Abstract:
:Many individuals with multiple or large colorectal adenomas or early-onset colorectal cancer (CRC) have no detectable germline mutations in the known cancer predisposition genes. Using whole-genome sequencing, supplemented by linkage and association analysis, we identified specific heterozygous POLE or POLD1 germline variants in several multiple-adenoma and/or CRC cases but in no controls. The variants associated with susceptibility, POLE p.Leu424Val and POLD1 p.Ser478Asn, have high penetrance, and POLD1 mutation was also associated with endometrial cancer predisposition. The mutations map to equivalent sites in the proofreading (exonuclease) domain of DNA polymerases ɛ and δ and are predicted to cause a defect in the correction of mispaired bases inserted during DNA replication. In agreement with this prediction, the tumors from mutation carriers were microsatellite stable but tended to acquire base substitution mutations, as confirmed by yeast functional assays. Further analysis of published data showed that the recently described group of hypermutant, microsatellite-stable CRCs is likely to be caused by somatic POLE mutations affecting the exonuclease domain.
journal_name
Nat Genetjournal_title
Nature geneticsauthors
Palles C,Cazier JB,Howarth KM,Domingo E,Jones AM,Broderick P,Kemp Z,Spain SL,Guarino E,Salguero I,Sherborne A,Chubb D,Carvajal-Carmona LG,Ma Y,Kaur K,Dobbins S,Barclay E,Gorman M,Martin L,Kovac MB,Humphray S,CORdoi
10.1038/ng.2503subject
Has Abstractpub_date
2013-02-01 00:00:00pages
136-44issue
2eissn
1061-4036issn
1546-1718pii
ng.2503journal_volume
45pub_type
杂志文章相关文献
NATURE GENETICS文献大全abstract::Translocation events are frequent in cancer and may create chimeric fusions or 'regulatory rearrangements' that drive oncogene overexpression. Here we identify super-enhancer translocations that drive overexpression of the oncogenic transcription factor MYB as a recurrent theme in adenoid cystic carcinoma (ACC). Whole...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/ng.3502
更新日期:2016-03-01 00:00:00
abstract::Schistosoma mansoni is the primary causative agent of schistosomiasis, which affects 200 million individuals in 74 countries. We generated 163,000 expressed-sequence tags (ESTs) from normalized cDNA libraries from six selected developmental stages of the parasite, resulting in 31,000 assembled sequences and 92% sampli...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/ng1237
更新日期:2003-10-01 00:00:00
abstract::Through whole-genome sequencing of 2,230 Icelanders, we detected a rare nonsynonymous SNP (minor allele frequency = 0.55%) in the C3 gene encoding a p.Lys155Gln substitution in complement factor 3, which, following imputation into a set of Icelandic cases with age-related macular degeneration (AMD) and controls, assoc...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/ng.2740
更新日期:2013-11-01 00:00:00
abstract::The Polycomb repressive complexes PRC1 and PRC2 maintain embryonic stem cell (ESC) pluripotency by silencing lineage-specifying developmental regulator genes. Emerging evidence suggests that Polycomb complexes act through controlling spatial genome organization. We show that PRC1 functions as a master regulator of mou...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/ng.3393
更新日期:2015-10-01 00:00:00
abstract::The majority of reported complex disease associations for common genetic variants have been identified through meta-analysis, a powerful approach that enables the use of large sample sizes while protecting against common artifacts due to population structure and repeated small-sample analyses sharing individual-level ...
journal_title:Nature genetics
pub_type: 杂志文章,meta分析
doi:10.1038/ng.2852
更新日期:2014-02-01 00:00:00
abstract::The syndrome of hyperactivity describes behavioural disorders existing mainly in children and characterized by increased levels of motor activity, inattention and impulsivity. Overall the aetiology is poorly understood due to the heterogeneity of the pathology although psychological, biological and social factors acti...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/ng1296-471
更新日期:1996-12-01 00:00:00
abstract::There is increasing evidence showing that the stromal cells surrounding cancer epithelial cells, rather than being passive bystanders, might have a role in modifying tumor outgrowth. The molecular basis of this aspect of carcinoma etiology is controversial. Some studies have reported a high frequency of genetic aberra...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/ng.117
更新日期:2008-05-01 00:00:00
abstract::To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant ex...
journal_title:Nature genetics
pub_type: 杂志文章,meta分析
doi:10.1038/ng.2897
更新日期:2014-03-01 00:00:00
abstract::Communication between distal chromosomal elements is essential for control of many nuclear processes. For example, genes in higher eukaryotes often require distant enhancer sequences for high-level expression. The mechanisms proposed for long-range enhancer action fall into two basic categories. Non-contact models pro...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/ng1051
更新日期:2002-12-01 00:00:00
abstract::The three-dimensional organization of the genome has an important role in orchestrating gene expression, but its regulation is poorly understood. Now, a new study uncovers a major role for Polycomb components of the PRC1 complex in organizing physical networks of genes that are co-repressed to maintain pluripotency. ...
journal_title:Nature genetics
pub_type: 评论,新闻
doi:10.1038/ng.3411
更新日期:2015-10-01 00:00:00
abstract::Pancreatic cancer has the lowest survival rate among human cancers, and there are no effective markers for its screening and early diagnosis. To identify genetic susceptibility markers for this cancer, we carried out a genome-wide association study on 981 individuals with pancreatic cancer (cases) and 1,991 cancer-fre...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/ng.1020
更新日期:2011-12-11 00:00:00
abstract::An earlier search in the human, mouse and rat genomes for sequences that are 100% conserved in orthologous segments and > or = 200 bp in length identified 481 distinct sequences. These human-mouse-rat sequences, which represent ultraconserved elements (UCEs), are believed to be important for functions involving DNA bi...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/ng1888
更新日期:2006-10-01 00:00:00
abstract::Long noncoding RNAs (lncRNAs) are prevalent genes with frequently precise regulation but mostly unknown functions. Here we demonstrate that lncRNAs guide the organismal DNA damage response. DNA damage activated transcription of the DINO (Damage Induced Noncoding) lncRNA via p53. DINO was required for p53-dependent gen...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/ng.3673
更新日期:2016-11-01 00:00:00
abstract::In embryonic stem cells (ESCs), developmental gene promoters are characterized by their bivalent chromatin state, with simultaneous modification by MLL2 and Polycomb complexes. Although essential for embryogenesis, bivalency is functionally not well understood. Here, we show that MLL2 plays a central role in ESC genom...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/s41588-018-0218-5
更新日期:2018-10-01 00:00:00
abstract::Methylation of cytosines within the sequence CpG is essential for mouse development and has been linked to transcriptional suppression in vertebrate systems. Methyl-CpG binding proteins (MeCPs) 1 and 2 bind preferentially to methylated DNA and can inhibit transcription. The gene for MeCP2 has been cloned and a methyl-...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/ng0797-256
更新日期:1997-07-01 00:00:00
abstract::Dilated cardiomyopathy (DCM) is a highly heterogeneous trait with sarcomeric gene mutations predominating. The cause of a substantial percentage of DCMs remains unknown, and no gene-specific therapy is available. On the basis of resequencing of 513 DCM cases and 1,150 matched controls from various cohorts of distinct ...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/ng.2963
更新日期:2014-06-01 00:00:00
abstract::The vast majority of patients with fragile X syndrome show a folate-sensitive fragile site at Xq27.3 (FRAXA) at the cytogenetic level, and both amplification of the (CGG)n repeat and hypermethylation of the CpG island in the 5' fragile X gene (FMR-1) at the molecular level. We have studied the FMR-1 gene of a patient ...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/ng0193-31
更新日期:1993-01-01 00:00:00
abstract::Interferon regulatory factor 6 (IRF6) belongs to a family of nine transcription factors that share a highly conserved helix-turn-helix DNA-binding domain and a less conserved protein-binding domain. Most IRFs regulate the expression of interferon-alpha and -beta after viral infection, but the function of IRF6 is unkno...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/ng985
更新日期:2002-10-01 00:00:00
abstract::The rate and pattern of sequence substitutions in the mitochondrial DNA (mtDNA) control region (CR) is of central importance to studies of human evolution and to forensic identity testing. Here, we report a direct measurement of the intergenerational substitution rate in the human CR. We compared DNA sequences of two ...
journal_title:Nature genetics
pub_type: 杂志文章,多中心研究
doi:10.1038/ng0497-363
更新日期:1997-04-01 00:00:00
abstract::Alström syndrome (OMIM 203800) is an autosomal recessive disease, characterized by cone-rod retinal dystrophy, cardiomyopathy and type 2 diabetes mellitus, that has been mapped to chromosome 2p13 (refs 1-5). We have studied an individual with Alström syndrome carrying a familial balanced reciprocal chromosome transloc...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/ng874
更新日期:2002-05-01 00:00:00
abstract::Trophoblast cells of the placenta are established at the blastocyst stage and differentiate into specialized subtypes after implantation. In mice, the outer layer of the placenta consists of trophoblast giant cells that invade the uterus and promote maternal blood flow to the implantation site by producing cytokines w...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/77076
更新日期:2000-07-01 00:00:00
abstract::A new study has identified rare de novo mutations in SHANK2 in individuals with autism and/or mental retardation. SHANK2 encodes a scaffolding protein present in excitatory synapses. This finding sheds some light on the pathophysiology of social and cognitive disability. ...
journal_title:Nature genetics
pub_type: 评论,新闻
doi:10.1038/ng0610-478
更新日期:2010-06-01 00:00:00
abstract::Hereditary dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant neurologic disorder characterized by variable combinations of myoclonus, epilepsy, cerebellar ataxia, choreoathetosis and dementia. By specifically searching published brain cDNA sequences for the presence of CAG repeats we identified uns...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/ng0194-9
更新日期:1994-01-01 00:00:00
abstract::Cretinism is marked by irreversible mental and growth retardation. We describe here an entirely new case of cretinism showing combined pituitary hormone deficiencies of thyrotropin, growth hormone and prolactin that appears to be caused by homozygosity for a nonsense mutation in the gene for the pituitary specific tra...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/ng0492-56
更新日期:1992-04-01 00:00:00
abstract::Dominant mutations in the MORC2 gene have recently been shown to cause axonal Charcot-Marie-Tooth (CMT) disease, but the cellular function of MORC2 is poorly understood. Here, through a genome-wide CRISPR-Cas9-mediated forward genetic screen, we identified MORC2 as an essential gene required for epigenetic silencing b...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/ng.3878
更新日期:2017-07-01 00:00:00
abstract::Identifying the genes involved in polygenic traits has been difficult. In the 1950s and 1960s, laboratory selection experiments for extreme geotaxic behavior in fruit flies established for the first time that a complex behavioral trait has a genetic basis. But the specific genes responsible for the behavior have never...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/ng893
更新日期:2002-08-01 00:00:00
abstract::The human genome sequence has been finished to very high standards; however, more than 340 gaps remained when the finished genome was published by the International Human Genome Sequencing Consortium in 2004. Using fosmid resources generated from multiple individuals, we targeted gaps in the euchromatic part of the hu...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/ng.2007.34
更新日期:2008-01-01 00:00:00
abstract::Both polygenicity (many small genetic effects) and confounding biases, such as cryptic relatedness and population stratification, can yield an inflated distribution of test statistics in genome-wide association studies (GWAS). However, current methods cannot distinguish between inflation from a true polygenic signal a...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/ng.3211
更新日期:2015-03-01 00:00:00
abstract::The human gut microbiome plays a key role in human health 1 , but 16S characterization lacks quantitative functional annotation 2 . The fecal metabolome provides a functional readout of microbial activity and can be used as an intermediate phenotype mediating host-microbiome interactions 3 . In this comprehensive desc...
journal_title:Nature genetics
pub_type: 杂志文章
doi:10.1038/s41588-018-0135-7
更新日期:2018-06-01 00:00:00
abstract::In the version of this article originally published, one of the two authors with the name Wei Zhao was omitted from the author list and the affiliations for both authors were assigned to the single Wei Zhao in the author list. In addition, the ORCID for Wei Zhao (Department of Biostatistics and Epidemiology, Perelman ...
journal_title:Nature genetics
pub_type: 杂志文章,已发布勘误
doi:10.1038/s41588-018-0082-3
更新日期:2018-05-01 00:00:00