Abstract:
:Patients with heritable cancer syndromes characterized by germline PTEN mutations (termed PTEN hamartoma tumor syndrome, PHTS) benefit from PTEN-enabled cancer risk assessment and clinical management. PTEN-wildtype patients (~50%) remain at increased risk of developing certain cancers. Existence of germline mutations in other known cancer susceptibility genes has not been explored in these patients, with implications for different medical management. We conducted a 4-year multicenter prospective study of incident patients with features of Cowden/Cowden-like (CS/CS-like) and Bannayan-Riley-Ruvalcaba syndromes (BRRS) without PTEN mutations. Exome sequencing and targeted analysis were performed including 59 clinically actionable genes from the American College of Medical Genetics and Genomics (ACMG) and 24 additional genes associated with inherited cancer syndromes. Pathogenic or likely pathogenic cancer susceptibility gene alterations were found in 7 of the 87 (8%) CS/CS-like and BRRS patients and included MUTYH, RET, TSC2, BRCA1, BRCA2, ERCC2 and HRAS. We found classic phenotypes associated with the identified genes in 5 of the 7 (71.4%) patients. Variant positive patients were enriched for the presence of second malignant neoplasms compared to patients without identified variants (OR = 6.101, 95% CI 1.143-35.98, p = 0.035). Germline variant spectrum and frequencies were compared to The Cancer Genome Atlas (TCGA), including 6 apparently sporadic cancers associated with PHTS. With comparable overall prevalence of germline variants, the spectrum of mutated genes was different in our patients compared to TCGA. Intriguingly, we also found notable enrichment of variants of uncertain significance (VUS) in our patients (OR = 2.3, 95% CI 1.5-3.5, p = 0.0002). Our data suggest that only a small subset of PTEN-wildtype CS/CS-like and BRRS patients could be accounted for by germline variants in some of the known cancer-related genes. Thus, the existence of alterations in other and more likely non-classic cancer-associated genes is plausible, reflecting the complexity of these heterogeneous hereditary cancer syndromes.
journal_name
PLoS Genetjournal_title
PLoS geneticsauthors
Yehia L,Ni Y,Sesock K,Niazi F,Fletcher B,Chen HJL,LaFramboise T,Eng Cdoi
10.1371/journal.pgen.1007352subject
Has Abstractpub_date
2018-04-23 00:00:00pages
e1007352issue
4eissn
1553-7390issn
1553-7404pii
PGENETICS-D-17-02402journal_volume
14pub_type
杂志文章,多中心研究相关文献
PLoS Genetics文献大全abstract::Detailed information about stage-specific changes in gene expression is crucial for the understanding of the gene regulatory networks underlying development. Here, we describe the global gene expression dynamics during early flower development, a key process in the life cycle of a plant, during which floral patterning...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.0020117.eor
更新日期:2006-07-01 00:00:00
abstract::The assimilation of nitrate, a most important soil nitrogen source, is tightly regulated in microorganisms and plants. In Aspergillus nidulans, during the transcriptional activation process of nitrate assimilatory genes, the interaction between the pathway-specific transcription factor NirA and the exportin KapK/CRM1 ...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1005297
更新日期:2015-07-01 00:00:00
abstract::Although endocrine changes are known to modulate the timing of major developmental transitions, the genetic mechanisms underlying these changes remain poorly understood. In insects, two developmental hormones, juvenile hormone (JH) and ecdysteroids, are coordinated with each other to induce developmental changes assoc...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1004425
更新日期:2014-06-19 00:00:00
abstract::The antigenic repertoire presented by MHC molecules is generated by the antigen processing and presentation (APP) pathway. We analyzed the evolutionary history of 45 genes involved in APP at the inter- and intra-species level. Results showed that 11 genes evolved adaptively in mammals. Several positively selected site...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1004189
更新日期:2014-03-27 00:00:00
abstract::Systemic lupus erythematosus (SLE) is an autoimmune disease with known genetic, epigenetic, and environmental risk factors. To assess the role of DNA methylation in SLE, we collected CD4+ T-cells, CD19+ B-cells, and CD14+ monocytes from 49 SLE patients and 58 controls, and performed genome-wide DNA methylation analysi...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1003678
更新日期:2013-01-01 00:00:00
abstract::Convergent phenotypic evolution is often caused by recurrent changes at particular nodes in the underlying gene regulatory networks (GRNs). The genes at such evolutionary 'hotspots' are thought to maximally affect the phenotype with minimal pleiotropic consequences. This has led to the suggestion that if a GRN is unde...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1007375
更新日期:2018-05-03 00:00:00
abstract::Quality control (QC) is a critical step in large-scale studies of genetic variation. While, on average, high-throughput single nucleotide polymorphism (SNP) genotyping assays are now very accurate, the errors that remain tend to cluster into a small percentage of "problem" SNPs, which exhibit unusually high error rate...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1000147
更新日期:2008-08-01 00:00:00
abstract::All living organisms exist in a precarious state of homeostasis that requires constant maintenance. A wide variety of stresses, including hypoxia, heat, and infection by pathogens perpetually threaten to imbalance this state. Organisms use a battery of defenses to mitigate damage and restore normal function. Previousl...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1006876
更新日期:2017-06-29 00:00:00
abstract::Insulator or enhancer-blocking elements are proposed to play an important role in the regulation of transcription by preventing inappropriate enhancer/promoter interaction. The zinc-finger protein CTCF is well studied in vertebrates as an enhancer blocking factor, but Drosophila CTCF has only been characterised recent...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.0030112
更新日期:2007-07-01 00:00:00
abstract::Complete metamorphosis (Holometaboly) is a key innovation that underlies the spectacular success of holometabolous insects. Phylogenetic analyses indicate that Holometabola form a monophyletic group that evolved from ancestors exhibiting hemimetabolous development (Hemimetaboly). However, the nature of the changes und...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1006020
更新日期:2016-05-02 00:00:00
abstract::Cockayne syndrome (CS) is a devastating progeria most often caused by mutations in the CSB gene encoding a SWI/SNF family chromatin remodeling protein. Although all CSB mutations that cause CS are recessive, the complete absence of CSB protein does not cause CS. In addition, most CSB mutations are located beyond exon ...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1000031
更新日期:2008-03-21 00:00:00
abstract::Patients with neonatal severe hyperparathyroidism (NSHPT) are homozygous for the calcium-sensing receptor (CaR) mutation and have very high circulating PTH, abundant parathyroid hyperplasia, and severe life-threatening hypercalcemia. Mice with homozygous deletion of CaR mimic the syndrome of NSHPT. To determine effect...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1002294
更新日期:2011-09-01 00:00:00
abstract::The evolution of metazoans from their choanoflagellate-like unicellular ancestor coincided with the acquisition of novel biological functions to support a multicellular lifestyle, and eventually, the unique cellular and physiological demands of differentiated cell types such as those forming the nervous, muscle and im...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1003804
更新日期:2013-01-01 00:00:00
abstract::Genomic instability is a hallmark of human cancer cells. To prevent genomic instability, chromosomal DNA is faithfully duplicated in every cell division cycle, and eukaryotic cells have complex regulatory mechanisms to achieve this goal. Here, we show that untimely activation of replication origins during the G1 phase...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1002136
更新日期:2011-06-01 00:00:00
abstract::The human genome encodes thousands of long noncoding RNA (lncRNA) genes; the function of majority of them is poorly understood. Aberrant expression of a significant number of lncRNAs is observed in various diseases, including cancer. To gain insights into the role of lncRNAs in breast cancer progression, we performed ...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1007802
更新日期:2018-11-29 00:00:00
abstract::Double strand breaks (DSBs) and interstrand crosslinks (ICLs) are toxic DNA lesions that can be repaired through multiple pathways, some of which involve shared proteins. One of these proteins, DNA Polymerase θ (Pol θ), coordinates a mutagenic DSB repair pathway named microhomology-mediated end joining (MMEJ) and is a...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1006813
更新日期:2017-05-25 00:00:00
abstract::The number of recombination events per meiosis varies extensively among individuals. This recombination phenotype differs between female and male, and also among individuals of each gender. In this study, we used high-density SNP genotypes of over 2,300 individuals and their offspring in two datasets to characterize r...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1000648
更新日期:2009-09-01 00:00:00
abstract::Fanconi Anemia (FA) is a rare autosomal recessive disorder characterized by hypersensitivity to inter-strand crosslinks (ICLs). FANCD2, a central factor of the FA pathway, is essential for the repair of double strand breaks (DSBs) generated during fork collapse at ICLs. While lesions different from ICLs can also trigg...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1005792
更新日期:2016-01-14 00:00:00
abstract::Ribosomes are the highly complex macromolecular assemblies dedicated to the synthesis of all cellular proteins from mRNA templates. The main principles underlying the making of ribosomes are conserved across eukaryotic organisms and this process has been studied in most detail in the yeast Saccharomyces cerevisiae. Ye...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1005565
更新日期:2015-10-08 00:00:00
abstract::HSPB7 is a member of the small heat-shock protein (HSPB) family and is expressed in the cardiomyocytes from cardiogenesis onwards. A dramatic increase in HSPB7 is detected in the heart and blood plasma immediately after myocardial infarction. Additionally, several single-nucleotide polymorphisms of HSPB7 have been ide...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1006984
更新日期:2017-08-21 00:00:00
abstract::Differences in transcriptional regulatory networks underlie much of the phenotypic variation observed across organisms. Changes to cis-regulatory elements are widely believed to be the predominant means by which regulatory networks evolve, yet examples of regulatory network divergence due to transcription factor (TF) ...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1005011
更新日期:2015-03-06 00:00:00
abstract::Cell-to-cell gene expression noise is thought to be an important mechanism for generating phenotypic diversity. Furthermore, telomeric regions are major sites for gene amplification, which is thought to drive genetic diversity. Here we found that individual subtelomeric TLO genes exhibit increased variation in transcr...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1004436
更新日期:2014-07-24 00:00:00
abstract::Pre-mRNAs are often processed in complex patterns in tissue-specific manners to produce a variety of protein isoforms from single genes. However, mechanisms orchestrating the processing of the entire transcript are not well understood. Muscle-specific alternative pre-mRNA processing of the unc-60 gene in Caenorhabditi...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1002991
更新日期:2012-01-01 00:00:00
abstract::CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) loci, together with cas (CRISPR-associated) genes, form the CRISPR/Cas adaptive immune system, a primary defense strategy that eubacteria and archaea mobilize against foreign nucleic acids, including phages and conjugative plasmids. Short spacer sequen...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1002441
更新日期:2012-01-01 00:00:00
abstract::[This corrects the article DOI: 10.1371/journal.pgen.1006425.]. ...
journal_title:PLoS genetics
pub_type: 杂志文章,已发布勘误
doi:10.1371/journal.pgen.1006831
更新日期:2017-06-07 00:00:00
abstract::The phenotype of the spontaneous mutant mouse hop-sterile (hop) is characterized by a hopping gait, polydactyly, hydrocephalus, and male sterility. Previous analyses of the hop mouse revealed a deficiency of inner dynein arms in motile cilia and a lack of sperm flagella, potentially accounting for the hydrocephalus an...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1004689
更新日期:2014-10-23 00:00:00
abstract::Reduced bacterial genomes and most genomes of cell organelles (chloroplasts and mitochondria) do not encode the full set of 32 tRNA species required to read all triplets of the genetic code according to the conventional wobble rules. Superwobbling, in which a single tRNA species that contains a uridine in the wobble p...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1003076
更新日期:2012-01-01 00:00:00
abstract::Marine ecosystems are changing rapidly as the oceans warm and become more acidic. The physical factors and the changes to ocean chemistry that they drive can all be measured with great precision. Changes in the biological composition of communities in different ocean regions are far more challenging to measure because...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1007943
更新日期:2019-02-08 00:00:00
abstract::Despite the well-documented role of remote enhancers in controlling developmental gene expression, the mechanisms that allocate enhancers to genes are poorly characterized. Here, we investigate the cis-regulatory organization of the locus containing the Tfap2c and Bmp7 genes in vivo, using a series of engineered chrom...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1004897
更新日期:2015-01-08 00:00:00
abstract::The genetics of lymphoma susceptibility reflect the marked heterogeneity of diseases that comprise this broad phenotype. However, multiple subtypes of lymphoma are observed in some families, suggesting shared pathways of genetic predisposition to these pathologically distinct entities. Using a two-stage GWAS, we teste...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1003220
更新日期:2013-01-01 00:00:00