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Nature Genetics Mar 2020About half of all cancers have somatic integrations of retrotransposons. Here, to characterize their role in oncogenesis, we analyzed the patterns and mechanisms of...
About half of all cancers have somatic integrations of retrotransposons. Here, to characterize their role in oncogenesis, we analyzed the patterns and mechanisms of somatic retrotransposition in 2,954 cancer genomes from 38 histological cancer subtypes within the framework of the Pan-Cancer Analysis of Whole Genomes (PCAWG) project. We identified 19,166 somatically acquired retrotransposition events, which affected 35% of samples and spanned a range of event types. Long interspersed nuclear element (LINE-1; L1 hereafter) insertions emerged as the first most frequent type of somatic structural variation in esophageal adenocarcinoma, and the second most frequent in head-and-neck and colorectal cancers. Aberrant L1 integrations can delete megabase-scale regions of a chromosome, which sometimes leads to the removal of tumor-suppressor genes, and can induce complex translocations and large-scale duplications. Somatic retrotranspositions can also initiate breakage-fusion-bridge cycles, leading to high-level amplification of oncogenes. These observations illuminate a relevant role of L1 retrotransposition in remodeling the cancer genome, with potential implications for the development of human tumors.
Topics: Carcinogenesis; Gene Rearrangement; Genome, Human; Humans; Long Interspersed Nucleotide Elements; Neoplasms; Retroelements
PubMed: 32024998
DOI: 10.1038/s41588-019-0562-0 -
Seminars in Pediatric Surgery Dec 2022Anomalies in tracheo-esophageal development result in a spectrum of congenital malformations ranging from, most commonly, esophageal atresia with or without...
Anomalies in tracheo-esophageal development result in a spectrum of congenital malformations ranging from, most commonly, esophageal atresia with or without trachea-esophageal fistula (EA+/-TEF) to esophageal web, duplication, stricture, tracheomalacia and tracheal agenesis. Despite the relative frequency of EA, however, the underlying etiology remains unknown and is likely due to a combination of genetic, epigenetic and environmental factors. In recent years, animal models have dramatically increased our understanding of the molecular and morphological processes involved in normal esophageal development during the key stages of anterior-posterior regionalization, dorsal-ventral patterning and morphogenic separation. Moreover, the use of animal models in conjunction with increasingly advanced techniques such as genomic sequencing, sophisticated live imaging studies and organoid models have more recently cast light on potential mechanisms involved in EA pathogenesis. This article aims to unravel some of the mysteries behind the anatomy and embryology of EA whilst providing insights into future directions for research.
Topics: Animals; Humans; Tracheoesophageal Fistula; Esophageal Atresia; Trachea; Tracheomalacia
PubMed: 36459913
DOI: 10.1016/j.sempedsurg.2022.151231 -
Human Molecular Genetics Oct 2020Deletions spanning the STS (steroid sulfatase) gene at Xp22.31 are associated with X-linked ichthyosis, corneal opacities, testicular maldescent, cardiac arrhythmia, and...
Deletions spanning the STS (steroid sulfatase) gene at Xp22.31 are associated with X-linked ichthyosis, corneal opacities, testicular maldescent, cardiac arrhythmia, and higher rates of developmental and mood disorders/traits, possibly related to the smaller volume of some basal ganglia structures. The consequences of duplication of the same genomic region have not been systematically assessed in large or adult samples, although evidence from case reports/series has indicated high rates of developmental phenotypes. We compared multiple measures of physical and mental health, cognition and neuroanatomy in male (n = 414) and female (n = 938) carriers of 0.8-2.5 Mb duplications spanning STS, and non-carrier male (n = 192, 826) and female (n = 227, 235) controls from the UK Biobank (recruited aged 40-69 from the UK general population). Clinical and self-reported diagnoses indicated a higher prevalence of inguinal hernia and mania/bipolar disorder respectively in male duplication carriers, and a higher prevalence of gastro-oesophageal reflux disease and blistering/desquamating skin disorder respectively in female duplication carriers; duplication carriers also exhibited reductions in several depression-related measures, and greater happiness. Cognitive function and academic achievement did not differ between comparison groups. Neuroanatomical analysis suggested greater lateral ventricle and putamen volume in duplication carriers. In conclusion, Xp22.31 duplications appear largely benign, but could slightly increase the likelihood of specific phenotypes (although results were only nominally-significant). In contrast to deletions, duplications might protect against depressive symptoms, possibly via higher STS expression/activity (resulting in elevated endogenous free steroid levels), and through contributing towards an enlarged putamen volume. These results should enable better genetic counselling of individuals with Xp22.31 microduplications.
Topics: Aged; Biological Specimen Banks; Chromosome Duplication; Chromosomes, Human, X; Cognition; Comparative Genomic Hybridization; Female; Genetic Diseases, X-Linked; Heterozygote; Humans; Ichthyosis, X-Linked; Male; Mental Health; Middle Aged; Neuroanatomy; Steryl-Sulfatase; United Kingdom
PubMed: 32766777
DOI: 10.1093/hmg/ddaa174 -
Mediastinum (Hong Kong, China) 2023Esophageal duplication represents one of the most common types of bronchopulmonary foregut malformations. These rare congenital anomalies occur secondary to... (Review)
Review
Esophageal duplication represents one of the most common types of bronchopulmonary foregut malformations. These rare congenital anomalies occur secondary to embryological aberrations between the 4th and 8th weeks of gestation. In order to be classified as an esophageal cyst a mediastinal cyst must have a close proximity with the esophagus, be lined by alimentary (squamous epithelium) or tracheobronchial mucosa and covered by two smooth muscle layers. These rare anomalies are often asymptomatic during adulthood. However, they can cause symptoms in early childhood, generally during the first 2 years of life. Variations in location, size, presence or absence of heterotopic mucosa, will dictate the clinical presentation. Dysphagia, food impaction, persistent cough and chest pain are common clinical presentations. Imaging studies including esophagram, computed tomography (CT) and magnetic resonance imaging (MRI) can provide key findings to reach the diagnosis. Nonetheless, endoscopic evaluation, particularly endoscopic ultrasound (EUS) is the most valuable tool to determine whether this lesion is cystic versus solid and or if there are abnormal mucosal findings. Needle biopsies are controversial but can help with drainage and to rule out malignant transformation. Therapeutic options include endoluminal drainage. However, more definitive therapies include surgical excision. Open and minimally invasive (laparoscopic and thoracoscopic) techniques have been demonstrated to be safe and effective at completely removing these lesions. Recently, robotic-assisted resections have gained more attention with case reports and series reporting excellent outcomes.
PubMed: 36926292
DOI: 10.21037/med-22-33 -
Endoscopic Ultrasound Jul 2014Gastrointestinal tract duplication cysts are rare congenital gastrointestinal malformation in young patients and adults. They consist of foregut duplication cysts, small... (Review)
Review
Gastrointestinal tract duplication cysts are rare congenital gastrointestinal malformation in young patients and adults. They consist of foregut duplication cysts, small bowel duplication cysts, and large bowel duplication cysts. Endoscopic ultrasound (EUS) has been widely used as a modality for the evaluation and diagnosis of duplication cysts. EUS is the diagnostic tool of choice to investigate duplication cysts since it can distinguish between solid and cystic lesions. The question of whether or not to perform EUS-fine needle aspiration (EUS-FNA) on a lesion suspected of being a duplication cyst is controversial as these lesions can become infected with significant consequences, although EUS-FNA is often required to obtain a definitive diagnosis and to rule out more ominous lesions. This manuscript will review the literature on duplication cysts throughout the body and will also focus on the role of EUS and FNA with regards to these lesions.
PubMed: 25184121
DOI: 10.4103/2303-9027.138783 -
Pediatrics and Neonatology Feb 2020
PubMed: 31558381
DOI: 10.1016/j.pedneo.2019.08.007 -
Annals of the New York Academy of... Oct 2013This paper presents commentaries on the microscopic morphology of esophageal squamous epithelium; the frequency of duplication of the muscularis mucosae (MM) in... (Review)
Review
This paper presents commentaries on the microscopic morphology of esophageal squamous epithelium; the frequency of duplication of the muscularis mucosae (MM) in Barrett's esophagus (BE); the significance of multilayered epithelium; whether cells in the lamina propria reflect those in the epithelium; how stem cells are identified in the squamous esophagus; dilated intercellular spaces; the metastasizing potential of early carcinoma-dependent, molecular or immunohistochemical tests that improve diagnosis; the role of immunohistochemistry IHC in grading of neoplasia in Barrett's esophagus and defining the risk of progression to adenocarcinoma; the roles of CDX1 and CDX2 in squamous and cardiac mucosa; and the role of desmosomal cadherins and lectins in squamous and cardiac mucosa.
Topics: Barrett Esophagus; Esophagus; Gastroesophageal Reflux; Humans; Immunohistochemistry; Mucous Membrane
PubMed: 24117640
DOI: 10.1111/nyas.12241 -
International Journal of Surgery Case... Dec 2021Thoraco-abdominal duplication is rare congenital malformations of the notochord that occurs in only 2% of cases of alimentary tract duplications. We report two rare...
INTRODUCTION
Thoraco-abdominal duplication is rare congenital malformations of the notochord that occurs in only 2% of cases of alimentary tract duplications. We report two rare cases of thoraco-abdominal duplication, emphasizing the value of radiological assessment and discussing the place of diagnostic and therapeutic laparoscopy.
PRESENTATION OF CASE
It was a 12-year-old girl and an 8-month-old boy, admitted for epigastralgia and dysphagia with respiratory distress respectively. Imaging was in favor of pancreatic duplication with intra-thoracic extension for the first patient and gastro-esophageal duplication for the second. A mass excision was done laparoscopically for the first and by a thoracotomy for the second. The aftermath of the surgery was simple in both cases.
CLINICAL DISCUSSION
Thoraco-abdominal duplications are rare congenital malformations that account for only 2% of cases of gastrointestinal duplications. Their diagnosis is difficult since the revealing symptomatology is not common. The treatment is only surgical is facilitated by the laparoscopy which has a diagnostic and therapeutic interest.
CONCLUSION
Our case reports focused on the difficulty of the diagnosis that is done by imaging and is confirmed by surgery with anatomopathological examination of the excised mass. Diagnostic and therapeutic minimally invasive approach should be used whenever possible.
PubMed: 34890978
DOI: 10.1016/j.ijscr.2021.106651 -
Cancers Feb 2022(1) Background: Oesophageal cancers are often late-presenting and have a poor 5-year survival rate. The standard treatment of oesophageal adenocarcinomas involves... (Review)
Review
(1) Background: Oesophageal cancers are often late-presenting and have a poor 5-year survival rate. The standard treatment of oesophageal adenocarcinomas involves neoadjuvant chemotherapy with or without radiotherapy followed by surgery. However, less than one third of patients respond to neoadjuvant therapy, thereby unnecessarily exposing patients to toxicity and deconditioning. Hence, there is an urgent need for biomarkers to predict response to neoadjuvant therapy. This review explores the current biomarker landscape. (2) Methods: MEDLINE, EMBASE and ClinicalTrial databases were searched with key words relating to "predictive biomarker", "neoadjuvant therapy" and "oesophageal adenocarcinoma" and screened as per the inclusion and exclusion criteria. All peer-reviewed full-text articles and conference abstracts were included. (3) Results: The search yielded 548 results of which 71 full-texts, conference abstracts and clinical trials were eligible for review. A total of 242 duplicates were removed, 191 articles were screened out, and 44 articles were excluded. (4) Discussion: Biomarkers were discussed in seven categories including imaging, epigenetic, genetic, protein, immunologic, blood and serum-based with remaining studies grouped in a miscellaneous category. (5) Conclusion: Although promising markers and novel methods have emerged, current biomarkers lack sufficient evidence to support clinical application. Novel approaches have been recommended to assess predictive potential more efficiently.
PubMed: 35205743
DOI: 10.3390/cancers14040996