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1.
《Diagnostic Histopathology》2014,20(1):1-11
Gastric polyps show significant morphologic overlap, and some polyps defy classification altogether. Nevertheless, gastric polyps, particularly when profuse, should prompt further clinical and endoscopic investigation, as it may lead to the diagnosis of a polyposis syndrome. This review summarizes the common gastric polyps that are found in familial and non-inherited polyposis syndromes of the gastrointestinal tract. Examples of the gastric polyps are illustrated, and a discussion of polyp morphology and distribution is paired with a discussion of relevant clinical features and diagnostic criteria of polyposis syndromes. This information provides pathologists guidance for further patient workup, genetic testing, and cancer surveillance. 相似文献
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STK11 Domain XI Mutations: Candidate Genetic Drivers Leading to the Development of Dysplastic Polyps in Peutz–Jeghers Syndrome
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Zhiqing Wang Baoping Wu Rebecca A. Mosig Yulan Chen Fei Ye Yali Zhang Wei Gong Lanbo Gong Fei Huang Xinying Wang Biao Nie Haoxuan Zheng Miao Cui Yadong Wang Juan Wang Chudi Chen Alexandros D. Polydorides David Y. Zhang John A. Martignetti Bo Jiang 《Human mutation》2014,35(7):851-858
Peutz–Jeghers syndrome (PJS) is a rare hereditary disorder resulting from mutations in serine/threonine kinase 11 (STK11) and characterized by gastrointestinal (GI) hamartomatous polyps, mucocutaneous pigmentation, and an increased risk for specific cancers. Little is known about the genetic implications of specific STK11 mutations with regard to their role in dysplastic and malignant transformation of GI polyps. Peripheral blood genomic DNA samples from 116 Chinese PJS patients from 52 unrelated families were investigated for STK11 mutations. Genotype–phenotype correlations were investigated. The mutation detection rate was 67.3% (51.9% point mutations, 15.4% large deletions). Fourteen out of the 25 point mutations identified were novel. Nearly one‐third of all mutations, 8/27 (29.6%), were in exon 7, the shortest out of the nine exons. Strikingly, mutations affecting protein kinase domain XI, encoded in part by exon 7, correlated with a 90% (9/10) incidence of GI polyp dysplasia. In contrast, only two out of 17 (11.8%) nondomain XI mutations were linked to polyp dysplasia (P = 0.0001). The extent of the association between dysplasia and the development of GI‐related cancers is currently unknown but our results highlight a novel STK11 genotype–phenotype association as the basis for future genetic counseling and basic research studies. 相似文献
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《Diagnostic Histopathology》2014,20(1):30-37
Serrated polyps represent a heterogeneous group of lesions, some of which have well-documented malignant potential. The histological classification of serrated polyps has evolved over the last two decades to recognize three major subtypes: hyperplastic polyp, sessile serrated adenoma/polyp and traditional serrated adenoma. Sessile serrated adenoma/polyp remains under-diagnosed while it represents up to 25% of all serrated polyps and is the precursor lesion to colorectal carcinoma evolving though the serrated neoplasia pathway with BRAF mutation and CpG island methylator phenotype. Pathologists need to be aware of the World Health Organisation criteria to correctly diagnose each entity as patient management guidelines are based upon the use of this classification. Serrated polyposis is an under-recognized syndrome with unknown genetic cause conferring an increased risk of colorectal carcinoma. Pathologists have a pivotal role in identifying these patients who should undergo yearly surveillance colonoscopy. 相似文献
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《Diagnostic Histopathology》2014,20(1):12-18
Colorectal polyps are frequently encountered in daily pathology practice. The accurate diagnosis of these polyps forms a key component of clinical care, both in determining the malignant potential (and thus the follow-up interval for colonoscopy) as well as raising suspicion for polyposis syndromes. As such, the pathologist plays an instrumental role in the care of patients with colon polyps. This review highlights the histologic features of several commonly (and uncommonly) encountered colon polyps and provides genetic and clinical features of several polyposis syndromes that can be diagnosed (or at least suspected) when evaluating biopsies of colon polyps. 相似文献
5.
James Robinson Cecilia Lai Alison Martin Emma Nye Ian Tomlinson Andrew Silver 《The Journal of pathology》2009,219(1):35-40
Patients with Peutz–Jeghers syndrome (PJS) are affected by hamartomatous intestinal polyposis and increased risk of cancers in multiple organs caused by germline mutations in the tumour suppressor gene LKB1. Murine models that recapitulate aspects of PJS have been created. Here we examine the therapeutic effect of rapamycin, a macrolide with anti‐tumourigenic and anti‐angiogenic properties, in reducing tumour incidence in a large cohort of Lkb1+/? mice. To study the influence of early intervention, the animals were dosed with rapamycin from the age of 8 weeks, well before the onset of polyposis. These mice continued to receive the drug, which was well tolerated, throughout their lives. At sacrifice, we observed a reduction in gastric tumour burden in the rapamycin‐treated mice (p = 0.0001) compared with age‐ and sex‐matched controls. Treated animals also have a lower number of polyps per mouse than controls. In the polyps from the treated mice, phosphorylation of ribosomal p70 S6 kinase was maintained, while the phosphorylation of AKT at serine‐473 was elevated, suggesting that mTORC1 function is maintained at this dosage. Despite this, a significant reduction in microvessel density was seen in polyps from the rapamycin‐treated mice compared to those from the control mice (p = 5 × 10?5), suggesting that the anti‐angiogenic effect of rapamycin played a role in polyp reduction. Overall, we demonstrated that prolonged oral administration of rapamycin from an early age is effective in lowering tumour burden in the Lkb1+/? mice without evident side effects. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. 相似文献
6.
The aim of this paper was to report another example of a rare type of colorectal polyps, the inflammatory myoglandular polyp, and to reaffirm this type of polyp as a distinct entity. This solitary pedunculated polyp was detected after a single episode of rectal bleeding. It was situated in the sigmoid colon, measured 2.5 cm in greatest diameter, and was composed almost exclusively of smooth muscles and hyperplastic glands. The patient had neither chronic colitis nor diverticula. Clinical presentation, localization, and histology give this type of polyp a unique appearance and justify its designation as a separate entity. 相似文献
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Juvenile polyposis (JP) is an autosomal dominant hamartomatous polyposis syndrome that carries a significant risk for the development of colorectal cancer. Microdeletions of one of the two predisposing genes to JP, BMPR1A, have been associated with a severe form of JP called juvenile polyposis of infancy. Many of these deletions have also been found to contiguously include PTEN, which is the gene responsible for the development of Cowden syndrome. The advent of molecular techniques that localize genomic copy number variations and others that target specific genes such as multiplex-ligation probe analysis has allowed researchers to explore this area further for deletions. Here, we review the literature for microdeletions described on chromosome 10q22-23 in patients with JP and other intestinal polyposis syndromes. 相似文献
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Laura Valle Eduardo Vilar Sean V Tavtigian Elena M Stoffel 《The Journal of pathology》2019,247(5):574-588
This article reviews genes and syndromes associated with predisposition to colorectal cancer (CRC), with an overview of gene variant classification. We include updates on the application of preventive and therapeutic measures, focusing on the use of non-steroidal anti-inflammatory drugs (NSAIDs) and immunotherapy. Germline pathogenic variants in genes conferring high or moderate risk to cancer are detected in 6–10% of all CRCs and 20% of those diagnosed before age 50. CRC syndromes can be subdivided into nonpolyposis and polyposis entities, the most common of which are Lynch syndrome and familial adenomatous polyposis, respectively. In addition to known and novel genes associated with highly penetrant CRC risk, identification of pathogenic germline variants in genes associated with moderate-penetrance cancer risk and/or hereditary cancer syndromes not traditionally linked to CRC may have an impact on genetic testing, counseling, and surveillance. The use of multigene panels in genetic testing has exposed challenges in the classification of variants of uncertain significance. We provide an overview of the main classification systems and strategies for improving these. Finally, we highlight approaches for integrating chemoprevention in the care of individuals with genetic predisposition to CRC and use of targeted agents and immunotherapy for treatment of mismatch repair-deficient and hypermutant tumors. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. 相似文献
12.
G Warden D Harnett J Green T Wish MO Woods R Green E Dicks P Rahman G Zhai P Parfrey 《Clinical genetics》2013,84(6):522-530
Hereditary non‐polyposis colorectal cancer (HNPCC) may be the result of Lynch syndrome (LS) caused by mutations in mismatch repair (MMR) genes, a syndrome of unknown etiology called familial colorectal cancer type‐X (FCCTX), or familial serrated neoplasia associated with the colorectal cancer (CRC) somatic BRAF mutation. To determine the cause of HNPCC in the founder population of the island of Newfoundland, we studied 37 families with LS and 29 families without LS who fulfilled the Amsterdam I criteria. In non‐LS, four index CRCs were BRAF mutation positive, one of which was microsatellite instable. Geographic clustering of LS families caused by three different founder mutations in MSH2 was observed. Nine unique MMR mutations in four MMR genes were identified in single families distributed in different geographic isolates. The geographic distribution of non‐LS was similar to LS. The coefficient of relatedness using genotype data was significantly higher for non‐LS than for all CRC. Extensive genealogic investigation failed to connect non‐LS families and in some clusters pathologic CRC heterogeneity was observed. We conclude that non‐LS HNPCC may be a heterogeneous disorder with different pathogenic pathways, and that the geographic distribution is consistent with multiple different mutations in unknown CRC susceptibility gene(s). 相似文献
13.
Search for ReCQL4 mutations in 39 patients genotyped for suspected Rothmund–Thomson/Baller‐Gerold syndromes
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J. Piard B. Aral P. Vabres M. Holder‐Espinasse A. Mégarbané S. Gauthier V. Capra G. Pierquin P. Callier C. Baumann L. Pasquier G. Baujat L. Martorell A. Rodriguez A. F. Brady F. Boralevi M. A. González‐Enseñat M. Rio C. Bodemer N. Philip M.‐P. Cordier A. Goldenberg B. Demeer M. Wright E. Blair E. Puzenat P. Parent Y. Sznajer C. Francannet N. DiDonato O. Boute V. Barlogis O. Moldovan D. Bessis C. Coubes M. Tardieu V. Cormier‐Daire A. B. Sousa J. Franques A. Toutain M. Tajir S. C. Elalaoui D. Geneviève J. Thevenon J.‐B. Courcet J.‐B. Rivière C. Collet N. Gigot L. Faivre C. Thauvin‐Robinet 《Clinical genetics》2015,87(3):244-251
14.
Whole exome sequencing identifies a POLRID mutation segregating in a father and two daughters with findings of Klippel–Feil and Treacher Collins syndromes
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Philip F. Giampietro Linlea Armstrong Alex Stoddard Robert D. Blank Janet Livingston Cathy L. Raggio Kristen Rasmussen Michael Pickart Rachel Lorier Amy Turner Sarah Sund Nara Sobrera Enid Neptune David Sweetser Alberto Santiago‐Cornier Ulrich Broeckel 《American journal of medical genetics. Part A》2015,167(1):95-102
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Anna Sarkozy Claudio Carta Sonia Moretti Giuseppe Zampino Maria C. Digilio Francesca Pantaleoni Anna Paola Scioletti Giorgia Esposito Viviana Cordeddu Francesca Lepri Valentina Petrangeli Maria L. Dentici Grazia M.S. Mancini Angelo Selicorni Cesare Rossi Laura Mazzanti Bruno Marino Giovanni B. Ferrero Margherita Cirillo Silengo Luigi Memo Franco Stanzial Francesca Faravelli Liborio Stuppia Efisio Puxeddu Bruce D. Gelb Bruno Dallapiccola Marco Tartaglia 《Human mutation》2009,30(4):695-702
Noonan, LEOPARD, and cardiofaciocutaneous syndromes (NS, LS, and CFCS) are developmental disorders with overlapping features including distinctive facial dysmorphia, reduced growth, cardiac defects, skeletal and ectodermal anomalies, and variable cognitive deficits. Dysregulated RAS–mitogen‐activated protein kinase (MAPK) signal traffic has been established to represent the molecular pathogenic cause underlying these conditions. To investigate the phenotypic spectrum and molecular diversity of germline mutations affecting BRAF, which encodes a serine/threonine kinase functioning as a RAS effector frequently mutated in CFCS, subjects with a diagnosis of NS (N=270), LS (N=6), and CFCS (N=33), and no mutation in PTPN11, SOS1, KRAS, RAF1, MEK1, or MEK2, were screened for the entire coding sequence of the gene. Besides the expected high prevalence of mutations observed among CFCS patients (52%), a de novo heterozygous missense change was identified in one subject with LS (17%) and five individuals with NS (1.9%). Mutations mapped to multiple protein domains and largely did not overlap with cancer‐associated defects. NS‐causing mutations had not been documented in CFCS, suggesting that the phenotypes arising from germline BRAF defects might be allele specific. Selected mutant BRAF proteins promoted variable gain of function of the kinase, but appeared less activating compared to the recurrent cancer‐associated p.Val600Glu mutant. Our findings provide evidence for a wide phenotypic diversity associated with mutations affecting BRAF, and occurrence of a clinical continuum associated with these molecular lesions. Hum Mutat 0:1–8, 2009. © 2009 Wiley‐Liss, Inc. 相似文献
17.
Michael Muriello Julia L. Clemens Weiyi Mu Phuong T. Tran Peter C. Rowe Christy H. Smith Clair Francomano Antonie D. Kline 《American journal of medical genetics. Part A》2018,176(9):1858-1864
The objective of this study was to explore the factors contributing to quality of life in pediatric patients with non‐vascular Ehlers–Danlos syndromes (EDS). Data were analyzed on 41 children with a diagnosis of non‐vascular EDS from the de‐identified data available from the National Institute on Aging (NIA) study of heritable disorders of connective tissue. Children under age 19 years were seen as part of a long‐term evaluation project from 2003 to 2013 on a larger natural history of patients with heritable disorders of connective tissue. Data collected included medical history, physical examination findings, diagnostic study results, and responses on validated questionnaires. We reviewed a sub‐cohort of children with a diagnosis of non‐vascular EDS and explored pain severity and interference via the Brief Pain Inventory, and sleep quality via the Pittsburgh Sleep Quality Index. Pain severity had a strong correlation with pain interference, and both were similar to other disorders that include chronic pain reported in the literature. Sleep quality did not correlate with pain severity or interference, but all patients had poor sleep quality in comparison to historical controls. We conclude that pain and sleep are significant issues in the pediatric non‐vascular EDS population, and future research may be directed toward these issues. 相似文献
18.
Congenital abnormalities and hepatoblastoma: A report from the Children's Oncology Group (COG) and the Utah Population Database (UPDB)
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Rajkumar Venkatramani Logan G. Spector Michael Georgieff Gail Tomlinson Mark Krailo Marcio Malogolowkin Wendy Kohlmann Karen Curtin Rachel K. Fonstad Joshua D. Schiffman 《American journal of medical genetics. Part A》2014,164(9):2250-2255
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Audrey Putoux Audrey Labalme Jean‐Marie André Marianne Till Caroline Schluth‐Bolard Jérôme Berard Yves Bertrand Patrick Edery Guy Putet Damien Sanlaville 《American journal of medical genetics. Part A》2013,161(2):331-337
We report on a child with Jacobsen syndrome (JBS, OMIM 147791) and abnormalities consistent with Beckwith–Wiedemann syndrome (BWS, OMIM 130650). The constitutional karyotype was apparently normal, but FISH analysis with probes specific for the short and long arms of chromosome 11 found 11qter deletion with 11pter trisomy in 80% of the cells studied. Array‐CGH identified breakpoints in the 11p15.3 and 11q24.1 regions consistent with Jacobsen and Beckwith–Wiedemann syndromes. We suggest that this chromosome imbalance results from a pericentric inversion of chromosome 11 inherited from the father, with mosaicism resulting from meiotic recombination of a paternal inversion followed by mitotic recombination during the first embryonic divisions. This hypothesis is supported by the results of microsatellite marker analysis. Three previous cases of pericentric inversion and recombination of chromosome 11 have been reported. Our case is unusual in that it combines the Jacobsen and Beckwith–Wiedemann syndromes with mosaicism. © 2013 Wiley Periodicals, Inc. 相似文献
20.
Sharri Cyrus Deepika Burkardt David D. Weaver William T. Gibson 《American journal of medical genetics. Part C, Seminars in medical genetics》2019,181(4):519-531
The EZH2, EED, and SUZ12 genes encode proteins that comprise core components of the polycomb repressive complex 2 (PRC2), an epigenetic “writer” with H3K27 methyltransferase activity, catalyzing the addition of up to three methyl groups on histone 3 at lysine residue 27 (H3K27). Partial loss‐of‐function variants in genes encoding the EZH2 and EED subunits of the complex lead to overgrowth, macrocephaly, advanced bone age, variable intellectual disability, and distinctive facial features. EZH2‐associated overgrowth, caused by constitutional heterozygous mutations within Enhancer of Zeste homologue 2 (EZH2), has a phenotypic spectrum ranging from tall stature without obvious intellectual disability or dysmorphic features to classical Weaver syndrome (OMIM #277590). EED‐associated overgrowth (Cohen–Gibson syndrome; OMIM #617561) is caused by germline heterozygous mutations in Embryonic Ectoderm Development (EED), and manifests overgrowth and intellectual disability (OGID), along with other features similar to Weaver syndrome. Most recently, rare coding variants in SUZ12 have also been described that present with clinical characteristics similar to the previous two syndromes. Here we review the PRC2 complex and clinical syndromes of OGID associated with core components EZH2, EED, and SUZ12. 相似文献