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Jelsig AM, Karstensen JG, Overeem Hansen TV. Progress report: Peutz-Jeghers syndrome. Fam Cancer 2024; 23:409-417. [PMID: 38493229 DOI: 10.1007/s10689-024-00362-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Accepted: 02/04/2024] [Indexed: 03/18/2024]
Abstract
Peutz-Jeghers syndrome is a rare, autosomal dominant polyposis syndrome. Presenting with a remarkable phenotype including development of characteristic gastrointestinal polyps, mucocutaneous pigmentations, and an increased risk of cancer, the syndrome has been subject to many studies concerning the natural course of disease. In most patients, pathogenic germline variants are detected in the STK11 gene including cases of mosaicism and structural variants. Yet, studies assessing the effect of surveillance, understanding of cancer development, as well as clinical studies evaluating chemoprevention are lacking. In addition, the impact of Peutz-Jeghers syndrome on mental health, education, and family planning are insufficiently addressed. In this progress report, we describe current knowledge, clinical phenotype, surveillance strategies, and future areas of research.
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Affiliation(s)
- Anne Marie Jelsig
- Department of Clinical Genetics, University Hospital of Copenhagen - Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark.
| | - John Gásdal Karstensen
- The Danish Polyposis Register, Gastro Unit and Department of Clinical Medicine, Amager and Hvidovre, Copenhagen University Hospital and University of Copenhagen-, Copenhagen, Denmark
| | - Thomas V Overeem Hansen
- Department of Clinical Genetics and Department of Clinical Medicine, University Hospital of Copenhagen, Rigshospitalet and Copenhagen University, Copenhagen, Denmark
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Chiraphapphaiboon W, Thongnoppakhun W, Limjindaporn T, Sawasdichai S, Roothumnong E, Prangphan K, Pamornpol B, Limwongse C, Pithukpakorn M. STK11 Causative Variants and Copy Number Variations Identified in Thai Patients With Peutz-Jeghers Syndrome. Cureus 2023; 15:e34495. [PMID: 36874343 PMCID: PMC9983355 DOI: 10.7759/cureus.34495] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/31/2023] [Indexed: 02/04/2023] Open
Abstract
Introduction Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant inherited disorder caused by germline mutations in the serine-threonine kinase 11 (STK11) tumor suppressor gene. This syndrome is characterized by hamartomatous gastrointestinal polyps, mucocutaneous melanin pigmentation, and a higher risk of developing various cancers. Methods We summarized the clinical and molecular characteristics of five unrelated Thai patients with PJS. Denaturing high-performance liquid chromatography (DHPLC) screening, coupled with direct DNA sequencing and multiplex ligation-dependent probe amplification (MLPA), were applied for the molecular analysis of STK11. Results A total of four STK11 pathogenic changeswere identified in the five PJS patients, including two frameshift variants (a novel c.199dup, p.Leu67ProfsTer96 and a known c.834_835del, p.Cys278TrpfsTer6) and two types of copy number variations (CNV), exon 1 deletion and exons 2-3 deletion. Among reported STK11 exonic deletions, exon 1 and exons 2-3 deletions were found to be the two most commonly deleted exons. Conclusion All identified STK11 mutations were null mutations that were associated with more severe PJS phenotypes and cancers. This study broadens the phenotypic and mutational spectrum of STK11 in PJS.
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Affiliation(s)
| | - Wanna Thongnoppakhun
- Siriraj Genomics, Office of the Dean, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, THA
| | | | - Sunisa Sawasdichai
- Siriraj Genomics, Office of the Dean, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, THA
| | - Ekkapong Roothumnong
- Division of Medical Genetics, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, THA
| | - Kanjana Prangphan
- Siriraj Genomics, Office of the Dean, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, THA
| | - Benjaporn Pamornpol
- Department of Anatomy, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, THA
| | - Chanin Limwongse
- Siriraj Genomics, Office of the Dean, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, THA.,Division of Medical Genetics, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, THA
| | - Manop Pithukpakorn
- Siriraj Genomics, Office of the Dean, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, THA.,Division of Medical Genetics, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, THA
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Pachler FR, Byrjalsen A, Karstensen JG, Jelsig AM. Hereditary polyposis syndromes remain a challenging disease entity: Old dilemmas and new insights. World J Gastrointest Surg 2023; 15:1-8. [PMID: 36741069 PMCID: PMC9896492 DOI: 10.4240/wjgs.v15.i1.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Revised: 11/18/2022] [Accepted: 01/04/2023] [Indexed: 01/17/2023] Open
Abstract
In this editorial we present an overview and insights of the management of hereditary polyposis syndromes. The primary focus was on familial adenomatous polyposis, juvenile polyposis syndrome and Peutz-Jegher syndrome. Genetic testing has become increasingly available and is easier than ever to integrate into clinical practice. Furthermore, several genes have been added to the expanding list of genes associated with hereditary polyposis syndromes, allowing for precise diagnostics and tailored follow-up. Endoscopic evaluation of patients with hereditary polyposis syndromes is paramount in the surveillance strategies. Current endoscopic procedures include both diagnostic procedures and surveillance as well as therapeutic interventions. Recommendations for endoscopic procedures in the upper and lower gastrointestinal canal were described. Surgery is still a key component in the management of patients with hereditary polyposis syndromes. The increased cancer risk in these patients often render prophylactic procedures or intended curative procedures in the case of cancer development. Surgical interventions in the upper and lower gastrointestinal canal were described with relevant considerations. Development of chemopreventive medications is ongoing. Few drugs have been investigated, including nonsteroidal anti-inflammatory drugs. It has been demonstrated that cyclooxygenase-2 inhibitors may lower the number of polyps. Other medications are currently under investigation, but none have, to date, consistently been able to prevent development of disease.
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Affiliation(s)
- Frederik Rønne Pachler
- Danish Polyposis Registry, Gastrounit, Copenhagen University Hospital - Amager and Hvidovre Hospital, Hvidovre 2650, Denmark
| | - Anna Byrjalsen
- Department of Clinical Genetics, University Hospital of Copenhagen, Rigshospitalet, Copenhagen 2100, Denmark
| | - John Gásdal Karstensen
- Danish Polyposis Registry, Gastrounit, Copenhagen University Hospital - Amager and Hvidovre Hospital, Hvidovre 2650, Denmark
- Department of Clinical Medicine, University of Copenhagen, Hvidovre 2650, Denmark
| | - Anne Marie Jelsig
- Department of Clinical Genetics, University Hospital of Copenhagen, Rigshospitalet, Copenhagen 2100, Denmark
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Yu Z, Liu L, Jiang F, Ji Y, Wang X, Liu L. A novel missense mutation of the STK11 gene in a Chinese family with Peutz-Jeghers syndrome. BMC Gastroenterol 2022; 22:536. [PMID: 36550395 PMCID: PMC9784088 DOI: 10.1186/s12876-022-02617-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Accepted: 12/13/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant inherited disease caused by mutations in the Serine-Threonine Kinase 11 (STK11) gene. This study aimed to diagnose a Chinese pedigree with PJS and to expand the spectrum of STK11 variants. METHODS We performed an inductive analysis of clinical features, gastrointestinal endoscopy, radiologic imaging, and pathological findings in a Chinese family with PJS. Whole-exome sequencing (WES), Sanger sequencing, and STK11 protein 3D structure prediction were performed for establishing a molecular diagnosis. RESULTS The proband, her mother, and grandfather presented with pigmentation spots on lips, oral mucosa, and fingers. Her mother and grandfather also had pigmentation spots on face and feet, while her brother had pigmentation spots only on the lower lip. On endoscopy, polyps were discovered in the proband, her mother, and grandfather. A novel heterozygous mutation (c.521A > C) in exon 4 of STK11 was identified in all four patients, leading to a change from histidine to proline in amino acid 174. The variable site p.H174 was highly conserved in different species on multiple sequence alignment analysis. CONCLUSIONS We diagnosed a Chinese pedigree with PJS based on clinical features, gastrointestinal endoscopy, and genetic testing results. Our results expanded the spectrum of STK11 variants, which will be helpful for genetic counseling.
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Affiliation(s)
- Zhen Yu
- grid.27255.370000 0004 1761 1174Department of Pediatrics, Qilu Hospital, Shandong University, 107 Wen Hua Xi Road, Jinan, 250012 Shandong People’s Republic of China
| | - Lin Liu
- grid.27255.370000 0004 1761 1174Shandong Provincial Maternal and Child Health Care Hospital, Shandong University, 238 Jing Shi Dong Road, Jinan, 250012 Shandong People’s Republic of China
| | - Fang Jiang
- grid.27255.370000 0004 1761 1174Department of Pediatrics, Qilu Hospital, Shandong University, 107 Wen Hua Xi Road, Jinan, 250012 Shandong People’s Republic of China
| | - Yimin Ji
- grid.27255.370000 0004 1761 1174Department of Pediatrics, Qilu Hospital, Shandong University, 107 Wen Hua Xi Road, Jinan, 250012 Shandong People’s Republic of China
| | - Xiao Wang
- grid.27255.370000 0004 1761 1174Department of Pediatrics, Qilu Hospital, Shandong University, 107 Wen Hua Xi Road, Jinan, 250012 Shandong People’s Republic of China
| | - Lili Liu
- grid.27255.370000 0004 1761 1174Department of Pediatrics, Qilu Hospital, Shandong University, 107 Wen Hua Xi Road, Jinan, 250012 Shandong People’s Republic of China
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Klimkowski S, Ibrahim M, Ibarra Rovira JJ, Elshikh M, Javadi S, Klekers AR, Abusaif AA, Moawad AW, Ali K, Elsayes KM. Peutz-Jeghers Syndrome and the Role of Imaging: Pathophysiology, Diagnosis, and Associated Cancers. Cancers (Basel) 2021; 13:cancers13205121. [PMID: 34680270 PMCID: PMC8533703 DOI: 10.3390/cancers13205121] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 10/07/2021] [Accepted: 10/08/2021] [Indexed: 02/03/2023] Open
Abstract
Simple Summary The Peutz-Jeghers Syndrome is a rare autosomal dominant syndrome characterized by mucocutaneous pigmentations, multiple gastrointestinal hamartomatous polyps, and an elevated risk of malignancy. Awareness of various Peutz-Jeghers Syndrome imaging patterns, associated malignancies, and their complications is crucial for accurate imaging interpretation and patient management. In this manuscript, we provide an overview of this condition, associated malignancies, and imaging surveillance protocols. Abstract The Peutz-Jeghers Syndrome (PJS) is an autosomal dominant neoplastic syndrome defined by hamartomatous polyps through the gastrointestinal tract, development of characteristic mucocutaneous pigmentations, and an elevated lifetime cancer risk. The majority of cases are due to a mutation in the STK11 gene located at 19p13.3. The estimated incidence of PJS ranges from 1:50,000 to 1:200,000. PJS carries an elevated risk of malignancies including gastrointestinal, breast, lung, and genitourinary (GU) neoplasms. Patients with PJS are at a 15- to 18-fold increased malignancy risk relative to the general population. Radiologists have an integral role in the diagnosis of these patients. Various imaging modalities are used to screen for malignancies and complications associated with PJS. Awareness of various PJS imaging patterns, associated malignancies, and their complications is crucial for accurate imaging interpretation and patient management. In this manuscript, we provide a comprehensive overview of PJS, associated malignancies, and surveillance protocols.
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Affiliation(s)
- Sergio Klimkowski
- Department of Abdominal Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77555, USA; (J.J.I.R.); (S.J.); (A.R.K.); (A.A.A.)
- Correspondence: (S.K.); (K.M.E.)
| | - Mohamed Ibrahim
- Department of Diagnostic and Interventional Radiology, University of Kansas-Wichita, Wichita, KS 67214, USA; (M.I.); (K.A.)
| | - Juan J. Ibarra Rovira
- Department of Abdominal Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77555, USA; (J.J.I.R.); (S.J.); (A.R.K.); (A.A.A.)
| | - Mohamed Elshikh
- Department of Diagnostic and Interventional Radiology, The University of Texas Medica Branch, Galveston, TX 77555, USA;
| | - Sanaz Javadi
- Department of Abdominal Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77555, USA; (J.J.I.R.); (S.J.); (A.R.K.); (A.A.A.)
| | - Albert R. Klekers
- Department of Abdominal Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77555, USA; (J.J.I.R.); (S.J.); (A.R.K.); (A.A.A.)
| | - Abdelraham A. Abusaif
- Department of Abdominal Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77555, USA; (J.J.I.R.); (S.J.); (A.R.K.); (A.A.A.)
| | - Ahmed W. Moawad
- Department of Diagnostic and Interventional Radiology, Mercy Catholic Health System, Darby, PA 19023, USA;
| | - Kamran Ali
- Department of Diagnostic and Interventional Radiology, University of Kansas-Wichita, Wichita, KS 67214, USA; (M.I.); (K.A.)
| | - Khaled M. Elsayes
- Department of Abdominal Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77555, USA; (J.J.I.R.); (S.J.); (A.R.K.); (A.A.A.)
- Correspondence: (S.K.); (K.M.E.)
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Daniell J, Plazzer JP, Perera A, Macrae F. An exploration of genotype-phenotype link between Peutz-Jeghers syndrome and STK11: a review. Fam Cancer 2019; 17:421-427. [PMID: 28900777 DOI: 10.1007/s10689-017-0037-3] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Peutz-Jeghers Syndrome (PJS) is an autosomal dominant hereditary polyposis syndrome. Clinical features include hamartomatous polyps, mucocutaneous pigmentation and an increased predisposition towards developing malignancy. Variants in STK11, a tumour suppressor gene, located on Chromosome 19, predispose to PJS. Peutz-Jeghers Syndrome is associated with increased rates of malignancy, particularly gastrointestinal. However, PJS is also associated with increased gynaecological, testicular and thyroid papillary malignancy. Truncating variants in STK11 are thought to predispose to a more severe phenotype. Phenotype severity is based on earlier onset of gastrointestinal pathology arising from the polyps, such as intussusception or earlier onset malignancy. Missense variants are generally considered less severe than truncating variants. There remain a large number of variants of undetermined significance. Studies have attempted to correlate the location of variants with impact on protein structure and overall severity of the PJS phenotype. The results from these cohort studies have consistently found a non-random distribution of variants. Nevertheless, a consensus on phenotype severity based on variant location is yet to be established. A centralised database that collates all known variants would facilitate the interpretation of these variants, best under the governance of an international disease-specific organisation (InSiGHT). In particular, it could help explore the significance of variants based on their type or location. Understanding the genotype-phenotype link between STK11 variants and PJS could allow more personalised care for PJS patients and their families via appropriate risk stratification and personalised and targeted cancer screening.
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Affiliation(s)
| | | | | | - Finlay Macrae
- The University of Melbourne, Melbourne, Australia.,The Royal Melbourne Hospital, Melbourne, Australia
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Management of Peutz-Jeghers Syndrome in Children and Adolescents: A Position Paper From the ESPGHAN Polyposis Working Group. J Pediatr Gastroenterol Nutr 2019; 68:442-452. [PMID: 30585892 DOI: 10.1097/mpg.0000000000002248] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Peutz-Jeghers syndrome (PJS) is a well-described inherited syndrome, characterized by the development of gastrointestinal polyps, and characteristic mucocutaneous freckling. Development of small bowel intestinal polyps may lead to intussusception in children may require emergency laparotomy with potential loss of bowel. Gastrointestinal polyps may lead to bleeding and anemia. This European Society for Paediatric Gastroenterology Hepatology and Nutrition position paper provides a guide for diagnosis, assessment, and management of PJS in children and adolescents and guidance on avoiding complications from PJS or from the endoscopic procedures performed on these patients.This is the first position paper regarding PJS published by European Society for Paediatric Gastroenterology Hepatology and Nutrition. Literature from PubMed, Medline, and Embase was reviewed and in the absence of evidence, recommendations reflect the opinion of pediatric and adult experts involved in the care of polyposis syndromes. Because many of the studies that form the basis for the recommendations were descriptive and/or retrospective in nature, some of the recommendations are based on expert opinion. This position paper will be helpful in the appropriate management and timing of procedures in children and adolescents with PJS.
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Zacharias SA, Prasad R, Ciullo S, Mallon MG, Marinovich A, Pall H. Small Bowel Intussusception in a 16-Month-Old Child With Peutz-Jeghers Syndrome. Clin Pediatr (Phila) 2018; 57:745-748. [PMID: 28929791 DOI: 10.1177/0009922817732148] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
| | - Rajeev Prasad
- 1 St Christopher's Hospital for Children, Philadelphia, PA, USA.,2 Drexel University College of Medicine, Philadelphia, PA, USA
| | - Sean Ciullo
- 1 St Christopher's Hospital for Children, Philadelphia, PA, USA.,2 Drexel University College of Medicine, Philadelphia, PA, USA
| | - Mary G Mallon
- 1 St Christopher's Hospital for Children, Philadelphia, PA, USA.,2 Drexel University College of Medicine, Philadelphia, PA, USA
| | | | - Harpreet Pall
- 1 St Christopher's Hospital for Children, Philadelphia, PA, USA.,2 Drexel University College of Medicine, Philadelphia, PA, USA
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Chiang JM, Chen TC. Clinical manifestations and STK11 germline mutations in Taiwanese patients with Peutz-Jeghers syndrome. Asian J Surg 2017; 41:480-485. [PMID: 28869103 DOI: 10.1016/j.asjsur.2017.08.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2017] [Revised: 07/14/2017] [Accepted: 08/04/2017] [Indexed: 11/28/2022] Open
Abstract
BACKGROUNDS Clinical manifestations and molecular basis of Taiwanese patients with Peutz-Jeghers syndrome (PJS) were investigated to add the knowledge of phenotype and genotype of the disease. METHODS Based on the Pathology Data Bank and the Colorectal Cancer Register, we collected their clinical data. The entire coding sequence of the STK11 gene was amplified and analyzed by sequencing using the genomic DNA. RESULTS Fifteen patients diagnosed with PJS from 11 unrelated families were collected until 2015. The median age at the onset of symptoms was 19 years with intussusception as the most frequent presenting symptom. Ten patients developing 11 cancers at various anatomical sites, including two cases of sinonasal cancer, two lung cancers, two breast cancers, two rectal cancers, two gynecological cancers and one small bowel cancer. Five of the deceased patients had died of cancers. The median age of diagnosis of first cancer in the probands was 32 years. Seventy patients (7 of 10) diagnosed before age of 40. Mutations found in eight families included five novel mutations (exon 6, c.843 ins G; exon 8, c.2065 delete A; exon 8, c.G923A, nonsense; exon 6, c.748dupA; and mTOR c.5107dupA) and three previously reported mutations. The other three PJS families without detectable STK11 mutations did not develop malignancies so far. CONCLUSION This is the first comprehensive study of patients with Peutz-Jeghers syndrome in the Taiwanese. We have demonstrated that the phenotype of Peutz-Jeghers syndrome varies greatly among the patients. Patients with detectable STK11 mutations have very high risk of developing cancers.
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Affiliation(s)
- Jy-Ming Chiang
- Division of Colon and Rectal Surgery, Department of Surgery, Chang Gung Memorial Hospital, Lin-Kou Medical Center, Tao-Yuan, Taiwan; Chang Gung University, College of Medicine, Tao-Yuan, Taiwan.
| | - Tse-Ching Chen
- Chang Gung University, College of Medicine, Tao-Yuan, Taiwan; Department of Pathology, Chang Gung Memorial Hospital, Lin-Kou Medical Center, Tao-Yuan, Taiwan.
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钟 超, 彭 亮, 李 冉, 陈 静, 陈 新, 曾 笛, 徐 晓, 王 志, 陈 楚, 王 亚, 李 爱, 刘 思, 吴 保. [LKB1 regulates epithelial-mesenchymal transition in Peutz-Jeghers hamartoma and intestinal epithelial cells]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2017; 37:1078-1084. [PMID: 28801289 PMCID: PMC6765722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 05/21/2017] [Indexed: 07/30/2024]
Abstract
OBJECTIVE To investigate the molecular mechanism by which LKB1 regulates epithelial-mesenchymal transition (EMT) in Peutz-Jeghers hamartoma and intestinal epithelial cells. METHODS Immunohistochemistry was used to detect gene expression of LKB1, E-cadherin, and vimentin in 20 hamartoma tissues and 10 normal intestinal tissues, and collagen fiber deposition was analyzed using Masson trichrome staining. Normal intestinal epithelial NCM460 cells were transfected with LKB1 shRNA plasmid or negative control via lentiviral vectors, and the role of LKB1 in cell polarization and migration were determined using CCK8 and Transwell assays. Western blotting, quantitative real-time PCR (qPCR) and immunofluorescence were used to assess the alterations of EMT markers in the cells with LKB1 knockdown. RESULTS Compared with normal intestinal tissues, hamartoma polyps showed significantly decreased LKB1 and E-cadherin expressions and increased vimentin expression with increased collagen fiber deposition. The cells with LKB1 knockdown exhibited enhanced cell proliferation and migration activities (P<0.01). Western blot analysis, qPCR and immunofluorescence all detected decreased E-cadherin and increased N-cadherin, vimentin, Snail, and Slug expressions in the cells with LKB1 knockdown. CONCLUSION s LKB1 deficiency triggers EMT in intestinal epithelial cells and Peutz-Jeghers hamartoma, suggesting that EMT can serve as the therapeutic target for treatment of Peutz-Jeghers syndrome.
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Affiliation(s)
- 超 钟
- 南方医科大学南方医院消化内科//广东省胃肠疾病重点实验室, 广东 广州 510515Guangdong Provincial Key Laboratory of Gastroenterology/Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - 亮 彭
- 南方医科大学南方医院消化内科//广东省胃肠疾病重点实验室, 广东 广州 510515Guangdong Provincial Key Laboratory of Gastroenterology/Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - 冉 李
- 青岛大学附属医院感染科, 山东 青岛 370200Department of Infectious Disease, Qingdao University Affiliated Hospital, Qingdao 370200, China
| | - 静 陈
- 南方医科大学南方医院消化内科//广东省胃肠疾病重点实验室, 广东 广州 510515Guangdong Provincial Key Laboratory of Gastroenterology/Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - 新琦 陈
- 南方医科大学南方医院消化内科//广东省胃肠疾病重点实验室, 广东 广州 510515Guangdong Provincial Key Laboratory of Gastroenterology/Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - 笛 曾
- 广东省广州市番禺区人民医院消化内科, 广东 广州 510000Department of Gastroenterology, Guangzhou Panyu Central Hospital, Guangzhou 510000, China
| | - 晓平 徐
- 南方医科大学南方医院消化内科//广东省胃肠疾病重点实验室, 广东 广州 510515Guangdong Provincial Key Laboratory of Gastroenterology/Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - 志青 王
- 南方医科大学南方医院消化内科//广东省胃肠疾病重点实验室, 广东 广州 510515Guangdong Provincial Key Laboratory of Gastroenterology/Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - 楚弟 陈
- 南方医科大学南方医院消化内科//广东省胃肠疾病重点实验室, 广东 广州 510515Guangdong Provincial Key Laboratory of Gastroenterology/Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - 亚东 王
- 南方医科大学南方医院消化内科//广东省胃肠疾病重点实验室, 广东 广州 510515Guangdong Provincial Key Laboratory of Gastroenterology/Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - 爱民 李
- 南方医科大学南方医院消化内科//广东省胃肠疾病重点实验室, 广东 广州 510515Guangdong Provincial Key Laboratory of Gastroenterology/Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - 思德 刘
- 南方医科大学南方医院消化内科//广东省胃肠疾病重点实验室, 广东 广州 510515Guangdong Provincial Key Laboratory of Gastroenterology/Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - 保平 吴
- 南方医科大学南方医院消化内科//广东省胃肠疾病重点实验室, 广东 广州 510515Guangdong Provincial Key Laboratory of Gastroenterology/Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
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钟 超, 彭 亮, 李 冉, 陈 静, 陈 新, 曾 笛, 徐 晓, 王 志, 陈 楚, 王 亚, 李 爱, 刘 思, 吴 保. [LKB1 regulates epithelial-mesenchymal transition in Peutz-Jeghers hamartoma and intestinal epithelial cells]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2017; 37:1078-1084. [PMID: 28801289 PMCID: PMC6765722 DOI: 10.3969/j.issn.1673-4254.2017.08.13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 05/21/2017] [Indexed: 06/07/2023]
Abstract
OBJECTIVE To investigate the molecular mechanism by which LKB1 regulates epithelial-mesenchymal transition (EMT) in Peutz-Jeghers hamartoma and intestinal epithelial cells. METHODS Immunohistochemistry was used to detect gene expression of LKB1, E-cadherin, and vimentin in 20 hamartoma tissues and 10 normal intestinal tissues, and collagen fiber deposition was analyzed using Masson trichrome staining. Normal intestinal epithelial NCM460 cells were transfected with LKB1 shRNA plasmid or negative control via lentiviral vectors, and the role of LKB1 in cell polarization and migration were determined using CCK8 and Transwell assays. Western blotting, quantitative real-time PCR (qPCR) and immunofluorescence were used to assess the alterations of EMT markers in the cells with LKB1 knockdown. RESULTS Compared with normal intestinal tissues, hamartoma polyps showed significantly decreased LKB1 and E-cadherin expressions and increased vimentin expression with increased collagen fiber deposition. The cells with LKB1 knockdown exhibited enhanced cell proliferation and migration activities (P<0.01). Western blot analysis, qPCR and immunofluorescence all detected decreased E-cadherin and increased N-cadherin, vimentin, Snail, and Slug expressions in the cells with LKB1 knockdown. CONCLUSION s LKB1 deficiency triggers EMT in intestinal epithelial cells and Peutz-Jeghers hamartoma, suggesting that EMT can serve as the therapeutic target for treatment of Peutz-Jeghers syndrome.
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Affiliation(s)
- 超 钟
- 南方医科大学南方医院消化内科//广东省胃肠疾病重点实验室, 广东 广州 510515Guangdong Provincial Key Laboratory of Gastroenterology/Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - 亮 彭
- 南方医科大学南方医院消化内科//广东省胃肠疾病重点实验室, 广东 广州 510515Guangdong Provincial Key Laboratory of Gastroenterology/Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - 冉 李
- 青岛大学附属医院感染科, 山东 青岛 370200Department of Infectious Disease, Qingdao University Affiliated Hospital, Qingdao 370200, China
| | - 静 陈
- 南方医科大学南方医院消化内科//广东省胃肠疾病重点实验室, 广东 广州 510515Guangdong Provincial Key Laboratory of Gastroenterology/Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - 新琦 陈
- 南方医科大学南方医院消化内科//广东省胃肠疾病重点实验室, 广东 广州 510515Guangdong Provincial Key Laboratory of Gastroenterology/Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - 笛 曾
- 广东省广州市番禺区人民医院消化内科, 广东 广州 510000Department of Gastroenterology, Guangzhou Panyu Central Hospital, Guangzhou 510000, China
| | - 晓平 徐
- 南方医科大学南方医院消化内科//广东省胃肠疾病重点实验室, 广东 广州 510515Guangdong Provincial Key Laboratory of Gastroenterology/Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - 志青 王
- 南方医科大学南方医院消化内科//广东省胃肠疾病重点实验室, 广东 广州 510515Guangdong Provincial Key Laboratory of Gastroenterology/Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - 楚弟 陈
- 南方医科大学南方医院消化内科//广东省胃肠疾病重点实验室, 广东 广州 510515Guangdong Provincial Key Laboratory of Gastroenterology/Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - 亚东 王
- 南方医科大学南方医院消化内科//广东省胃肠疾病重点实验室, 广东 广州 510515Guangdong Provincial Key Laboratory of Gastroenterology/Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - 爱民 李
- 南方医科大学南方医院消化内科//广东省胃肠疾病重点实验室, 广东 广州 510515Guangdong Provincial Key Laboratory of Gastroenterology/Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - 思德 刘
- 南方医科大学南方医院消化内科//广东省胃肠疾病重点实验室, 广东 广州 510515Guangdong Provincial Key Laboratory of Gastroenterology/Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - 保平 吴
- 南方医科大学南方医院消化内科//广东省胃肠疾病重点实验室, 广东 广州 510515Guangdong Provincial Key Laboratory of Gastroenterology/Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
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Chen HY, Jin XW, Li BR, Zhu M, Li J, Mao GP, Zhang YF, Ning SB. Cancer risk in patients with Peutz-Jeghers syndrome: A retrospective cohort study of 336 cases. Tumour Biol 2017; 39:1010428317705131. [PMID: 28653895 DOI: 10.1177/1010428317705131] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Peutz-Jeghers syndrome is a rare autosomal dominant inherited disorder characterized by mucocutaneous pigmentation and hamartomatous gastrointestinal polyposis. A growing body of evidence has shown that Peutz-Jeghers syndrome could cause an increased risk of various cancers, yet the range of cancer risk estimates was wide among different studies. In this retrospective cohort study, 336 patients with Peutz-Jeghers syndrome in China were enrolled. The clinical characteristics, cancer spectrum, relative cancer risks, and cumulative cancer risks were analyzed. In total, 52 patients were diagnosed of cancer in the follow-up period, at a median age of 41 years (range: 21-67). The relative risk for cancer in Peutz-Jeghers syndrome patients was 63.858 (confidence interval: 47.514-85.823), and the cumulative cancer risk at the age of 60 years was 55%. Colorectal cancer was the most common cancer for Peutz-Jeghers syndrome patients (relative risk: 237.918, confidence interval: 154.417-366.572) and the cumulative cancer risk at the age of 60 years was 28%. There was a statistically significant difference in the cumulative cancer risk between patients with family history and those without family history, as well as between patients living in rural area and those living in urban areas ( p < 0.05), while no significant effects of gender and intussusception history on the cumulative cancer risk was found ( p > 0.05). Hopefully, our study may contribute to the management of this rare disorder and establishment of related surveillance projects, especially in China.
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Affiliation(s)
- Hong-Yu Chen
- 1 Department of Gastroenterology, Clinical College of Air Force General Hospital, Anhui Medical University, Beijing, China
| | - Xiao-Wei Jin
- 1 Department of Gastroenterology, Clinical College of Air Force General Hospital, Anhui Medical University, Beijing, China
| | - Bai-Rong Li
- 1 Department of Gastroenterology, Clinical College of Air Force General Hospital, Anhui Medical University, Beijing, China
| | - Ming Zhu
- 1 Department of Gastroenterology, Clinical College of Air Force General Hospital, Anhui Medical University, Beijing, China
| | - Jing Li
- 1 Department of Gastroenterology, Clinical College of Air Force General Hospital, Anhui Medical University, Beijing, China
| | - Gao-Ping Mao
- 1 Department of Gastroenterology, Clinical College of Air Force General Hospital, Anhui Medical University, Beijing, China
| | - Ya-Fei Zhang
- 1 Department of Gastroenterology, Clinical College of Air Force General Hospital, Anhui Medical University, Beijing, China.,2 Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Shou-Bin Ning
- 1 Department of Gastroenterology, Clinical College of Air Force General Hospital, Anhui Medical University, Beijing, China
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A Clinical and Molecular Genetic Study in 11 Chinese Children With Peutz-Jeghers Syndrome. J Pediatr Gastroenterol Nutr 2017; 64:559-564. [PMID: 27467201 DOI: 10.1097/mpg.0000000000001316] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
OBJECTIVES Peutz-Jeghers syndrome (PJS) is caused by the germline mutations in serine/threonine kinase 11 (STK11) gene. The aim of the present study was to investigate the spectrum of STK11 gene mutations using multiplex ligation-dependent probe amplification (MLPA) assay in combination with direct sequencing in Chinese children with PJS. METHODS Nine children who met the clinical criteria for PJS and 2 presumed patients with PJS were enrolled in the present study. Patients' clinical information on polyp characteristics, polyp-related complications, family histories, and so on were reviewed and analyzed. After obtaining informed consent, we performed a mutation analysis of STK11 gene in 11 Chinese patients using MLPA assay and direct sequencing. RESULTS By means of MLPA method, we detected exonic deletions in 5 patients. In details, 1 patient had the complete deletion of all 10 exons, 3 patients showed deletions of promoter region and exon 1, and 1 patient had exon deletions from 1 to 9. By direct sequencing of the coding region of STK11 gene, we identified point mutations in 4 patients at c.548T>G/p.Leu183Arg, c.580G>T/p.Asp194Tyr, c.152_153insGG/Asp53GlyfsX12, and c.631delC/Arg211GlyfsX76, respectively, and 3 of them are novel mutations. We failed to find any mutation in left 2 patients who met the clinical criteria of PJS. CONCLUSIONS MLPA plus direct sequencing revealed large genomic deletions of STK11 gene in Chinese children with PJS and increased the detecting rate of STK11 gene mutations in Chinese patients with PJS. MLPA combined with direct sequencing could serve as a better strategy for the genetic diagnosis of PJS in Chinese population.
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First report of somatic mosaicism for mutations in STK11 in four patients with Peutz-Jeghers syndrome. Fam Cancer 2016; 15:57-61. [PMID: 26386697 DOI: 10.1007/s10689-015-9839-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Peutz-Jeghers syndrome (PJS) is an autosomal dominant cancer predisposition syndrome characterised by gastrointestinal polyposis and mucocutaneous pigmentation. Mutations in STK11, a serine-threonine protein kinase, have been associated with PJS in up to 100 % of published series. The hypothesis that a further genetic locus for PJS exists is controversial. No mutations in any other genes have been described in association with PJS. To date, no instances of somatic mosaicism for STK11 have been described. DNA extracted from peripheral lymphocytes and buccal cells was screened by sequence analysis for mutations in STK11. Dosage analysis was undertaken by multiplex ligation-dependent probe amplification (MLPA). Four patients have been shown to have mosaicism in STK11: two had mosaic deletions of specific exons (2-3 and 3-10) of the STK11 gene; one had a mosaic nonsense mutation in exon 5; and one had a mosaic frameshift mutation in exon 8. This report details the first four reported cases of somatic mosaicism for STK11 associated with PJS. This shows that techniques in addition to direct sequencing such as MLPA must be used to assess for large scale genomic deletions in patients meeting clinical diagnostic criteria for PJS. This also adds further weight to the hypothesis of a single genetic locus for PJS.
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Jelsig AM, Qvist N, Sunde L, Brusgaard K, Hansen T, Wikman FP, Nielsen CB, Nielsen IK, Gerdes AM, Bojesen A, Ousager LB. Disease pattern in Danish patients with Peutz-Jeghers syndrome. Int J Colorectal Dis 2016; 31:997-1004. [PMID: 26979979 DOI: 10.1007/s00384-016-2560-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/07/2016] [Indexed: 02/04/2023]
Abstract
PURPOSE In this paper, we aimed to collect genetic and medical information on all Danish patients with Peutz-Jeghers syndrome (PJS), in order to contribute to the knowledge of phenotype and genotype. Peutz-Jeghers syndrome is a hereditary syndrome characterized by multiple hamartomatous polyps in the GI tract, mucocutaneous pigmentations, and an increased risk of cancer in the GI tract and at extraintestinal sites. Over 90 % of patients harbour a pathogenic mutation in STK11. METHODS Based on the Danish Pathology Data Bank, the Danish National Patient Register, as well as information from relevant departments at Danish hospitals, we identified patients and collected clinical and genetic information. RESULTS We identified 43 patients of which 14 were deceased. The prevalence was estimated to be ∼1 in 195,000 individuals. The median age at first symptom was 27.5 with invagination of the small bowel as the most frequent presenting symptom. We noted 18 occurrences of cancer at various anatomical sites, including a case of thyroid cancer and penile cancer. Eight of the deceased patients had died of cancer. Eighteen different mutations in STK11 had been detected in 28 patients. CONCLUSION This is the first comprehensive study of patients with Peutz-Jeghers syndrome in the Danish population identified from nationwide registers and databases. We have demonstrated that the expressivity of Peutz-Jeghers syndrome varies greatly among the patients, even within the same families, underlining the great phenotypic spectrum. Patients with PJS should be offered surveillance from childhood in order to prevent morbidity and reduce mortality.
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Affiliation(s)
- A M Jelsig
- Department of Clinical Genetics, Odense University Hospital, Sdr. Boulevard 29, 5000, Odense, Denmark. .,Institute of Clinical Research, University of Southern Denmark, Winsløwparken 19, 3, 5000, Odense, Denmark.
| | - N Qvist
- Department of Surgery A, Odense University Hospital, Sdr. Boulevard 29, 5000, Odense, Denmark
| | - L Sunde
- Department of Clinical Genetics, Aarhus University Hospital, Brendstrupgaardsvej 21 C, 8200, Aarhus, Denmark
| | - K Brusgaard
- Department of Clinical Genetics, Odense University Hospital, Sdr. Boulevard 29, 5000, Odense, Denmark.,Institute of Clinical Research, University of Southern Denmark, Winsløwparken 19, 3, 5000, Odense, Denmark
| | - Tvo Hansen
- Center for Genomic Medicine, Rigshospitalet, University Hospital of Copenhagen, Blegdamsvej 9, 2100, Copenhagen, Denmark
| | - F P Wikman
- Department of Molecular Medicine, Aarhus University Hospital, Brendstrupgaardsvej 21 C, 8200, Aarhus, Denmark
| | - C B Nielsen
- Department of Surgery, Hvidovre Hospital, Kettegårds Alle 30, 2650, Hvidovre, Denmark
| | - I K Nielsen
- Department of Clinical Genetics, Aalborg University Hospital, Ladegaardsgade 5, 9000, Aalborg, Denmark
| | - A M Gerdes
- Department of Clinical Genetics, University Hospital of Copenhagen, Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark
| | - A Bojesen
- Department of Clinical Genetics, Vejle Hospital, Lillebaelt Hospital, Kabbeltoft 25, 7100, Vejle, Denmark.,Institute of Regional Health Research, University of Southern Denmark, Winsløwparken 19, 3, 5000, Odense, Denmark
| | - L B Ousager
- Department of Clinical Genetics, Odense University Hospital, Sdr. Boulevard 29, 5000, Odense, Denmark.,Institute of Clinical Research, University of Southern Denmark, Winsløwparken 19, 3, 5000, Odense, Denmark
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Partanen JI, Tervonen TA, Klefström J. Breaking the epithelial polarity barrier in cancer: the strange case of LKB1/PAR-4. Philos Trans R Soc Lond B Biol Sci 2013; 368:20130111. [PMID: 24062587 DOI: 10.1098/rstb.2013.0111] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
The PAR clan of polarity regulating genes was initially discovered in a genetic screen searching for genes involved in asymmetric cell divisions in the Caenorhabditis elegans embryo. Today, investigations in worms, flies and mammals have established PAR proteins as conserved and fundamental regulators of animal cell polarization in a broad range of biological phenomena requiring cellular asymmetries. The human homologue of invertebrate PAR-4, a serine-threonine kinase LKB1/STK11, has caught attention as a gene behind Peutz-Jeghers polyposis syndrome and as a bona fide tumour suppressor gene commonly mutated in sporadic cancer. LKB1 functions as a master regulator of AMP-activated protein kinase (AMPK) and 12 other kinases referred to as the AMPK-related kinases, including four human homologues of PAR-1. The role of LKB1 as part of the energy sensing LKB1-AMPK module has been intensively studied, whereas the polarity function of LKB1, in the context of homoeostasis or cancer, has gained less attention. Here, we focus on the PAR-4 identity of LKB1, discussing the weight of evidence indicating a role for LKB1 in regulation of cell polarity and epithelial integrity across species and highlight recent investigations providing new insight into the old question: does the PAR-4 identity of LKB1 matter in cancer?
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Affiliation(s)
- Johanna I Partanen
- Cancer Cell Circuitry Laboratory, Translational Cancer Biology Research Program and Institute of Biomedicine, University of Helsinki, , Biomedicum Helsinki, Rm B507b, PO Box 63, Haartmaninkatu 8, 00014 Helsinki, Finland
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Borun P, Bartkowiak A, Banasiewicz T, Nedoszytko B, Nowakowska D, Teisseyre M, Limon J, Lubinski J, Kubaszewski L, Walkowiak J, Czkwianianc E, Siolek M, Kedzia A, Krokowicz P, Cichy W, Plawski A. High Resolution Melting analysis as a rapid and efficient method of screening for small mutations in the STK11 gene in patients with Peutz-Jeghers syndrome. BMC MEDICAL GENETICS 2013; 14:58. [PMID: 23718779 PMCID: PMC3681719 DOI: 10.1186/1471-2350-14-58] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/23/2012] [Accepted: 05/23/2013] [Indexed: 12/19/2022]
Abstract
Background Peutz-Jeghers syndrome (PJS) is a rare hereditary syndrome characterized by the occurrence of hamartomatous polyps in the gastrointestinal tract, mucocutaneous pigmentation and increased risk of cancer in multiple internal organs. Depending on the studied population, its incidence has been estimated to range from 1:200 000 even up to 1:50 000 births. Being an autosomal disease, PJS is caused in most cases by mutations in the STK11 gene. Methods The majority of causative DNA changes identified in patients with PJS are small mutations and, therefore, developing a method of their detection is a key aspect in the advancement of genetic diagnostics of PJS patients. We designed 13 pairs of primers, which amplify at the same temperature and enable examination of all coding exons of the STK11 gene by the HRM analysis. Results In our group of 41 families with PJS small mutations of the STK11 gene were detected in 22 families (54%). In the remaining cases all of the coding exons were sequenced. However, this has not allowed to detect any additional mutations. Conclusions The developed methodology is a rapid and cost-effective screening tool for small mutations in PJS patients and makes it possible to detect all the STK11 gene sequence changes occurring in this group.
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Affiliation(s)
- Pawel Borun
- Institute of Human Genetics, Polish Academy of Sciences, Strzeszyńska 32, Poznan, 60-479, Poland
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Abstract
BACKGROUND AND AIMS We reviewed our institution's experience with Peutz-Jegher syndrome (PJS) in children to determine whether current recommendations on timing of screening and follow-up should be modified. METHODS We reviewed the charts of all of the children with a diagnosis of PJS at our institution from 2000 to 2011 abstracting data on intussusceptions events, polyp characteristics, Sertoli cell (SC) tumors, family history, imaging, and interventions. RESULTS Of 14 children identified, 10 were boys. Median age at first clinical evaluation was 4.5 years, and family history and/or mucocutaneous pigmentation were the 2 most common factors stimulating screening. Median age at first screening test was 5 years (range 1-16), and at first polyp identification, 5 years (range 1 to 18). There were 7 intussusception events in 5 children, with median age of 10 and range 5 to 16 for first event. Two boys had SC tumors at 8 and 11 years. Polyps were identified during initial screening in 9 of 14 patients. Polyps were found in the stomach or duodenum in 5 (36%), small bowel in 7, (50%) and colon in 3 (21%) children. Large polyps were identified in 9 children at median age of 7 years. CONCLUSIONS Polyps causing significant clinical consequences can occur frequently in children with PJS younger than 8 years. Revised guidelines should consider initial screening at age 4 to 5 with capsule endoscopy and upper and lower endoscopy as well as evaluation for SC tumors and re-evaluation whenever symptoms suggest polyp-associated complications.
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Liu WL, Li F, He ZX, Jiang HY, Ai R, Zhu XP, Chen XX, Ma HW. Identification of a Novel de Novo STK11 Mutation in a Chinese Child with Peutz-Jeghers Syndrome. J Int Med Res 2011; 39:2033-8. [PMID: 22118009 DOI: 10.1177/147323001103900551] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant inherited disorder characterized by gastrointestinal polyposis and mucocutaneous pigmentation. PJS patients have an increased risk of cancer in multiple locations. Germ-line mutations in the STK11 gene have been found to be responsible for most PJS cases. DNA samples were obtained from a Chinese child with PJS, his clinically unaffected parents and 50 unrelated normal individuals, and the exons and flanking intronic sequences of the STK11 gene were analysed by polymerase chain reaction and direct sequencing. A novel de novo mutation (c.698_699insG; F234LfsX3) was identified in exon 5 of STK11, that resulted in a translational frameshift leading to termination at codon 236. This mutation was not found in the parents or unrelated individuals. These results enlarge the genotypic spectrum of STK11, particularly with regard to early onset, as observed in the present sporadic PJS case. This study may have important future implications for precise genotype-phenotype correlation research.
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Affiliation(s)
- W-L Liu
- Department of Developmental Paediatrics, The Affiliated Shengjing Hospital of China Medical University, Shenyang, China
- Department of Paediatrics, Affiliated Hospital of Guiyang Medical College, Guiyang, China
| | - F Li
- Department of Ophthalmology, Affiliated Hospital of Guiyang Medical College, Guiyang, China
| | - Z-X He
- Department of Paediatrics, Affiliated Hospital of Guiyang Medical College, Guiyang, China
| | - H-Y Jiang
- Department of Paediatrics, Affiliated Hospital of Guiyang Medical College, Guiyang, China
| | - R Ai
- Department of Paediatrics, Affiliated Hospital of Guiyang Medical College, Guiyang, China
| | - X-P Zhu
- Department of Paediatrics, Affiliated Hospital of Guiyang Medical College, Guiyang, China
| | - X-X Chen
- Department of Paediatrics, Affiliated Hospital of Guiyang Medical College, Guiyang, China
| | - H-W Ma
- Department of Developmental Paediatrics, The Affiliated Shengjing Hospital of China Medical University, Shenyang, China
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van Lier MGF, Korsse SE, Mathus-Vliegen EMH, Kuipers EJ, van den Ouweland AMW, Vanheusden K, van Leerdam ME, Wagner A. Peutz-Jeghers syndrome and family planning: the attitude towards prenatal diagnosis and pre-implantation genetic diagnosis. Eur J Hum Genet 2011; 20:236-9. [PMID: 21829227 DOI: 10.1038/ejhg.2011.152] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Peutz-Jeghers syndrome (PJS) is a hereditary disorder caused by LKB1 gene mutations, and is associated with considerable morbidity and decreased life expectancy. This study was conducted to assess the attitude of PJS patients towards family planning, prenatal diagnosis (PND) and pregnancy termination, and pre-implantation genetic diagnosis (PGD). In a cross-sectional study, 61 adult PJS patients were asked to complete a questionnaire concerning genetic testing, family planning, PND and PGD. The questionnaire was completed by 52 patients (85% response rate, 44% males) with a median age of 44 (range 18-74) years. A total of 37 (71%) respondents had undergone genetic testing. In all, 24 respondents (46%, 75% males) had children. A total of 15 (29%) respondents reported that their diagnosis of PJS had influenced their decisions regarding family planning, including 10 patients (19%, 9/10 females) who did not want to have children because of their disease. Termination of pregnancy after PND in case of a foetus with PJS was considered 'acceptable' for 15% of the respondents, whereas 52% considered PGD acceptable. In conclusion, the diagnosis of PJS influences the decisions regarding family planning in one third of PJS patients, especially in women. Most patients have a negative attitude towards pregnancy termination after PND, while PGD in case of PJS is judged more acceptable. These results emphasise the importance of discussing aspects regarding family planning with PJS patients, including PND and PGD.
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Affiliation(s)
- Margot G F van Lier
- Departments of Gastroenterology and Hepatology, Erasmus University Medical Centre, Rotterdam, The Netherlands
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van Lier MGF, Mathus-Vliegen EMH, Wagner A, van Leerdam ME, Kuipers EJ. High cumulative risk of intussusception in patients with Peutz-Jeghers syndrome: time to update surveillance guidelines? Am J Gastroenterol 2011; 106:940-5. [PMID: 21157440 DOI: 10.1038/ajg.2010.473] [Citation(s) in RCA: 101] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Peutz-Jeghers syndrome (PJS) is characterized by gastrointestinal hamartomas. The hamartomas are located predominantly in the small intestine and may cause intussusceptions. We aimed to assess the characteristics, risk, and onset of intussusception in a large cohort of PJS patients to determine whether enteroscopy with polypectomy should be incorporated into surveillance recommendations. METHODS All PJS patients from two academic hospitals were included in this cohort study (prospective follow-up between 1995 and July 2009). We obtained clinical data by interview and chart review. Deceased family members with PJS were included retrospectively. Cumulative intussusception risks were calculated by Kaplan–Meier analysis. RESULTS We included 110 PJS patients (46% males) from 50 families. In all, 76 patients (69%) experienced at least one intussusception (range 1-6), at a median age of 16 (3-50) years at first occurrence. The intussusception risk was 50% at the age of 20 years (95% confidence interval 17-23 years) and the risk was independent of sex, family history, and mutation status. The intussusceptions occurred in the small intestine in 95% of events, and 80% of all intussusceptions (n=128) presented as an acute abdomen. Therapy was surgical in 92.5% of events. Based on 37 histology reports, the intussusceptions were caused by polyps with a median size of 35 mm (range 15-60 mm). CONCLUSIONS PJS patients carry a high cumulative intussusception risk at young age. Intussusceptions are generally caused by polyps >15 mm and treatment is mostly surgical. These results support the approach of enteroscopic surveillance, with removal of small-intestinal polyps >10-15 mm to prevent intussusceptions. The effect of such an approach on the incidence of intussusception remains to be established in prospective trials.
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Affiliation(s)
- M G F van Lier
- Department of Gastroenterology and Hepatology, University Medical Center, Rotterdam, The Netherlands.
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Tomasello C, Franceschi E, Tosoni A, Brandes A. Gangliogliomas: recent advances in classification and treatment. FUTURE NEUROLOGY 2010. [DOI: 10.2217/fnl.10.26] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Gangliogliomas are uncommon neoplasms of the CNS and, as a consequence, few randomized, clinical trials have been performed, thereby limiting treatment guidelines. The best management of newly diagnosed gangliogliomas entails a complete resection, corroborated by postoperative contrast-enhanced MRI. If an incomplete resection is documented, a second attempt at gross total resection should be considered, given the prognostic significance of complete resection. Small-volume residual disease is best managed with involved-field radiotherapy. The role of chemotherapy is uncertain and, in general, would be reserved for patients having previously failed surgery and radiotherapy. This article summarizes the most important available up-to-date information on clinical, prognostic, radiological, pathological and therapeutic findings for gangliogliomas in order to provide valuable guidance for the diagnosis and management of such uncommon tumors. This information may be considered as possible background for future studies designed to clarify the complex management of these tumors.
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Affiliation(s)
- Chiara Tomasello
- Department of Medical Oncology, Azienda USL Bell aria-Maggiore Hospital, Bologna, Italy
| | - Enrico Franceschi
- Department of Medical Oncology, Azienda USL Bell aria-Maggiore Hospital, Bologna, Italy
| | - Alicia Tosoni
- Department of Medical Oncology, Azienda USL Bell aria-Maggiore Hospital, Bologna, Italy
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High cancer risk in Peutz-Jeghers syndrome: a systematic review and surveillance recommendations. Am J Gastroenterol 2010; 105:1258-64; author reply 1265. [PMID: 20051941 DOI: 10.1038/ajg.2009.725] [Citation(s) in RCA: 301] [Impact Index Per Article: 20.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Peutz-Jeghers syndrome (PJS) is an autosomal dominant inherited disorder associated with increased cancer risk. Surveillance and patient management are, however, hampered by a wide range in cancer risk estimates. We therefore performed a systematic review to assess cancer risks in PJS patients and used these data to develop a surveillance recommendation. METHODS A systematic PubMed search was performed up to February 2009, and all original articles dealing with PJS patients with confirmed cancer diagnoses were included. Data involving cancer frequencies, mean ages at cancer diagnosis, relative risks (RRs), and cumulative risks were collected. RESULTS Twenty-one original articles, 20 cohort studies, and one meta-analysis fulfilled the inclusion criteria. The cohort studies showed some overlap in the patient population and included a total of 1,644 patients; 349 of them developed 384 malignancies at an average age of 42 years. The most common malignancy was colorectal cancer, followed by breast, small bowel, gastric, and pancreatic cancers. The reported lifetime risk for any cancer varied between 37 and 93%, with RRs ranging from 9.9 to 18 in comparison with the general population. Age-related cumulative risks were given for any cancer and gastrointestinal, gynecological, colorectal, pancreatic, and lung cancers. CONCLUSIONS PJS patients are markedly at risk for several malignancies, in particular gastrointestinal cancers and breast cancer. On the basis of these elevated risks, a surveillance recommendation is developed to detect malignancies in an early phase and to remove polyps that may be premalignant and may cause complications, so as to improve the outcome.
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Van Lier MGF, Mathus-Vliegen EMH, Van Leerdam ME, Kuipers EJ, Looman CWN, Wagner A, Vanheusden K. Section Editor:
Aad Tibben, email: Tibben@lumc.nl: Quality of life and psychological distress in patients with Peutz-Jeghers syndrome. Clin Genet 2010; 78:219-26. [DOI: 10.1111/j.1399-0004.2010.01469.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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Kopacova M, Tacheci I, Rejchrt S, Bures J. Peutz-Jeghers syndrome: Diagnostic and therapeutic approach. World J Gastroenterol 2009; 15:5397-408. [PMID: 19916169 PMCID: PMC2778095 DOI: 10.3748/wjg.15.5397] [Citation(s) in RCA: 125] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Peutz-Jeghers syndrome (PJS) is an inherited, autosomal dominant disorder distinguished by hamartomatous polyps in the gastrointestinal tract and pigmented mucocutaneous lesions. Prevalence of PJS is estimated from 1 in 8300 to 1 in 280 000 individuals. PJS predisposes sufferers to various malignancies (gastrointestinal, pancreatic, lung, breast, uterine, ovarian and testicular tumors). Bleeding, obstruction and intussusception are common complications in patients with PJS. Double balloon enteroscopy (DBE) allows examination and treatment of the small bowel. Polypectomy using DBE may obviate the need for repeated urgent operations and small bowel resection that leads to short bowel syndrome. Prophylaxis and polypectomy of the entire small bowel is the gold standard in PJS patients. Intraoperative enteroscopy (IOE) was the only possibility for endoscopic treatment of patients with PJS before the DBE era. Both DBE and IOE facilitate exploration and treatment of the small intestine. DBE is less invasive and more convenient for the patient. Both procedures are generally safe and useful. An overall recommendation for PJS patients includes not only gastrointestinal multiple polyp resolution, but also regular lifelong cancer screening (colonoscopy, upper endoscopy, computed tomography, magnetic resonance imaging or ultrasound of the pancreas, chest X-ray, mammography and pelvic examination with ultrasound in women, and testicular examination in men). Although the incidence of PJS is low, it is important for clinicians to recognize these disorders to prevent morbidity and mortality in these patients, and to perform presymptomatic testing in the first-degree relatives of PJS patients.
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Ausavarat S, Leoyklang P, Vejchapipat P, Chongsrisawat V, Suphapeetiporn K, Shotelersuk V. Novel mutations in the STK11 gene in Thai patients with Peutz-Jeghers syndrome. World J Gastroenterol 2009; 15:5364-7. [PMID: 19908348 PMCID: PMC2776867 DOI: 10.3748/wjg.15.5364] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Peutz-Jeghers syndrome (PJS), a rare autosomal dominant inherited disorder, is characterized by hamartomatous gastrointestinal polyps and mucocutaneous pigmentation. Patients with this syndrome have a predisposition to a variety of cancers in multiple organs. Mutations in the serine/threonine kinase 11 (STK11) gene have been identified as a major cause of PJS. Here we present the clinical and molecular findings of two unrelated Thai individuals with PJS. Mutation analysis by Polymerase Chain Reaction-sequencing of the entire coding region of STK11 revealed two potentially pathogenic mutations. One harbored a single nucleotide deletion (c.182delG) in exon 1 resulting in a frameshift leading to premature termination at codon 63 (p.Gly61AlafsX63). The other carried an in-frame 9-base-pair (bp) deletion in exon 7, c.907_915del9 (p.Ile303_Gln305del). Both deletions were de novo and have never been previously described. This study has expanded the genotypic spectrum of the STK11 gene.
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Abstract
Hamartomatous polyposis syndromes are a diverse group of inherited conditions grouped together because they exhibit hamartomatous rather than epithelial polyp histology. Each syndrome exhibits characteristic polyp histology, gastrointestinal polyp distribution, gastrointestinal cancer risks, extra-intestinal benign findings and often extra-intestinal cancer risks. Identifying individuals at risk for these syndromes and accurately defining the precise diagnosis are necessary for planning surveillance and management in order to prevent the benign and malignant complications. Characteristic syndrome features including gastrointestinal findings, pathology, genetics, and management options for the three most common hamartomatous polyposis syndromes, Peutz-Jeghers syndrome, PTEN hamartoma tumour syndrome, and juvenile polyposis will be presented in this review.
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Affiliation(s)
- Amanda Gammon
- Huntsman Cancer Institute, 2000 Circle of Hope, Salt Lake City, UT 84112-5550, Phone: 801-585-5938, Fax: 801-585-2980,
| | - Kory Jasperson
- Huntsman Cancer Institute, 2000 Circle of Hope, Salt Lake City, UT 84112-5550, Phone: 801-581-7316, Fax: 801-585-2980,
| | - Wendy Kohlmann
- Huntsman Cancer Institute, 2000 Circle of Hope, Salt Lake City, UT 84112-5550, Phone: 801-587-5556, Fax: 801-585-2980,
| | - Randall W. Burt
- Huntsman Cancer Institute, 2000 Circle of Hope, Salt Lake City, UT 84112-5550, Phone: 801-585-3281, Fax: 801-581-3389,
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Wang SL, Gu GL. Present status and problems in diagnosis and treatment of Peutz-Jeghers syndrome. Shijie Huaren Xiaohua Zazhi 2008; 16:2385-2389. [DOI: 10.11569/wcjd.v16.i21.2385] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Peutz-Jeghers syndrome (PJS) is an autosomal dominant inherited disease, which is caused by inactivating germline mutations in LKB1/STK11 and characterized by mucocutaneous pigmentation, multiple gastrointestinal hamartomatous polyps and family history. Life-threatening complications include intestinal obstruction, an increasing risk for developing gastrointestinal malignancies and extraintestinal cancers. PJS more frequently happens to teenagers. Besides susceptibility to malignant cancer, it was characterized by complications associated with polyps, repeated hospitalizations and operations, as well as a high cost of medical cost, which especially brings harm to one-child family in China. This paper focuses on the diagnoses and treatments in PJS, such as clinical use of double-balloon enteroscopy and open surgery combined with intraoperative endoscopy. Also, COX-2 inhibitors and rapamycin for chemoprevention are introduced.
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Mas E, Breton A. Pathologies digestives, infections intestinales et invagination intestinale aiguë. Arch Pediatr 2007; 14 Suppl 3:S159-64. [DOI: 10.1016/s0929-693x(07)80021-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
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Burkart AL, Sheridan T, Lewin M, Fenton H, Ali NJ, Montgomery E. Do sporadic Peutz-Jeghers polyps exist? Experience of a large teaching hospital. Am J Surg Pathol 2007; 31:1209-14. [PMID: 17667545 DOI: 10.1097/pas.0b013e3180339944] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Most types of sporadic gastrointestinal (GI) polyps vastly outnumber their syndromic counterparts. In contrast, the incidence of sporadic Peutz-Jeghers polyps (PJP) is unknown. We examined all potential PJP seen at our hospital over a 22-year (y) period to assess the incidence of sporadic PJP. The pathology database of a large hospital was searched for "Peutz-Jeghers polyp(s)," yielding 121 polyps from 38 patients. The polyps were reviewed by 3 pathologists to confirm the diagnosis. Clinical information to confirm or refute a diagnosis of Peutz-Jeghers syndrome (PJS) was collected. Of the 102 polyps included after histologic review, 94 polyps arose in patients meeting the World Health Organization criteria for PJS. These PJS polyps were eliminated from further analysis. Clinical information was obtained for the remaining 8 patients with potential "sporadic" PJP (1 to 50 y; mean=14 y; median=4 y). Of the 8 potential sporadic PJP, only 3 polyps from 3 patients had unequivocal PJP histologic features, all from the small intestine. All 3 patients had clinical histories suggesting syndromic PJP although they did not meet World Health Organization criteria, that is, 2 developed pancreatic cancer, 1 had bilateral "ovarian cystic masses" and a glomus tympanicum tumor, and 1 had strong family history of GI malignancies. The 5 remaining patients each had a colonic polyp with features suggestive, but not definitely diagnostic of, PJP. In these cases, prolapse lesions could not be excluded. One patient had a history of high-grade dysplasia in a tubulovillous adenoma in the colon at 53 years, but no family cancer history. Another had a family GI cancer history. Another had a history of pituitary adenoma at age 39, and the last had ductal breast carcinoma diagnosed 4 years before the discovery of the polyp. Our findings suggest that if sporadic PJP exist, they are extremely rare. Moreover, our data suggest that individuals with a single PJP may have a cumulative lifetime risk of cancer similar to those with the syndrome.
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Affiliation(s)
- Ashlie L Burkart
- Department of Pathology, The Johns Hopkins Hospital, Baltimore, MD, USA
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