ligand binding. RET mutations further co-operated with alterations in TP53 and RB1, suggesting that osteosarcoma pathogenesis bears reminiscence to the stepwise model of medullary thyroid carcinoma. CONCLUSIONS: After Li-Fraumeni-predisposing mutations in TP53, RET becomes the second most mutated cancer-predisposing gene in the germline of patients with osteosarcoma. Hence, early identification of RET mutation carriers can help to identify at-risk family members and carry out preventive measures.
Assuntos
Carcinoma Neuroendócrino/genética , Osteossarcoma/genética , Proteínas Proto-Oncogênicas c-ret/genética , Proteínas de Ligação a Retinoblastoma/genética , Neoplasias da Glândula Tireoide/genética , Proteína Supressora de Tumor p53/genética , Ubiquitina-Proteína Ligases/genética , Adulto , Idoso , Carcinoma Neuroendócrino/complicações , Carcinoma Neuroendócrino/epidemiologia , Carcinoma Neuroendócrino/patologia , Feminino , Predisposição Genética para Doença , Mutação em Linhagem Germinativa/genética , Humanos , Masculino , Osteossarcoma/complicações , Osteossarcoma/epidemiologia , Osteossarcoma/patologia , Pediatria , Proto-Oncogene Mas , Neoplasias da Glândula Tireoide/complicações , Neoplasias da Glândula Tireoide/epidemiologia , Neoplasias da Glândula Tireoide/patologiaRESUMO
BACKGROUND: Colorectal cancer (CRC) screening might be improved by using a measure of prior risk to modulate screening intensity or the faecal immunochemical test threshold. Intermediate molecular biomarkers could aid risk prediction by capturing both known and unknown risk factors. METHODS: We sampled normal bowel mucosa from the proximal colon, distal colon and rectum of 317 individuals undergoing colonoscopy. We defined cases as having a personal history of colorectal polyp(s)/cancer, and controls as having no history of colorectal neoplasia. Molecular analyses were performed for: telomere length (TL); global methylation; and the expression of genes in molecular pathways associated with colorectal tumourigenesis. We also calculated a polygenic risk score (PRS) based on CRC susceptibility polymorphisms. RESULTS: Bowel TL was significantly longer in cases than controls, but was not associated with blood TL. PRS was significantly and independently higher in cases. Hypermethylation showed a suggestive association with case:control status. No gene or pathway was differentially expressed between cases and controls. Gene expression often varied considerably between bowel locations. CONCLUSIONS: PRS and bowel TL (but not blood TL) may be clinically-useful predictors of CRC risk. Sample collection to assess these biomarkers is feasible in clinical practice, especially where population screening uses flexible sigmoidoscopy or colonoscopy.
Assuntos
Biomarcadores Tumorais/genética , Colo/química , Neoplasias Colorretais/diagnóstico , Reto/química , Homeostase do Telômero , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Colonoscopia , Neoplasias Colorretais/genética , Metilação de DNA , Detecção Precoce de Câncer , Feminino , Redes Reguladoras de Genes , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Adulto JovemRESUMO
Since the publication of this paper, the authors noticed that James E. East was assigned to the incorrect affiliation. The affiliation information is provided correctly, above.
RESUMO
PURPOSE: The molecular events that determine intestinal cell differentiation are poorly understood and it is unclear whether it is primarily a passive event or an active process. It is clinically important to gain a greater understanding of the process, because in colorectal cancer, the degree of differentiation of a tumor is associated with patient survival. SGK1 has previously been identified as a gene that is principally expressed in differentiated intestinal cells. In colorectal cancer, there is marked downregulation of SGK1 compared with normal tissue.Experimental Design: An inducible SGK1 viral overexpression system was utilized to induce reexpression of SGK1 in colorectal cancer cell lines. Transcriptomic and phenotypic analyses of these colorectal cancer lines was performed and validation in mouse and human cohorts was performed. RESULTS: We demonstrate that SGK1 is upregulated in response to, and an important controller of, intestinal cell differentiation. Reexpression of SGK1 in colorectal cancer cell lines results in features of differentiation, decreased migration rates, and inhibition of metastasis in an orthotopic xenograft model. These effects may be mediated, in part, by SGK1-induced PKP3 expression and increased degradation of MYC. CONCLUSIONS: Our results suggest that SGK1 is an important mediator of differentiation of colorectal cells and may inhibit colorectal cancer metastasis.
Assuntos
Neoplasias Colorretais/sangue , Neoplasias Colorretais/patologia , Proteínas Imediatamente Precoces/sangue , Proteínas Serina-Treonina Quinases/sangue , Animais , Biomarcadores Tumorais , Diferenciação Celular , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Modelos Animais de Doenças , Feminino , Expressão Gênica , Genes Reporter , Humanos , Proteínas Imediatamente Precoces/genética , Camundongos , Gradação de Tumores , Metástase Neoplásica , Prognóstico , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , RNA Mensageiro , Ratos , Transdução de Sinais , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Expression of the mismatch repair gene MutL homolog 1 (MLH1) is silenced in a clinically important subgroup of sporadic colorectal cancers. These cancers exhibit hypermutability with microsatellite instability (MSI) and differ from microsatellite-stable (MSS) colorectal cancers in both prognosis and response to therapies. Loss of MLH1 is usually due to epigenetic silencing with associated promoter methylation; coding somatic mutations rarely occur. Here we use the presence of a colorectal cancer (CRC) risk variant (rs1800734) within the MLH1 promoter to investigate the poorly understood mechanisms of MLH1 promoter methylation and loss of expression. We confirm the association of rs1800734 with MSI+ but not MSS cancer risk in our own data and by meta-analysis. Using sensitive allele-specific detection methods, we demonstrate that MLH1 is the target gene for rs1800734 mediated cancer risk. In normal colon tissue, small allele-specific differences exist only in MLH1 promoter methylation, but not gene expression. In contrast, allele-specific differences in both MLH1 methylation and expression are present in MSI+ cancers. We show that MLH1 transcriptional repression is dependent on DNA methylation and can be reversed by a methylation inhibitor. The rs1800734 allele influences the rate of methylation loss and amount of re-expression. The transcription factor TFAP4 binds to the rs1800734 region but with much weaker binding to the risk than the protective allele. TFAP4 binding is absent on both alleles when promoter methylation is present. Thus we propose that TFAP4 binding shields the protective rs1800734 allele of the MLH1 promoter from BRAF induced DNA methylation more effectively than the risk allele.