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Gebhart P, Singer C, Muhr D, Stein C, Tan YY. A De Novo PTEN Pathogenic Variant in a Young Girl with Sporadic Cowden Syndrome-A Case Report. Pediatr Rep 2025; 17:54. [PMID: 40407579 PMCID: PMC12101143 DOI: 10.3390/pediatric17030054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2025] [Revised: 03/31/2025] [Accepted: 04/19/2025] [Indexed: 05/26/2025] Open
Abstract
Cowden syndrome (CS) is a rare hereditary disorder characterized by benign overgrowth in various tissues and a high risk of breast and thyroid cancer. CS is closely associated with pathogenic variants (PVs) in the phosphatase and tensin homolog (PTEN) tumor suppressor gene. PVs in PTEN are usually inherited and estimates of de novo frequencies remain inconclusive. The diagnosis of PTEN-associated syndromes remains a challenge in clinical practice, due to patients showing seemingly unrelated symptoms. We report on the clinical management of a now 18-year-old female CS patient, who initially presented with macrosomia, motor development delay and later, lipomas on the abdominal wall. Genetic testing revealed a de novo PTEN PV c.1003C>T(p.Arg335X). The PV was detected in leukocyte DNA of the patient. Using direct DNA sequencing, as well as NGS, the PV was not found in any of the tissues derived from immediate family members. However, the PV was detected in multiple samples representing other germ layers of the affected patient, which renders constitutional mosaicism unlikely. This case constitutes the first description of a de novo PTEN PV, in which constitutional mosaicism was systematically ruled out and underscores the importance of timely genetic testing of patients and their relatives. The diagnosis of a PTEN PV in early childhood allows for the implementation of a comprehensive, lifelong care plan that addresses both pediatric and adult medical needs as well as cancer risk surveillance and family planning. This not only accounts for the affected patients, but also their close family members who might be susceptible to the same PV.
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Affiliation(s)
- Paulina Gebhart
- Department of OB/GYN and Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria; (C.S.); (D.M.); (Y.Y.T.)
| | - Christian Singer
- Department of OB/GYN and Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria; (C.S.); (D.M.); (Y.Y.T.)
| | - Daniela Muhr
- Department of OB/GYN and Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria; (C.S.); (D.M.); (Y.Y.T.)
| | - Christina Stein
- Center for Forensic Medicine, DNA Central Laboratory, Medical University of Vienna, 1090 Vienna, Austria;
| | - Yen Y. Tan
- Department of OB/GYN and Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria; (C.S.); (D.M.); (Y.Y.T.)
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Maeda Y, Ikeda T, Sato A, Matsumoto A, Jinno H. Breast Cancer with a Newly Diagnosed Variant in the PTEN Gene: A Case Report. Surg Case Rep 2025; 11:24-0082. [PMID: 39974553 PMCID: PMC11835985 DOI: 10.70352/scrj.cr.24-0082] [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] [Received: 06/27/2024] [Accepted: 12/29/2024] [Indexed: 02/21/2025] Open
Abstract
INTRODUCTION The phosphatase and tensin homolog hamartoma tumor syndrome (PHTS) refers to a spectrum of disorders caused by variants of the phosphatase and tensin homolog (PTEN) gene, including Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome, adult Lhermitte-Duclos disease, and autism spectrum disorders associated with macrocephaly. PHTS is characterized by hamartomas in multiple organs and is associated with an increased risk of developing malignant tumors including, breast, thyroid, endometrial, colorectal, and kidney tumors. Breast cancer is the most common malignancy associated with PHTS. CASE PRESENTATION We describe the case of a 44-year-old female patient with invasive ductal carcinoma of the right breast. Cobblestone papillomatosis was present in the gingiva. She had a medical history of bilateral adenomatous goiters for 10 years. Her mother had been diagnosed with breast cancer, thyroid and tongue tumors, gastric polyps, hepatic hemangioma, and collagen disease. Additionally, the patient's maternal grandmother had a history of colon cancer. Based on the patient's family history and physical findings, CS was suspected, and direct DNA sequencing analysis revealed a haplotype c.634del mutation in exon 7 of the PTEN gene. Although there is no clear evidence supporting risk-reducing surgery for PHTS, a right nipple-sparing mastectomy, sentinel lymph node biopsy, and tissue expander reconstruction were performed. CONCLUSIONS We report a case of breast cancer with a newly diagnosed c.634del mutation in the PTEN gene. We also reviewed the current literature on PTEN genetic variants and breast cancer subtypes.
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Affiliation(s)
- Yuka Maeda
- Department of Surgery, School of Medicine, Teikyo University, Tokyo, Japan
| | - Tatsuhiko Ikeda
- Department of Surgery, School of Medicine, Teikyo University, Tokyo, Japan
| | - Ayana Sato
- Department of Surgery, School of Medicine, Teikyo University, Tokyo, Japan
| | - Akiko Matsumoto
- Department of Surgery, School of Medicine, Teikyo University, Tokyo, Japan
| | - Hiromitsu Jinno
- Department of Surgery, School of Medicine, Teikyo University, Tokyo, Japan
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Schultz KAP, MacFarland SP, Perrino MR, Mitchell SG, Kamihara J, Nelson AT, Mallinger PHR, Brzezinski JJ, Maxwell KN, Woodward ER, Gallinger B, Kim SY, Greer MLC, Schneider KW, Scollon SR, Das A, Wasserman JD, Eng C, Malkin D, Foulkes WD, Michaeli O, Bauer AJ, Stewart DR. Update on Pediatric Surveillance Recommendations for PTEN Hamartoma Tumor Syndrome, DICER1-Related Tumor Predisposition, and Tuberous Sclerosis Complex. Clin Cancer Res 2025; 31:234-244. [PMID: 39540884 PMCID: PMC11747828 DOI: 10.1158/1078-0432.ccr-24-1947] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 10/04/2024] [Accepted: 11/13/2024] [Indexed: 11/16/2024]
Abstract
Phosphate and tensin homolog hamartoma tumor syndrome, DICER1-related tumor predisposition, and tuberous sclerosis complex are rare conditions, which each increases risk for distinct spectra of benign and malignant neoplasms throughout childhood and adulthood. Surveillance considerations for each of these conditions focus on patient and family education, early detection, and multidisciplinary care. In this article, we present updated surveillance recommendations and considerations for children and adolescents with phosphate and tensin homolog hamartoma tumor syndrome, DICER1-related tumor predisposition, and tuberous sclerosis complex and provide suggestions for further research in each of these conditions.
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Affiliation(s)
- Kris Ann P. Schultz
- International Pleuropulmonary Blastoma/DICER1 Registry, Cancer and Blood Disorders, Children’s Minnesota, Minneapolis, MN
| | - Suzanne P. MacFarland
- Division of Oncology, The Children’s Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
| | - Melissa R. Perrino
- Department of Oncology, St Jude Children’s Research Hospital, Memphis, TN
| | - Sarah G. Mitchell
- Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA
| | - Junne Kamihara
- Department of Pediatric Oncology, Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA
| | - Alexander T. Nelson
- International Pleuropulmonary Blastoma/DICER1 Registry, Cancer and Blood Disorders, Children’s Minnesota, Minneapolis, MN
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
| | - Paige H. R. Mallinger
- International Pleuropulmonary Blastoma/DICER1 Registry, Cancer and Blood Disorders, Children’s Minnesota, Minneapolis, MN
| | - Jack J. Brzezinski
- Division of Haematology/Oncology, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON
| | - Kara N. Maxwell
- Department of Medicine, Division of Hematology/Oncology and Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Emma R. Woodward
- Manchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Manchester, UK
- Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Bailey Gallinger
- Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON
- Department of Molecular Genetics, The University of Toronto, Toronto, ON
| | - Sun Young Kim
- Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, College of Medicine, University of Cincinnati, Cincinnati, OH
| | - Mary-Louise C. Greer
- Department of Diagnostic and Interventional Radiology, The Hospital for Sick Children, Department of Medical Imaging, University of Toronto, Toronto, ON
| | - Kami Wolfe Schneider
- Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Sarah R. Scollon
- Department of Pediatrics, Texas Children’s Cancer and Hematology Center, Baylor College of Medicine, Houston, TX
| | - Anirban Das
- Division of Haematology/Oncology, The Hospital for Sick Children, Department of Pediatrics, University of Toronto, Toronto, ON
| | - Jonathan D. Wasserman
- Division of Endocrinology, The Hospital for Sick Children, Department of Pediatrics, University of Toronto, Toronto, ON
| | - Charis Eng
- Genomic Medicine Institute, Lerner Research Institute, and Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH
| | - David Malkin
- Division of Haematology/Oncology, The Hospital for Sick Children, Department of Pediatrics, University of Toronto, Toronto, ON
| | | | - Orli Michaeli
- Division of Hematology and Oncology, Schneider Children’s Medical Center of Israel, Petach Tikva, Israel
| | - Andrew J. Bauer
- Division of Endocrinology and Diabetes, The Children’s Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
| | - Douglas R. Stewart
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD
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Schei-Andersen AJ, van Oirschot B, Drissen MMCM, Schieving J, Schuurs-Hoeijmakers JHM, Vos JR, Barton CM, Hoogerbrugge N. Exploring the Prevalence of Oral Features for Early Detection of PTEN Hamartoma Tumour Syndrome. Int Dent J 2024; 74:1424-1431. [PMID: 38697906 PMCID: PMC11551572 DOI: 10.1016/j.identj.2024.04.014] [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: 02/23/2024] [Revised: 04/04/2024] [Accepted: 04/07/2024] [Indexed: 05/05/2024] Open
Abstract
AIMS Patients with PTEN hamartoma tumour syndrome (PHTS) have an increased risk of developing cancer due to a pathogenic germline variant in the PTEN tumour suppressor gene. Early recognition of PHTS facilitates initiation of cancer surveillance which is highly effective in preventing the development of advanced malignancies. PHTS is rare and due to its varied phenotype, even within families, oral abnormalities may be a valuable tool in the identification of these patients at an early stage before cancer development. MATERIALS AND METHODS Between 1997 and 2020, phenotypic characteristics were evaluated in 81 paediatric (median age: 9 years) and 86 adult (median age: 40 years) PHTS patients by one of 2 medical experts during yearly surveillance visits at a Dutch PHTS expertise centre. Oral features evaluated included gingival hypertrophy, oral papillomas, and high palate (in adults). RESULTS Within adults, gingival hypertrophy was present in 94%, oral papillomas in 88%, and a high palate in 89%. All adult patients had at least one of these oral features, and 99% showed at least 2 oral features. Oral features were less common in paediatric patients, especially under 11 years of age. Gingival hypertrophy was observed in 44% and oral papillomas in 54% of paediatric patients. CONCLUSIONS The presence of 2 or 3 oral features may indicate PHTS in adults or adolescents, especially if macrocephaly is present. Dental professionals are well-positioned to recognise these oral manifestations could be related to PHTS. They can initiate an overall clinical assessment of the patient by alerting the patient's medical practitioner of the findings and the possible need for genetic testing. This could significantly improve outcomes, including life expectancy, for patients and possibly for their relatives. CLINICAL RELEVANCE Dental professionals are ideally placed to recognise oral features and initiate early assessment of PHTS which could significantly improve patient outcomes.
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Affiliation(s)
- Ane J Schei-Andersen
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands; Radboud Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Bart van Oirschot
- Department of Dentistry, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Meggie M C M Drissen
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands; Radboud Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Jolanda Schieving
- Department of Paediatric Neurology, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Janneke H M Schuurs-Hoeijmakers
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands; Radboud Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Janet R Vos
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands; Radboud Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Claire M Barton
- PTEN Research Foundation, Registered office: 4th Floor, St James House, St James Square, Cheltenham, UK; Barton Oncology Ltd, Dormers, The Green, Croxley Green, Hertfordshire, UK
| | - Nicoline Hoogerbrugge
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands; Radboud Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, the Netherlands.
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Cabrera S, de la Calle I, Baulies S, Gil-Moreno A, Colas E. Screening Strategies to Improve Early Diagnosis in Endometrial Cancer. J Clin Med 2024; 13:5445. [PMID: 39336931 PMCID: PMC11432712 DOI: 10.3390/jcm13185445] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Revised: 09/07/2024] [Accepted: 09/09/2024] [Indexed: 09/30/2024] Open
Abstract
Endometrial cancer is the most common gynecological malignancy in high-income countries and the sixth most common cancer in women. Overall incidence has risen in the last few decades as a consequence of the increase in the prevalence of its risk factors, mainly obesity and the aging of the population, and although diagnoses have increased across all age groups, the incidence rates have doubled in women under the age of 40 years. The survival rates of endometrial cancer are highly dependent on its stage at diagnosis, bringing to the fore the importance of early diagnosis. The aim of a screening strategy in this type of tumor should be to detect the disease in the pre-invasive or early stage (before developing myometrial invasion), which would improve cure rates, reduce the morbidity associated with aggressive treatment and offer uterus-sparing management options for younger women. The ideal screening tool in this scenario would be a minimally invasive, inexpensive and easy-to-perform test or auto-test, which could be implemented in a routine gynecologic checkup of patients at-risk or in the general adult population. In this comprehensive review, we aim to define the populations at higher risk of developing endometrial cancer, to assess the performance of current diagnostic tools when used in a screening setting and to discuss the accuracy of new molecular screening strategies.
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Affiliation(s)
- Silvia Cabrera
- Gynecologic Oncology Unit, Department of Gynecology and Obstetrics, Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain
- Fundación Santiago Dexeus Font, Gynecology, Obstetrics and Reproductive Medicine Department, Dexeus Mujer, 08028 Barcelona, Spain
| | - Irene de la Calle
- Research Group in Gynecology, Vall d'Hebron Institut de Recerca, 08035 Barcelona, Spain
| | - Sonia Baulies
- Fundación Santiago Dexeus Font, Gynecology, Obstetrics and Reproductive Medicine Department, Dexeus Mujer, 08028 Barcelona, Spain
| | - Antonio Gil-Moreno
- Research Group in Gynecology, Vall d'Hebron Institut de Recerca, 08035 Barcelona, Spain
| | - Eva Colas
- Research Group in Gynecology, Vall d'Hebron Institut de Recerca, 08035 Barcelona, Spain
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6
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Jitpasutham T, Andrianus S, Gubbiotti M, Nosé V, Baloch ZW, Madrigal E, Faquin WC. Thyroid nodules with DICER1 mutation or PTEN alteration: A comparative cytologic, clinical, and molecular study of 117 FNA cases. Cancer Cytopathol 2024; 132:370-385. [PMID: 38558329 DOI: 10.1002/cncy.22811] [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: 10/29/2023] [Revised: 02/12/2024] [Accepted: 02/13/2024] [Indexed: 04/04/2024]
Abstract
BACKGROUND DICER1 mutations and PTEN alterations are increasingly detected by thyroid fine-needle aspiration (FNA). Both are associated with nodular thyroid disease and cancer. The authors analyzed a large comparative thyroid FNA cohort with DICER1 mutation or PTEN alteration. METHODS A total of 117 thyroid FNAs with DICER1 or PTEN alterations were retrieved from the databases of two academic medical institutions. Demographic, clinical, and radiologic data were collected; FNA slides were analyzed for 29 cytomorphologic features. RESULTS Of 117 thyroid FNAs, 36 (30.8%) had DICER1 mutation and 81 (69.2%) showed PTEN alteration. The DICER1 cohort had 33 (91.7%) females and three (8.3%) males (mean, 40.9 years); 61.8% had multinodular disease. FNAs were classified as atypia of undetermined significance (AUS), 23 (63.9%); follicular neoplasm (FN), 12 (33.3%); and malignant, 1 (2.8%). The PTEN subgroup had 66 (81.5%) females and 15 (18.5%) males (mean, 55.2 years) with increased multinodular disease (93.8%, p = .0016). PTEN FNAs had greater cytologic diversity: non-diagnostic, 2 (2.5%); benign, 5 (6.2%); AUS, 44 (54.3%); FN, 24 (29.6%); and malignant, 6 (7.4%). Both DICER1 and PTEN cases showed a range of resected tumor subtypes. The DICER1 cohort included thyroblastoma, and the PTEN group included anaplastic carcinoma. The cytomorphology of DICER1 and PTEN cases showed overlapping features, especially microfollicular patterns. Minor cytomorphologic differences included papillary patterns in DICER1 (p = .039), and oncocytic changes (p < .0001) in PTEN. CONCLUSIONS DICER1 and PTEN FNAs reveal many cytologic similarities. DICER1 patients are younger, and PTEN patients had multinodular disease. Awareness of these genetic cohorts can identify patients at risk for thyroid cancer.
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Affiliation(s)
- Tikamporn Jitpasutham
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
- Faculty of Medicine, Department of Pathology, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand
| | - Stefen Andrianus
- Department of Pathology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Maria Gubbiotti
- Department of Pathology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Vania Nosé
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Zubair W Baloch
- Department of Pathology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Emilio Madrigal
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - William C Faquin
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
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7
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Yari K, Hakimi A, Mohammadi M, Ammari-Allahyari M, Salari N, Ghasemi H. The Association of PTEN Gene Mutations with the Breast Cancer Risk: A Systematic Review and Meta-analysis. Biochem Genet 2024; 62:1617-1635. [PMID: 37658255 DOI: 10.1007/s10528-023-10464-z] [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: 12/06/2022] [Accepted: 07/18/2023] [Indexed: 09/03/2023]
Abstract
Breast cancer (BC) is the most common malignancy in women in western countries. A significant part of malignant cases is caused by genetic mutation. Mutations in the gene phosphatase and tensin homologue deleted on chromosome (PTEN) have been proven in various malignancies. The present study was conducted with the aim of investigating the prevalence of BC due to PTEN gene mutation, as well as estimating the chance of developing BC due to the occurrence of PTEN gene mutation. The present study was conducted using a systematic review method based on PRISMA 2020 statements. The search was done in PubMed, Web of Science (WOS), Scopus, and direct scientific databases. The search was performed using the keywords breast cancer, breast malignancy, PTEN, polymorphism, mutation, variant, and their equivalents. Statistical analysis was performed using the second version of Comprehensive Meta-Analysis Software. A total of 2138 articles were collected. After removing duplicate articles, checking the title and abstract, and then checking the full text of the documents, finally 64 articles were approved and entered the systematic review process. Analysis of these studies with a sample size of 231,179 showed the prevalence of breast cancer patients with PTEN mutations. The combined results of 64 studies showed that the prevalence of PTEN mutations has a 3.3 (95% CI 2.2-5) in BC patients, and an analysis of 6 studies showed that the odds ratio of developing BC due to PTEN mutation is 3.7 (95% CI 1.1-11.9). The results of this study show that mutation in the PTEN gene increases the chance of developing BC. However, it was found that a small part of patients gets BC due to the occurrence of mutation in this gene.
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Affiliation(s)
- Kheirollah Yari
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Ali Hakimi
- Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Masoud Mohammadi
- Cellular and Molecular Research Center, Gerash University of Medical Sciences, Gerash, Iran
| | | | - Nader Salari
- Department of Biostatistics, School of Health, Kermanshah University of Medical Sciences, Kermanshah, Iran.
- Sleep Disorders Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran.
| | - Hooman Ghasemi
- Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah, Iran.
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Fernández-Villares M, Villegas-Romero I, Collantes-Rodríguez C, Linares-Barrios M, Benito-Godino AS, Mora-Lopez F. A New Variant of the PTEN Gene in Relation to Cowden Syndrome Type 1. Indian J Dermatol 2024; 69:274-276. [PMID: 39119301 PMCID: PMC11305488 DOI: 10.4103/ijd.ijd_633_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/10/2024] Open
Affiliation(s)
| | - Isabel Villegas-Romero
- Department of Dermatology and Venereology, Puerta del Mar University Hospital, Cádiz, Spain
| | | | - Mario Linares-Barrios
- Department of Dermatology and Venereology, Puerta del Mar University Hospital, Cádiz, Spain
| | - Ana S Benito-Godino
- From the Department of Medicine Laboratory, Puerta del Mar University Hospital, Cádiz, Spain
| | - Francisco Mora-Lopez
- Department of Immunology, Puerta del Mar University Hospital, Cádiz, Spain E-mail:
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9
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Caligayahan M, Wolpowitz D, Brem CE. Giant cell collagenoma in a patient with Cowden syndrome: A rare case report and literature review with a focus on the spectrum of sclerotic fibroma and giant cell collagenoma. J Cutan Pathol 2024; 51:267-271. [PMID: 38140907 DOI: 10.1111/cup.14584] [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: 07/11/2023] [Revised: 12/09/2023] [Accepted: 12/12/2023] [Indexed: 12/24/2023]
Abstract
Sclerotic fibroma (SF) is a rare subset of dermal fibromas that occurs sporadically or in association with Cowden syndrome (CS). We report a case of a patient with known CS and a solitary lesion on the scalp. Histologic examination demonstrated a well-circumscribed lesion with sclerotic dermis and a whorled collagen pattern, multinucleated giant cells, and dendritic spindle cells. Nuclear atypia or mitotic figures were not noted. The giant cells were negative for Melan-A, SOX-10, EMA, SOX-10, and factor XIIIa. These findings are consistent with a giant cell collagenoma (GCC). Despite possible overlap with SF, GCC has not been associated with CS. This makes our case unique and suggests that GCC should be included in the spectrum of CS-associated cutaneous lesions. The diagnosis of SF may lead to the identification of previously undiagnosed CS; accordingly, GCC, even when present as a solitary lesion, may indicate the need for further work-up and screening for CS.
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Affiliation(s)
- Marian Caligayahan
- Section of Dermatopathology, Department of Dermatology, Boston University Chobanian Avedisian School of Medicine, Boston, Massachusetts, USA
| | - Deon Wolpowitz
- Section of Dermatopathology, Department of Dermatology, Boston University Chobanian Avedisian School of Medicine, Boston, Massachusetts, USA
| | - Candice E Brem
- Section of Dermatopathology, Department of Dermatology, Boston University Chobanian Avedisian School of Medicine, Boston, Massachusetts, USA
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10
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Malik N, Sahu B. Counselling and management of women with genetic predisposition to gynaecological cancers. Eur J Obstet Gynecol Reprod Biol 2024; 294:44-48. [PMID: 38215600 DOI: 10.1016/j.ejogrb.2023.11.008] [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: 04/04/2023] [Revised: 09/29/2023] [Accepted: 11/07/2023] [Indexed: 01/14/2024]
Abstract
OBJECTIVE To review the literature with reference to counselling and management of women with genetic predisposition to gynaecological cancers. METHODS Histochemical analysis, ultrasound, blood investigations, genetic testing, screening and risk-reducing surgery (RRS) are important tools for the management of gynaecological cancers and mortality reduction. Counselling can assist in timely management of gynaecological cancers. Systematic reviews, review articles, observational studies and clinical trials on PubMed, published in the English language, were included in this review. RESULTS The management of women with genetic predisposition to gynaecological cancers through screening tests and RRS has led to a significant decrease in the risk of malignancy through RRS in cases with BRCA1 and BRCA2 gene mutations. RRS and screening have also been found to reduce the mortality rate and increase the survival rate in women with BRCA1 and BRCA2 gene mutations. The efficacy of endometrial cancer surveillance in women with Lynch syndrome is still unproven. RRS has not been reported to be effective in women with Cowden syndrome. The risk of ovarian malignancies in individuals with germline mutations remains minimal in the general population in comparison with genetic mutations. CONCLUSION Genetic testing and RRS should be implemented in addition to genetic counselling for proper management and mortality reduction of women predisposed to gynaecological cancers.
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11
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Mansilla-Polo M, Escutia-Muñoz B, Llavador-Ros M, Botella-Estrada R. Identification of c.104T>G, p.Met35Arg (NM_00314.8) heterozygous variant in exon 2 of PTEN as the causative factor for Cowden syndrome: a medical case study. Clin Exp Dermatol 2024; 49:203-205. [PMID: 37819013 DOI: 10.1093/ced/llad344] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 09/15/2023] [Accepted: 10/01/2023] [Indexed: 10/13/2023]
Abstract
A representative case of Cowden syndrome with florid mucocutaneous manifestations is presented. A genetic study revealed the c.104T>G, p.Met35Arg (NM_00314.8) heterozygous variant in exon 2 of PTEN. A satisfactory response of skin lesions to sirolimus was obtained.
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Affiliation(s)
- Miguel Mansilla-Polo
- Dermatology Department
- Instituto de Investigación Sanitaria La Fe (IIS La Fe), Valencia, Spain
| | - Begoña Escutia-Muñoz
- Dermatology Department
- Instituto de Investigación Sanitaria La Fe (IIS La Fe), Valencia, Spain
| | | | - Rafael Botella-Estrada
- Dermatology Department
- Instituto de Investigación Sanitaria La Fe (IIS La Fe), Valencia, Spain
- Faculty of Medicine, Universidad de Valencia, Valencia, Spain
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Takayama T, Muguruma N, Igarashi M, Ohsumi S, Oka S, Kakuta F, Kubo Y, Kumagai H, Sasaki M, Sugai T, Sugano K, Takeda Y, Doyama H, Banno K, Fukahori S, Furukawa Y, Horimatsu T, Ishikawa H, Iwama T, Okazaki Y, Saito Y, Matsuura N, Mutoh M, Tomita N, Akiyama T, Yamamoto T, Ishida H, Nakayama Y. Clinical Guidelines for Diagnosis and Management of Cowden Syndrome/PTEN Hamartoma Tumor Syndrome in Children and Adults-Secondary Publication. J Anus Rectum Colon 2023; 7:284-300. [PMID: 37900693 PMCID: PMC10600266 DOI: 10.23922/jarc.2023-028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Accepted: 05/30/2023] [Indexed: 10/31/2023] Open
Abstract
Cowden syndrome (CS)/PTEN hamartoma tumor syndrome (PHTS) is a rare autosomal dominantly inherited condition caused by germline pathogenesis. It is associated with multiple hamartomatous lesions occurring in various organs and tissues, including the gastrointestinal tract, skin, mucous membranes, breast, thyroid, endometrium, and brain. Macrocephaly or multiple characteristic mucocutaneous lesions commonly develop in individuals in their 20s. This syndrome is occasionally diagnosed in childhood due to the occurrence of multiple gastrointestinal polyps, autism spectrum disorders, and intellectual disability. CS/PHTS can be diagnosed taking the opportunity of multigene panel testing in patients with cancer. Appropriate surveillance for early diagnosis of associated cancers is required because patients have a high risk of cancers including breast, thyroid, colorectal, endometrial, and renal cancers. Under these circumstances, there is growing concern regarding the management of CS/PHTS in Japan, but there are no available practice guidelines. To address this situation, the guideline committee, which included specialists from multiple academic societies, was organized by the Research Group on Rare and Intractable Diseases granted by the Ministry of Health, Labour, and Welfare, Japan. The present clinical guidelines explain the principles in the diagnosis and management of CS/PHTS, together with four clinical questions and the corresponding recommendations, incorporating the concept of the Grading of Recommendations Assessment, Development, and Evaluation system. Herein, we present an English version of the guideline, some of which have been updated, to promote seamless implementation of accurate diagnosis and appropriate management of pediatric, adolescent, and adult patients with CS/PHTS.
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Affiliation(s)
- Tetsuji Takayama
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Naoki Muguruma
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Masahiro Igarashi
- Department of Lower GI Medicine, Cancer Institute Hospital of JFCR, Tokyo, Japan
| | - Shozo Ohsumi
- Department of Breast Oncology, NHO Shikoku Cancer Center, Matsuyama, Japan
| | - Shiro Oka
- Department of Gastroenterology, Hiroshima University Hospital, Hiroshima, Japan
| | - Fumihiko Kakuta
- Division of General Pediatrics and Gastroenterology, Miyagi Children's Hospital, Sendai, Japan
| | - Yoshiaki Kubo
- Department of Dermatology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Hideki Kumagai
- Department of Pediatrics, Jichi Medical University, Shimotsuke, Japan
| | - Mika Sasaki
- Department of Pediatrics, National Hospital Organization Morioka Medical Center, Morioka, Japan
| | - Tamotsu Sugai
- Department of Molecular Diagnostic Pathology, Iwate Medical University, Morioka, Japan
| | - Kokichi Sugano
- Oncogene Res Unit, Cancer Prevention Unit Tochigi Cancer Center Research Institute, Cancer Prevention, Genetic Counseling Clinic, Genome Center, Tochigi Cancer Center, Utsunomiya, Japan
- Department of Genetic Medicine, Sasaki Foundation, Kyoundo Hospital, Tokyo, Japan
| | - Yuko Takeda
- Faculty of Nursing and Medical Care, Graduate School of Health Management, Keio University, Tokyo, Japan
| | - Hisashi Doyama
- Department of Gastroenterology, Ishikawa Prefectural Central Hospital, Kanazawa, Japan
| | - Kouji Banno
- Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan
| | - Suguru Fukahori
- Department of Pediatric Surgery, Kurume University School of Medicine, Kurume, Japan
| | - Yoichi Furukawa
- Division of Clinical Genome Research, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Takahiro Horimatsu
- Department of Real World Data Research and Development, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hideki Ishikawa
- Department of Molecular-Targeting Prevention, Kyoto Prefectural University of Medicine, Kyoto, Japan
- Ishikawa Gastroenterology Clinic, Osaka, Japan
| | - Takeo Iwama
- Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, Kawagoe, Japan
| | - Yasushi Okazaki
- Intractable Disease Research Center, Graduate School of Medicine, Juntendo University, Tokyo, Japan
| | - Yutaka Saito
- Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan
| | | | - Michihiro Mutoh
- Department of Molecular-Targeting Prevention, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Naohiro Tomita
- Cancer Treatment Center, Toyonaka Municipal Hospital, Toyonaka, Japan
| | - Takashi Akiyama
- Department of Pediatric Surgery, Chuden Hospital, Hiroshima, Japan
| | - Toshiki Yamamoto
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan
| | - Hideyuki Ishida
- Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, Kawagoe, Japan
| | - Yoshiko Nakayama
- Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan
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13
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Alanazi AI, Alanezi T, Aljofan ZF, Alarabi A, Elwatidy S. Lhermitte-Duclos disease: A systematic review. Surg Neurol Int 2023; 14:351. [PMID: 37810307 PMCID: PMC10559389 DOI: 10.25259/sni_555_2023] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Accepted: 09/02/2023] [Indexed: 10/10/2023] Open
Abstract
Background Lhermitte-Duclos disease (LDD) is a rare tumor, with only about 300 reported cases. It often shows comorbidity with Cowden syndrome (CS); however, it can occur by itself. Radiologically, the "tiger-stripe" appearance is considered pathognomonic. Surgical resection remains the mainstay of treatment. This report aims to describe the clinical and radiological characteristics of LDD and its relationship with CS according to age group. Methods PubMed electronic databases were searched in August 2022. The search terms included "Lhermitte- Duclos disease" and "dysplastic gangliocytoma," which yielded 297 and 103 research articles, respectively. The articles were collected and reviewed by three researchers. Results Out of 400 identified articles, we analyzed 302 reported cases. The mean age at presentation was 33.6 ± 16 years; 171 patients (56.6%) were female, and 123 (40.7%) were male. The most commonly reported symptom was headache (174 patients, 57.6%), followed by ataxia (109, 36.1%). In addition, 99 cases (32.8%) were associated with CS, and 60 (19.9%) had a confirmed phosphatase and tensin homolog (PTEN) mutation. A tiger-stripe appearance was observed in 208 cases (58.7%); surgical resection was performed in 64.2% of the cases. Mortality and recurrence rates were 4.3% and 8.6%, respectively. No statistically significant difference was found between adult- and pediatric-onset LDD for the association with CS (P = 0.128). Conclusion Our findings suggest that adult and pediatric LDD have major commonalities; however, further prospective studies are warranted.
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Affiliation(s)
- Aued Iaed Alanazi
- Department of Surgery, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Tariq Alanezi
- Department of Surgery, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Ziyad Fahad Aljofan
- Department of Surgery, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Alwaleed Alarabi
- Department of Surgery, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Sherif Elwatidy
- Department of Neurosurgery, King Saud University, Riyadh, Saudi Arabia
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Asai T, Yokota M, Isomura H, Koide H, Sakurai N, Okamoto A, Ando H, Dewa T, Oku N. Treatment of PTEN-Null Breast Cancer by a Synthetic Lethal Approach Involving PARP1 Gene Silencing. J Pharm Sci 2023; 112:1908-1914. [PMID: 36828124 DOI: 10.1016/j.xphs.2023.02.017] [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: 01/12/2023] [Revised: 02/17/2023] [Accepted: 02/17/2023] [Indexed: 02/24/2023]
Abstract
The loss of the phosphatase and tensin homolog (PTEN) deleted from chromosome 10 is frequently observed in a variety of human cancers and appears to be an ideal target in synthetic lethality-based treatment. In this study, the synthetic lethal interaction between PTEN loss and the gene silencing of poly [ADP-ribose] polymerase 1 (PARP1) was examined in human triple-negative breast cancer cells (PTEN-null MDA-MB-468 and PTEN-positive MDA-MB-231 cells). Polycation liposomes previously developed by us were employed to deliver the small interfering ribonucleic acid (siRNA) targeted toward PARP1 (siPARP1) into the cancer cells. The silencing of the PARP1 gene exerted a cytocidal effect on the MDA-MB-468 cells but had no effect on the MDA-MB-231 cells and the human umbilical vein endothelial cells employed as normal cells. The simultaneous knockdown of PARP1 and PTEN in the MDA-MB-231 cells resulted in the significant inhibition of cell growth. The data suggest that the effects of the PARP1 knockdown on the cells were dependent on the PTEN status. A significant increase in the DNA breaks and the extent of apoptosis, possibly due to the failure of DNA repair, was observed upon PARP1 knockdown in the MDA-MB-468 cells compared with the case in the MDA-MB-231 cells. Our findings suggest that the synthetic lethal approach via PARP1 gene silencing holds promise for the treatment of patients with PTEN-null breast cancer.
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Affiliation(s)
- Tomohiro Asai
- Department of Medical Biochemistry, University of Shizuoka School of Pharmaceutical Sciences, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
| | - Masafumi Yokota
- Department of Medical Biochemistry, University of Shizuoka School of Pharmaceutical Sciences, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
| | - Hideki Isomura
- Department of Medical Biochemistry, University of Shizuoka School of Pharmaceutical Sciences, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
| | - Hiroyuki Koide
- Department of Medical Biochemistry, University of Shizuoka School of Pharmaceutical Sciences, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
| | - Naoyuki Sakurai
- Department of Medical Biochemistry, University of Shizuoka School of Pharmaceutical Sciences, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
| | - Ayaka Okamoto
- Department of Medical Biochemistry, University of Shizuoka School of Pharmaceutical Sciences, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan; Japan Society for the Promotion of Science (JSPS), 8 Ichibancho, Chiyoda-ku, Tokyo 102-8472, Japan
| | - Hidenori Ando
- Department of Medical Biochemistry, University of Shizuoka School of Pharmaceutical Sciences, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
| | - Takehisa Dewa
- Department of Life and Materials Engineering, Nagoya Institute of Technology, Gokiso-cho, Showa-ku, Nagoya, Aichi, 466-8555 Japan
| | - Naoto Oku
- Department of Medical Biochemistry, University of Shizuoka School of Pharmaceutical Sciences, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan; Faculty of Pharma-Science, Teikyo University, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605 Japan
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15
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Cummings S, Alfonso A, Hughes E, Kucera M, Mabey B, Singh N, Eng C. Cancer Risk Associated With PTEN Pathogenic Variants Identified Using Multigene Hereditary Cancer Panel Testing. JCO Precis Oncol 2023; 7:e2200415. [PMID: 36634299 PMCID: PMC9928870 DOI: 10.1200/po.22.00415] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
PURPOSE PTEN-associated clinical syndromes such as Cowden syndrome (CS) increase cancer risk and have historically been diagnosed based upon phenotypic criteria. Because not all patients clinically diagnosed with CS have PTEN pathogenic variants (PVs), and not all patients with PTEN PVs have been clinically diagnosed with CS, the cancer risk conferred by PTEN PVs calculated from cohorts of patients with clinical diagnoses of CS/CS-like phenotypes may be inaccurate. METHODS We assessed a consecutive cohort of 727,091 individuals tested clinically for hereditary cancer risk, with a multigene panel between September 2013 and February 2022. Multivariable logistic regression models accounting for personal and family cancer history, age, sex, and ancestry were used to quantify disease risks associated with PTEN PVs. RESULTS PTEN PVs were detected in 0.027% (193/727,091) of the study population, and were associated with a high risk of female breast cancer (odds ratio [OR], 7.88; 95% CI, 5.57 to 11.16; P = 2.3 × 10-31), endometrial cancer (OR, 13.51; 95% CI, 8.77 to 20.83; P = 4.2 × 10-32), thyroid cancer (OR, 4.88; 95% CI, 2.64 to 9.01; P = 4.0 × 10-7), and colon polyposis (OR, 31.60; CI, 15.60 to 64.02; P = 9.0 × 10-22). We observed modest evidence suggesting that PTEN PVs may be associated with ovarian cancer risk (OR, 3.77; 95% CI, 1.71 to 8.32; P = 9.9 × 10-4). Among patients with similar personal/family history and ancestry, every 5-year increase in age of diagnosis decreased the likelihood of detecting a PTEN PV by roughly 60%. CONCLUSION We demonstrate that PTEN PVs are associated with significantly increased risk for a range of cancers. Together with the observation that PTEN PV carriers had earlier disease onset relative to otherwise comparable noncarriers, our results may guide screening protocols, inform risk-management strategies, and warrant enhanced surveillance approaches that improve clinical outcomes for PTEN PV carriers, regardless of their clinical presentation.
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Affiliation(s)
- Shelly Cummings
- Myriad Genetics Inc, Salt Lake City, UT,Shelly Cummings, MS, 320 Wakara Way, Salt Lake City, UT 84108; e-mail:
| | | | | | | | | | | | - Charis Eng
- Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH,Center for Personalized Genetic Healthcare, Cleveland Clinic Community Care, Cleveland, OH,Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH,Department of Genetics and Genome Sciences, and CASE Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH
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Altered Extracellular Matrix as an Alternative Risk Factor for Epileptogenicity in Brain Tumors. Biomedicines 2022; 10:biomedicines10102475. [PMID: 36289737 PMCID: PMC9599244 DOI: 10.3390/biomedicines10102475] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 09/23/2022] [Accepted: 09/26/2022] [Indexed: 11/17/2022] Open
Abstract
Seizures are one of the most common symptoms of brain tumors. The incidence of seizures differs among brain tumor type, grade, location and size, but paediatric-type diffuse low-grade gliomas/glioneuronal tumors are often highly epileptogenic. The extracellular matrix (ECM) is known to play a role in epileptogenesis and tumorigenesis because it is involved in the (re)modelling of neuronal connections and cell-cell signaling. In this review, we discuss the epileptogenicity of brain tumors with a focus on tumor type, location, genetics and the role of the extracellular matrix. In addition to functional problems, epileptogenic tumors can lead to increased morbidity and mortality, stigmatization and life-long care. The health advantages can be major if the epileptogenic properties of brain tumors are better understood. Surgical resection is the most common treatment of epilepsy-associated tumors, but post-surgery seizure-freedom is not always achieved. Therefore, we also discuss potential novel therapies aiming to restore ECM function.
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17
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Syndromic vascular malformations related to the PIK3CA and RAS pathways: A clinical and imaging review. Clin Imaging 2022; 89:162-173. [DOI: 10.1016/j.clinimag.2022.06.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2022] [Revised: 06/08/2022] [Accepted: 06/26/2022] [Indexed: 01/19/2023]
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Teramae S, Muguruma N, Okamoto K, Oseto K, Nishikawa R, Tanoue T, Hirata K, Yanai S, Matsumoto T, Shimizu S, Miwa J, Sasaki Y, Yashima K, Ohnuma H, Sato Y, Kitayama Y, Ohda Y, Yamauchi A, Sanomura Y, Tanaka K, Kubo Y, Ishikawa H, Bando Y, Sonoda T, Takayama T. Cancer risk and genotype-phenotype correlation in Japanese patients with Cowden syndrome. Int J Clin Oncol 2022; 27:639-647. [PMID: 35106660 DOI: 10.1007/s10147-022-02116-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Accepted: 12/26/2021] [Indexed: 01/25/2023]
Abstract
BACKGROUND Cowden syndrome (CS) is an autosomal-dominant hereditary disorder caused by a germline PTEN variant and characterized by multiple hamartomas and a high risk of cancers. However, no detailed data on CS in Asian patients nor genotype-phenotype correlation have been reported. METHODS We performed the first Japanese nationwide questionnaire survey on CS and obtained questionnaire response data on 49 CS patients. RESULTS Patients included 26 females (median age 48 years). The incidence of breast, thyroid, endometrium, and colorectal cancer was 32.7%, 12.2%, 19.2% (among females), and 6.1%, respectively. The incidence of any cancers was relatively high among all patients (46.9%, 23/49), and particularly female patients (73.1%, 19/26), compared with previous reports from Western countries. Gastrointestinal (GI) polyps were more frequently found throughout the GI tract compared with previous studies. PTEN variants were detected in 95.6% (22/23) of patients; 12 in the N-terminal region (11 in phosphatase domain) and 10 in the C-terminal (C2 domain) region. The incidence of cancer in the C2 domain group was significantly higher than in the N-terminal region (phosphatase) group. All female patients with C2 domain variant had breast cancer. CONCLUSION Our data suggest that Japanese patients with CS, particularly female patients and patients with C2 domain variant may have a high risk of cancers.
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Affiliation(s)
- Satoshi Teramae
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, 3-18-15, Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Naoki Muguruma
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, 3-18-15, Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Koichi Okamoto
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, 3-18-15, Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Kumiko Oseto
- Department of Obstetrics and Gynecology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan
| | - Ryutaro Nishikawa
- Department of Obstetrics and Gynecology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan
| | - Takayuki Tanoue
- Department of Surgery I, School of Medicine, University of Occupational and Environmental Health, Fukuoka, Japan
| | - Keiji Hirata
- Department of Surgery I, School of Medicine, University of Occupational and Environmental Health, Fukuoka, Japan
| | - Shunichi Yanai
- Division of Gastroenterology, Department of Internal Medicine, Iwate Medical University, Iwate, Japan
| | - Takayuki Matsumoto
- Division of Gastroenterology, Department of Internal Medicine, Iwate Medical University, Iwate, Japan
| | - Seiji Shimizu
- Department of Gastroenterology, Osaka General Hospital of West Japan Railway Company, Osaka, Japan
| | - Jun Miwa
- Department of Gastroenterology, Toshiba Hospital, Tokyo, Japan
| | - Yu Sasaki
- Department of Gastroenterology, Faculty of Medicine, Yamagata University, Yamagata, Japan
| | - Kazuo Yashima
- Department of Gastroenterology, Tottori University Hospital, Tottori, Japan
| | - Hiroyuki Ohnuma
- Department of Medical Oncology, Sapporo Medical University, Hokkaido, Japan
| | - Yasushi Sato
- Department of Medical Oncology, Sapporo Medical University, Hokkaido, Japan
| | - Yoshitaka Kitayama
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Hyogo College of Medicine, Hyogo, Japan
| | - Yoshio Ohda
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Hyogo College of Medicine, Hyogo, Japan
| | - Atsushi Yamauchi
- Department of Gastroenterology and Hepatology, Tazuke Kofukai Medical Research Institute, Kitano Hospital, Osaka, Japan
| | - Yoji Sanomura
- Department of Endoscopy, Hiroshima University Hospital, Hiroshima, Japan
| | - Kumiko Tanaka
- The Post-Graduate Education Center, Tokushima University Hospital, Tokushima University, Tokushima, Japan
| | - Yoshiaki Kubo
- Department of Dermatology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Hideki Ishikawa
- Department of Molecular-Targeting Cancer Prevention, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Yoshimi Bando
- Division of Pathology, Tokushima University Graduate School, Tokushima, Japan
| | - Tomoko Sonoda
- Department of Public Health, Sapporo Medical University School of Medicine, Hokkaido, Japan
| | - Tetsuji Takayama
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, 3-18-15, Kuramoto-cho, Tokushima, 770-8503, Japan.
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Nonmalignant Features Associated with Inherited Colorectal Cancer Syndromes-Clues for Diagnosis. Cancers (Basel) 2022; 14:cancers14030628. [PMID: 35158896 PMCID: PMC8833640 DOI: 10.3390/cancers14030628] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 01/22/2022] [Accepted: 01/23/2022] [Indexed: 12/13/2022] Open
Abstract
Simple Summary Familiarity with nonmalignant features and comorbidities of cancer predisposition syndromes may raise awareness and assist clinicians in the diagnosis and interpretation of molecular test results. Genetic predisposition to colorectal cancer (CRC) should be suspected mainly in young patients, in patients with significant family histories, multiple polyps, mismatch repair-deficient tumors, and in association with malignant or nonmalignant comorbidities. The aim of this review is to describe the main nonmalignant comorbidities associated with selected CRC predisposition syndromes that may serve as valuable diagnostic clues for clinicians and genetic professionals. Abstract Genetic diagnosis of affected individuals and predictive testing of their at-risk relatives, combined with intensive cancer surveillance, has an enormous cancer-preventive potential in these families. A lack of awareness may be part of the reason why the underlying germline cause remains unexplained in a large proportion of patients with CRC. Various extracolonic features, mainly dermatologic, ophthalmic, dental, endocrine, vascular, and reproductive manifestations occur in many of the cancer predisposition syndromes associated with CRC and polyposis. Some are mediated via the WNT, TGF-β, or mTOR pathways. However the pathogenesis of most features is still obscure. Here we review the extracolonic features of the main syndromes, the existing information regarding their prevalence, and the pathways involved in their pathogenesis. This knowledge could be useful for care managers from different professional disciplines, and used to raise awareness, enable diagnosis, and assist in the process of genetic testing and interpretation.
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Nees LK, Heublein S, Steinmacher S, Juhasz-Böss I, Brucker S, Tempfer CB, Wallwiener M. Endometrial hyperplasia as a risk factor of endometrial cancer. Arch Gynecol Obstet 2022; 306:407-421. [PMID: 35001185 PMCID: PMC9349105 DOI: 10.1007/s00404-021-06380-5] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Accepted: 12/23/2021] [Indexed: 12/30/2022]
Abstract
Endometrial hyperplasia (EH) is the precursor lesion for endometrioid adenocarcinoma of the endometrium (EC), which represents the most common malignancy of the female reproductive tract in industrialized countries. The most important risk factor for the development of EH is chronic exposure to unopposed estrogen. Histopathologically, EH can be classified into EH without atypia (benign EH) and atypical EH/endometrial intraepithelial neoplasia (EIN). Clinical management ranges from surveillance or progestin therapy through to hysterectomy, depending on the risk of progression to or concomitant EC and the patient´s desire to preserve fertility. Multiple studies support the efficacy of progestins in treating both benign and atypical EH. This review summarizes the evidence base regarding risk factors and management of EH. Additionally, we performed a systematic literature search of the databases PubMed and Cochrane Controlled Trials register for studies analyzing the efficacy of progestin treatment in women with EH.
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Affiliation(s)
- Lisa K Nees
- Department of Obstetrics and Gynecology, University of Heidelberg, Im Neuenheimer Feld 440, 69120, Heidelberg, Germany
| | - Sabine Heublein
- Department of Obstetrics and Gynecology, University of Heidelberg, Im Neuenheimer Feld 440, 69120, Heidelberg, Germany
| | - Sahra Steinmacher
- Department of Obstetrics and Gynecology, Universität Tübingen, Tübingen, Germany
| | - Ingolf Juhasz-Böss
- Department of Obstetrics and Gynecology, Universität Freiburg, Freiburg, Germany
| | - Sara Brucker
- Department of Obstetrics and Gynecology, Universität Tübingen, Tübingen, Germany
| | - Clemens B Tempfer
- Comprehensive Cancer Center, Ruhr University Bochum (RUCCC), Bochum, Germany
| | - Markus Wallwiener
- Department of Obstetrics and Gynecology, University of Heidelberg, Im Neuenheimer Feld 440, 69120, Heidelberg, Germany.
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21
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Cummings K, Watkins A, Jones C, Dias R, Welham A. Behavioural and psychological features of PTEN mutations: a systematic review of the literature and meta-analysis of the prevalence of autism spectrum disorder characteristics. J Neurodev Disord 2022; 14:1. [PMID: 34983360 PMCID: PMC8903687 DOI: 10.1186/s11689-021-09406-w] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 11/08/2021] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Phosphatase and tensin homologue (PTEN) is a cancer suppressor gene. Constitutional mutations affecting this gene are associated with several conditions, collectively termed PTEN hamartoma tumour syndromes (PHTS). In addition to hamartomas, PTEN aberrations have been associated with a range of non-tumoural phenotypes such as macrocephaly, and research indicates possibly increased rates of developmental delay and autism spectrum disorder (ASD) for people with germline mutations affecting PTEN. METHOD A systematic review of literature reporting behavioural and psychological variables for people with constitutional PTEN mutations/PHTS was conducted using four databases. Following in-depth screening, 25 articles met the inclusion criteria and were used in the review. Fourteen papers reported the proportion of people with PTEN mutations/PTHS meeting criteria for or having characteristics of ASD and were thus used in a pooled prevalence meta-analysis. RESULTS Meta-analysis using a random effects model estimated pooled prevalence of ASD characteristics at 25% (95% CI 16-33%), although this should be interpreted cautiously due to possible biases in existing literature. Intellectual disability and developmental delay (global, motor and speech and language) were also reported frequently. Emotional difficulties and impaired cognitive functioning in specific domains were noted but assessed/reported less frequently. Methods of assessment of psychological/behavioural factors varied widely (with retrospective examination of medical records common). CONCLUSIONS Existing research suggests approximately 25% of people with constitutional PTEN mutations may meet criteria for or have characteristics of ASD. Studies have also begun to establish a range of possible cognitive impairments in affected individuals, especially when ASD is also reported. However, further large-scale studies are needed to elucidate psychological/behavioural corollaries of this mutation, and how they may relate to physiological/physical characteristics.
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Affiliation(s)
- Katherine Cummings
- Department of Neuroscience, Psychology and Behaviour, University of Leicester, Lancaster Road, Leicester, LE1 7HA UK
| | - Alice Watkins
- Neuropsychology Service, Great Ormond Street Hospital, London, WC1N 3JH UK
- Department of Psychology, University of Birmingham, Birmingham, B15 2TT UK
| | - Chris Jones
- Department of Psychology, University of Birmingham, Birmingham, B15 2TT UK
| | - Renuka Dias
- Department of Endocrinology and Diabetes, Birmingham Children’s Hospital, Birmingham Women’s, and Children’s NHS Foundation Trust, Steelhouse Lane, Birmingham, UK B4 6NH
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston Birmingham, UK B15 2TT
| | - Alice Welham
- Department of Neuroscience, Psychology and Behaviour, University of Leicester, Lancaster Road, Leicester, LE1 7HA UK
- Department of Psychology, University of Birmingham, Birmingham, B15 2TT UK
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22
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ROBERTI V, CALVIERI S, GIUSTINI S. A case of Cowden Syndrome associated with melanoma: the role of the dermatologist. Ital J Dermatol Venerol 2022; 156:29-31. [DOI: 10.23736/s2784-8671.19.06272-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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23
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Duarte M, Milikowski C. Gastrointestinal polyposis with associated cutaneous manifestations. Pathology 2021; 54:157-166. [PMID: 34763900 DOI: 10.1016/j.pathol.2021.08.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2021] [Accepted: 08/23/2021] [Indexed: 02/06/2023]
Abstract
Cutaneous findings are commonly associated with underlying gastrointestinal disorders and, in many instances, may be the first manifestation. Many such syndromes have incomplete penetrance and variable expressivity, making them difficult to recognise. Skin manifestations may be an easily recognised feature of the underlying disorder. Most of these syndromes are hereditary but not all are associated with malignancies; either benign or premalignant extraintestinal lesions can be the initial manifestation. Some involve a single organ system, while others involve multiple organs of the gastrointestinal tract. In this review, we have focused on Lynch syndrome (hereditary nonpolyposis colon cancer and Muir-Torre syndrome), familial adenomatous polyposis, the hamartomatous polyposis syndromes that include Peutz-Jeghers syndrome and the PTEN hamartoma syndromes, which include Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome and, lastly, Cronkhite-Canada syndrome, which is not heritable. Some of these are associated with colorectal cancer, of which 15% are heritable. The majority are inherited in an autosomal dominant fashion. These syndromes are uncommon. However, because of the strong association with the cutaneous findings, early detection and screening may be possible and are key to decreasing the morbidity and mortality associated with them, for both the patient and family members. The clinical findings, epidemiological findings, underlying genetic alterations and pathological findings are reviewed.
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Affiliation(s)
- Melissa Duarte
- Department of Pathology, Jackson Memorial Hospital/University of Miami Miller School of Medicine, Miami, FL, USA
| | - Clara Milikowski
- Department of Pathology, Jackson Memorial Hospital/University of Miami Miller School of Medicine, Miami, FL, USA.
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24
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Drissen MMCM, Schieving JH, Schuurs-Hoeijmakers JHM, Vos JR, Hoogerbrugge N. Red flags for early recognition of adult patients with PTEN Hamartoma Tumour Syndrome. Eur J Med Genet 2021; 64:104364. [PMID: 34637944 DOI: 10.1016/j.ejmg.2021.104364] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 10/05/2021] [Accepted: 10/08/2021] [Indexed: 11/17/2022]
Abstract
Patients with PTEN Hamartoma Tumour Syndrome (PHTS) are at increased risk of developing cancer. Many adult PHTS patients are not recognized as such and do not receive the cancer surveillance they need. Our aim was to define phenotypic characteristics that can easily be assessed and manifest by early adulthood, and hence could serve as red flags (i.e. alerting signals) for early recognition of adult patients at high risk of PHTS. Phenotypic characteristics including macrocephaly, multinodular goitre (MNG), and oral features were examined in 81 paediatric and 86 adult PHTS patients by one of two medical experts during yearly surveillance visits at our Dutch PHTS expert centre between 1997 and 2020. MNG was defined as signs of thyroid nodules and/or goitre. Oral features included gingival hypertrophy, high palate (adults only) and oral papillomas. Based on the characteristics' prevalence in different age groups, combinations of phenotypic characteristics were defined and evaluated on their potential to recognize individuals with PHTS. Macrocephaly was present in 100% of paediatric and 67% of adult patients. The prevalence of MNG was ∼50% in paediatric and gradually increased to >90% in adult patients. Similar percentages were observed for any of the oral features. Scoring two out of three of these characteristics yielded a sensitivity of 100% (95%CI 94-100%) in adults. The presence of the combination macrocephaly, MNG, or multiple oral features could serve as a red flag for general practitioners, medical specialists, and dentists to consider further assessment of the diagnosis PHTS in adults. In this way, recognition of adult PHTS patients might be improved and cancer surveillance can be offered timely.
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Affiliation(s)
- Meggie M C M Drissen
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands; Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, the Netherlands
| | - Jolanda H Schieving
- Department of Paediatric Neurology, Radboud University Medical Center, Nijmegen, the Netherlands
| | | | - Janet R Vos
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands; Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, the Netherlands
| | - Nicoline Hoogerbrugge
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands; Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands.
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25
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Innella G, Bonora E, Neri I, Virdi A, Guglielmo A, Pradella LM, Ceccarelli C, Amato LB, Lanzoni A, Miccoli S, Gasparre G, Zuntini R, Turchetti D. PTEN Hamartoma Tumor Syndrome: Skin Manifestations and Insights Into Their Molecular Pathogenesis. Front Med (Lausanne) 2021; 8:688105. [PMID: 34386506 PMCID: PMC8353102 DOI: 10.3389/fmed.2021.688105] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 06/30/2021] [Indexed: 12/13/2022] Open
Abstract
Germline PTEN pathogenic variants cause a spectrum of disorders collectively labeled PTEN Hamartoma Tumor Syndrome (PHTS) and featured by hamartomas, developmental anomalies and increased cancer risk. Studies on experimental models provided evidence that PTEN is a “haploinsufficient” tumor-suppressor gene, however, mechanisms involved in the pathogenesis of clinical manifestations in PHTS patients remain elusive. Beyond analyzing clinical and molecular features of a series of 20 Italian PHTS patients, we performed molecular investigations to explore the mechanisms involved in the pathogenesis of PTEN-associated manifestations, with special focus on mucocutaneous manifestations. Typical mucocutaneous features were present in all patients assessed, confirming that these are the most important clue to the diagnosis. The most frequent were papules located in the trunk or extremities (73.7%), oral mucosa papules (68.4%), acral/palmoplantar keratosis and facial papules (both 57.9%), according with literature data. Molecular analyses on one trichilemmoma suggested that the wild-type PTEN allele was retained and expressed, reinforcing the evidence that PTEN does not require a second somatic hit to initiate pathogenic processes. Unexpectedly, one patient also displayed a cutaneous phenotype consistent with atypical mole/melanoma syndrome; no variants were detected in known melanoma genes, but Whole Exome Sequencing showed the rare truncating variant c.495G>A in the CDH13 gene that might have cooperated with PTEN-haploinsufficiency to generate such phenotype. Our findings confirm the reproducibility of known PHTS manifestations in real-world practice, highlighting the role of mucocutaneous manifestations in facilitating prompt diagnosis of the syndrome, and provide some insights into the pathogenic process induced by PTEN alterations, which may contribute to its understanding.
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Affiliation(s)
- Giovanni Innella
- Department of Medical and Surgical Sciences, Center for Studies on Hereditary Cancer, University of Bologna, Bologna, Italy.,Unit of Medical Genetics, IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Elena Bonora
- Department of Medical and Surgical Sciences, Center for Studies on Hereditary Cancer, University of Bologna, Bologna, Italy
| | - Iria Neri
- Unit of Dermatology, IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Annalucia Virdi
- Unit of Dermatology, IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Alba Guglielmo
- Unit of Dermatology, IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Laura Maria Pradella
- Department of Medical and Surgical Sciences, Center for Studies on Hereditary Cancer, University of Bologna, Bologna, Italy
| | - Claudio Ceccarelli
- Department of Experimental, Diagnostic and Specialty Medicine, Alma Mater Studiorum University of Bologna, Bologna, Italy
| | - Laura Benedetta Amato
- Department of Medical and Surgical Sciences, Center for Studies on Hereditary Cancer, University of Bologna, Bologna, Italy
| | - Anna Lanzoni
- Unit of Dermatology, Ospedale Bellaria-Maggiore di Bologna, Bologna, Italy
| | - Sara Miccoli
- Unit of Medical Genetics, IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Giuseppe Gasparre
- Department of Medical and Surgical Sciences, Center for Studies on Hereditary Cancer, University of Bologna, Bologna, Italy.,Center for Applied Biomedical Research (CRBA), Bologna, Italy
| | - Roberta Zuntini
- Department of Medical and Surgical Sciences, Center for Studies on Hereditary Cancer, University of Bologna, Bologna, Italy
| | - Daniela Turchetti
- Department of Medical and Surgical Sciences, Center for Studies on Hereditary Cancer, University of Bologna, Bologna, Italy.,Unit of Medical Genetics, IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
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26
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Wang F, Cheng H, Zhang X, Shan L, Bai B, Chen K, lou F, Cao S, Wang H, Dai S. Comparative genomic signatures in young and old Chinese patients with colorectal cancer. Cancer Med 2021; 10:4375-4386. [PMID: 34041865 PMCID: PMC8267122 DOI: 10.1002/cam4.3987] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 04/21/2021] [Accepted: 04/26/2021] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Occurrence at a young age is known to be associated with unique clinical features in colorectal cancer (CRC). However, the genomic differences between young and old patients with CRC are not well elucidated and, to the best of our knowledge, have never been investigated in a Chinese population. METHODS Tumor tissue samples from 29 young (age ≤50 years) and 46 old (age >50 years) patients with CRC were collected. Targeted sequencing of 808 cancer-related genes was conducted to characterize the genomic landscape for Chinese CRC. RESULTS Overall, mutational profiles exhibited notable differences between the two groups. In particular, APC and PIK3CA mutations were more frequently observed in old patients (p = 0.009 and p = 0.012, respectively), while SMAD4 mutations tended to occur in young patients (p = 0.054). Mutation loci distributions of KRAS in the young cohort differed from those in the old cohort, and a higher frequency of KRAS codon 12 mutations was potentially associated with a young age (p = 0.076). The frequencies of clinically actionable alterations were analyzed by defined age categories, which unveiled a distinctive targeted genomic profile in the young group. Furthermore, among patients with mismatch repair-proficient (pMMR) CRC, tumor mutation burden (TMB) was positively correlated with age (Pearson's r = 0.306, p = 0.011), and genomic alterations associated with high TMB in young patients differentiated from those in old patients. CONCLUSIONS These findings revealed different molecular characterization between young and old Chinese patients with CRC, which may provide novel insights for the personalized treatment of CRC.
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Affiliation(s)
- Fei Wang
- Division of Colorectal SurgerySir Run Run Shaw HospitalZhejiang University School of MedicineHangzhouChina
| | - Huanqing Cheng
- Prenatal Diagnosis CenterAffiliated Hospital of Weifang Medical UniversityWeifangChina
| | - Xiao Zhang
- Division of Obstetrics and GynecologySir Run Run Shaw HospitalZhejiang University School of MedicineHangzhouChina
| | - Lina Shan
- Division of Colorectal SurgerySir Run Run Shaw HospitalZhejiang University School of MedicineHangzhouChina
| | - Bingjun Bai
- Division of Colorectal SurgerySir Run Run Shaw HospitalZhejiang University School of MedicineHangzhouChina
| | - Kangke Chen
- Division of Colorectal SurgerySir Run Run Shaw HospitalZhejiang University School of MedicineHangzhouChina
- Zhejiang Province Key Laboratory of Biological TreatmentHangzhouChina
| | - Feng lou
- Division of MedicineAcornmed Biotechnology Co., Ltd.BeijingChina
| | - Shanbo Cao
- Division of MedicineAcornmed Biotechnology Co., Ltd.BeijingChina
| | - Huina Wang
- Division of MedicineAcornmed Biotechnology Co., Ltd.BeijingChina
| | - Sheng Dai
- Division of Colorectal SurgerySir Run Run Shaw HospitalZhejiang University School of MedicineHangzhouChina
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27
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Abstract
Cowden syndrome (CS) is an autosomal dominant condition caused by mutations in the phosphatase and tensin homolog (PTEN) gene, and is characterized by multiple hamartomas and a predisposition to malignant tumors. Characteristic skin lesions include trichilemmomas, acral keratosis, mucocutaneous neuromas, oral papillomas, and penile macules, and are often the first clues to the underlying diagnosis. Here, we discuss the mucocutaneous manifestations of CS, differential diagnoses of genetic causes of each cutaneous finding, genetic analyses for patients with skin manifestations, management of patients with CS, and potential new targeted therapies for CS.
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Affiliation(s)
- Agnes Lim
- Cancer Genetics Service, Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
| | - Joanne Ngeow
- Cancer Genetics Service, Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore.,Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.,Oncology Academic Clinical Program, Duke-NUS Medical School, Singapore, Singapore
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28
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Taylor H, Yerlioglu D, Phen C, Ballauff A, Nedelkopoulou N, Spier I, Loverdos I, Busoni VB, Heise J, Dale P, de Meij T, Sweet K, Cohen MC, Fox VL, Mas E, Aretz S, Eng C, Buderus S, Thomson M, Rojas I, Uhlig HH. mTOR inhibitors reduce enteropathy, intestinal bleeding and colectomy rate in patients with juvenile polyposis of infancy with PTEN-BMPR1A deletion. Hum Mol Genet 2021; 30:1273-1282. [PMID: 33822054 PMCID: PMC8804886 DOI: 10.1093/hmg/ddab094] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 03/28/2021] [Accepted: 03/30/2021] [Indexed: 12/14/2022] Open
Abstract
Ultra-rare genetic disorders can provide proof of concept for efficacy of targeted therapeutics and reveal pathogenic mechanisms relevant to more common conditions. Juvenile polyposis of infancy (JPI) is caused by microdeletions in chromosome 10 that result in haploinsufficiency of two tumor suppressor genes: phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and bone morphogenetic protein receptor type IA (BMPR1A). Loss of PTEN and BMPR1A results in a much more severe phenotype than deletion of either gene alone, with infantile onset pan-enteric polyposis and a high mortality rate. No effective pharmacological therapy exists. A multi-center cohort analysis was performed to characterize phenotype and investigate the therapeutic effect of mammalian target of rapamycin (mTOR) inhibition (adverse events, disease progression, time to colectomy and mortality) in patients with JPI. Among 25 JPI patients identified (mean age of onset 13 months), seven received mTOR inhibitors (everolimus, n = 2; or sirolimus, n = 5). Treatment with an mTOR inhibitor reduced the risk of colectomy (hazard ratio = 0.27, 95% confidence interval = 0.07-0.954, P = 0.042) and resulted in significant improvements in the serum albumin level (mean increase = 16.3 g/l, P = 0.0003) and hemoglobin (mean increase = 2.68 g/dl, P = 0.0077). Long-term mTOR inhibitor treatment was well tolerated over an accumulated follow-up time of 29.8 patient years. No serious adverse events were reported. Early therapy with mTOR inhibitors offers effective, pathway-specific and personalized treatment for patients with JPI. Inhibition of the phosphoinositol-3-kinase-AKT-mTOR pathway mitigates the detrimental synergistic effects of combined PTEN-BMPR1A deletion. This is the first effective pharmacological treatment identified for a hamartomatous polyposis syndrome.
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Affiliation(s)
- Henry Taylor
- Department of Surgery and Cancer, Imperial College London, London SW7 2BX, UK
| | - Dilay Yerlioglu
- Faculty of Medicine, Istanbul University, Istanbul, Fatih 34093, Turkey
| | - Claudia Phen
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Antje Ballauff
- Zentrum für Kinder- und Jugendmedizin Gastroenterology, HELIOS Klinikum Krefeld, Krefeld, Nordrhein-Westfalen 47805, Germany
| | - Natalia Nedelkopoulou
- Pediatric Gastroenterology, Sheffield Children's Hospital NHS Foundation Trust, Sheffield, Yorkshire S10 2TH, UK
| | - Isabel Spier
- Institute of Human Genetics, Medical Faculty, University of Bonn, Bonn, Nordrhein-Westfalen 53012, Germany.,National Centre for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Nordrhein-Westfalen 53126, Germany
| | - Inés Loverdos
- Pediatric Gastroenterology Hepatology and Nutrition Unit, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, Sabadell, Catalonia comunidad 08208, Spain
| | - Veronica B Busoni
- Pediatric Gastroenterology, Hepatology and Liver-Intestine Transplantation Division, Hospital Italiano de Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina
| | - Jürgen Heise
- Zentrum für Kinder- und Jugendmedizin Gastroenterology, HELIOS Klinikum Krefeld, Krefeld, Nordrhein-Westfalen 47805, Germany
| | - Peter Dale
- Royal Gwent Hospital, Newport NP20 2UB, UK
| | - Tim de Meij
- VU University Medical Center, Amsterdam 1081, The Netherlands
| | - Kevin Sweet
- Division of Human Genetics, Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Marta C Cohen
- Histopathology Department, Sheffield Children's Hospital NHS Foundation Trust, Sheffield, Yorkshire S10 2TH, UK
| | - Victor L Fox
- Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA 02115, USA
| | - Emmanuel Mas
- Unité de Gastroentérologie, Hépatologie, Nutrition, Diabétologie et Maladies Héréditaires du Métabolisme, Hôpital des Enfants, CHU de Toulouse, and IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, Toulouse, Occitanie 31300, France
| | - Stefan Aretz
- Institute of Human Genetics, Medical Faculty, University of Bonn, Bonn, Nordrhein-Westfalen 53012, Germany.,National Centre for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Nordrhein-Westfalen 53126, Germany
| | - Charis Eng
- Genomic Medicine Institute, Lerner Research Institute, and Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA.,Department of Genetics and Genome Sciences, and CASE Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
| | - Stephan Buderus
- GFO-Kliniken Bonn, St. Marien-Hospital, Bonn, Nordrhein-Westfalen 53115, Germany
| | - Mike Thomson
- Pediatric Gastroenterology, Sheffield Children's Hospital NHS Foundation Trust, Sheffield, Yorkshire S10 2TH, UK
| | - Isabel Rojas
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Holm H Uhlig
- Translational Gastroenterology Unit, University of Oxford, Oxford, Oxfordshire OX3 9DU, UK.,Department of Pediatrics, University of Oxford, Oxford, Oxfordshire OX3 9DU, UK.,Biomedical Research Centre, University of Oxford, Oxford, Oxfordshire OX4 2PG, UK
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29
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Luna S, Torices L, Mingo J, Amo L, Rodríguez-Escudero I, Ruiz-Ibarlucea P, Erramuzpe A, Cortés JM, Tejada MI, Molina M, Nunes-Xavier CE, López JI, Cid VJ, Pulido R. A global analysis of the reconstitution of PTEN function by translational readthrough of PTEN pathogenic premature termination codons. Hum Mutat 2021; 42:551-566. [PMID: 33600059 DOI: 10.1002/humu.24186] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 01/15/2021] [Accepted: 02/14/2021] [Indexed: 12/29/2022]
Abstract
The PTEN tumor suppressor gene is mutated with high incidence in tumors and in the germline of patients with cancer predisposition or with macrocephaly associated with autism. PTEN nonsense mutations generating premature termination codons (PTC) and producing nonfunctional truncated PTEN proteins are frequent in association with human disease. However, there are no studies addressing the restoration of full-length PTEN proteins from the PTC-mutated PTEN gene by translational readthrough. Here, we have performed a global translational and functional readthrough analysis of the complete collection of PTEN PTC somatic or hereditary mutations found in tumors or in the germline of patients (disease-associated PTEN PTCome), and we set standards for the analysis of the potential of readthrough functional reconstitution in disease-relevant genes. Our analysis indicates that prevalent pathogenic PTEN PTC mutations are susceptible to PTEN functional restoration in response to readthrough-inducing compounds. Comprehensive readthrough analyses of disease-associated PTComes will be valuable tools for the implementation of readthrough-based precision interventions in specific groups of patients.
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Affiliation(s)
- Sandra Luna
- Biocruces Bizkaia Health Research Institute, Barakaldo, Spain
| | - Leire Torices
- Biocruces Bizkaia Health Research Institute, Barakaldo, Spain
| | - Janire Mingo
- Biocruces Bizkaia Health Research Institute, Barakaldo, Spain
| | - Laura Amo
- Biocruces Bizkaia Health Research Institute, Barakaldo, Spain
| | - Isabel Rodríguez-Escudero
- Departamento de Microbiología y Parasitología, Facultad de Farmacia, UCM & Instituto Ramón y Cajal de Investigaciones Sanitarias (IRYCIS), Madrid, Spain
| | | | - Asier Erramuzpe
- Biocruces Bizkaia Health Research Institute, Barakaldo, Spain
| | - Jesús M Cortés
- Biocruces Bizkaia Health Research Institute, Barakaldo, Spain.,Ikerbasque, The Basque Foundation for Science, Bilbao, Spain
| | - María I Tejada
- Biocruces Bizkaia Health Research Institute, Barakaldo, Spain
| | - María Molina
- Departamento de Microbiología y Parasitología, Facultad de Farmacia, UCM & Instituto Ramón y Cajal de Investigaciones Sanitarias (IRYCIS), Madrid, Spain
| | - Caroline E Nunes-Xavier
- Biocruces Bizkaia Health Research Institute, Barakaldo, Spain.,Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - José I López
- Biocruces Bizkaia Health Research Institute, Barakaldo, Spain.,Department of Pathology, Cruces University Hospital, Barakaldo, Spain
| | - Víctor J Cid
- Departamento de Microbiología y Parasitología, Facultad de Farmacia, UCM & Instituto Ramón y Cajal de Investigaciones Sanitarias (IRYCIS), Madrid, Spain
| | - Rafael Pulido
- Biocruces Bizkaia Health Research Institute, Barakaldo, Spain.,Ikerbasque, The Basque Foundation for Science, Bilbao, Spain
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30
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Innella G, Miccoli S, Colussi D, Pradella LM, Amato LB, Zuntini R, Salfi NCM, Collina G, Ferrara F, Ricciardiello L, Turchetti D. Colorectal polyposis as a clue to the diagnosis of Cowden syndrome: Report of two cases and literature review. Pathol Res Pract 2021; 218:153339. [PMID: 33482532 DOI: 10.1016/j.prp.2020.153339] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 12/30/2020] [Accepted: 12/30/2020] [Indexed: 11/26/2022]
Abstract
Cowden Syndrome (CS) is an autosomal dominant disorder characterized by hamartomatous growth in several organs and by an increased risk of malignancies, which makes its recognition essential to undertake risk reduction measures. Although the involvement of gastrointestinal tract is extremely common, awareness of this entity among gastroenterologists appears limited. We report on two unrelated patients: a 46-year-old male and a 38-year-old woman, who were referred to the Genetic Clinic because of the endoscopic finding of multiple colorectal polyps. Despite both displayed striking clinical (and, in the first case, familial) manifestations of Cowden Syndrome (PTEN Hamartoma Tumor Syndrome-PHTS), they had not been recognized before. Diagnosis of PHTS was confirmed by the detection of causative PTEN variants. Pathological examination of the polyps showed multiple histology types: hyperplastic, juvenile, serrated and lymphoid. Hyperplastic polyps analyzed from both patients failed to show BRAF V600E and KRAS codon 12/13 mutations, which provides evidence against their potential to evolve to colorectal cancer through the serrated pathway. We then reviewed the literature on gastrointestinal polyps detected in patients with Cowden Syndrome, in order to provide a comprehensive scenario of presentations: among a total of 568 patients reported in the literature, 91.7 % presented with colon polyps, with 63.0 % having two or more different histological types of polyps; besides, 58.5 % had extra-colonic polyps (located either in stomach and/or in small intestine). Finding multiple polyps with mixed and/or unusual histology should alert gastroenterologists and pathologists about the possible diagnosis of Cowden Syndrome and prompt the search for other manifestations of this condition in the patient.
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Affiliation(s)
- Giovanni Innella
- Dipartimento di Scienze Mediche e Chirurgiche: Centro di Ricerca sui Tumori Ereditari, Università di Bologna, Italy; UO Genetica Medica, Azienda Ospedaliero-Universitaria di Bologna Policlinico S.Orsola-Malpighi, Bologna, Italy.
| | - Sara Miccoli
- Dipartimento di Scienze Mediche e Chirurgiche: Centro di Ricerca sui Tumori Ereditari, Università di Bologna, Italy; UO Genetica Medica, Azienda Ospedaliero-Universitaria di Bologna Policlinico S.Orsola-Malpighi, Bologna, Italy.
| | - Dora Colussi
- UO Gastroenterologia, Azienda Ospedaliero-Universitaria di Bologna Policlinico S.Orsola-Malpighi, Bologna, Italy.
| | - Laura Maria Pradella
- Dipartimento di Scienze Mediche e Chirurgiche: Centro di Ricerca sui Tumori Ereditari, Università di Bologna, Italy; UO Genetica Medica, Azienda Ospedaliero-Universitaria di Bologna Policlinico S.Orsola-Malpighi, Bologna, Italy.
| | - Laura Benedetta Amato
- Dipartimento di Scienze Mediche e Chirurgiche: Centro di Ricerca sui Tumori Ereditari, Università di Bologna, Italy; UO Genetica Medica, Azienda Ospedaliero-Universitaria di Bologna Policlinico S.Orsola-Malpighi, Bologna, Italy.
| | - Roberta Zuntini
- Dipartimento di Scienze Mediche e Chirurgiche: Centro di Ricerca sui Tumori Ereditari, Università di Bologna, Italy; UO Genetica Medica, Azienda Ospedaliero-Universitaria di Bologna Policlinico S.Orsola-Malpighi, Bologna, Italy.
| | - Nunzio Cosimo Mario Salfi
- UO Anatomia e Istologia Patologica, Azienda Ospedaliero-Universitaria di Bologna Policlinico S.Orsola-Malpighi, Bologna, Italy.
| | - Guido Collina
- UOC Anatomia Patologica, Ospedale "C e G. Mazzoni", Ascoli Piceno, Italy.
| | - Francesco Ferrara
- UO Gastroenterologia ed Endoscopia Digestiva, AUSL di Bologna, Ospedale Bellaria, Bologna, Italy.
| | - Luigi Ricciardiello
- Dipartimento di Scienze Mediche e Chirurgiche: Centro di Ricerca sui Tumori Ereditari, Università di Bologna, Italy; UO Gastroenterologia, Azienda Ospedaliero-Universitaria di Bologna Policlinico S.Orsola-Malpighi, Bologna, Italy.
| | - Daniela Turchetti
- Dipartimento di Scienze Mediche e Chirurgiche: Centro di Ricerca sui Tumori Ereditari, Università di Bologna, Italy; UO Genetica Medica, Azienda Ospedaliero-Universitaria di Bologna Policlinico S.Orsola-Malpighi, Bologna, Italy.
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Abstract
Hamartomatous polyposis syndromes (HPS) are rare autosomal-dominant inherited disorders associated with gastrointestinal (GI) tract and other cancers. HPS include Peutz-Jeghers syndrome (PJS), juvenile polyposis syndrome (JPS), and phosphatase and tensin homolog hamartomatous tumor syndromes (PHTS). Diagnosis, management, and outcome prediction of HPS pose a clinical challenge. To characterize genotype, phenotype, histology and outcomes of individuals with HPS.
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Burkitt Lymphoma as Fourth Neoplasia in a Patient Affected by Cowden Syndrome with a Novel PTEN Germline Pathogenic Variant. Mediterr J Hematol Infect Dis 2020; 12:e2020034. [PMID: 32670512 PMCID: PMC7340242 DOI: 10.4084/mjhid.2020.034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Accepted: 06/02/2020] [Indexed: 11/17/2022] Open
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33
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Gervas P, Molokov A, Schegoleva A, Kiselev A, Babyshkina N, Pisareva L, Tyukalov Y, Choynzonov E, Cherdyntseva N. New germline mutations in non-BRCA genes among breast cancer women of Mongoloid origin. Mol Biol Rep 2020; 47:5315-5321. [PMID: 32601921 DOI: 10.1007/s11033-020-05612-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2020] [Accepted: 06/20/2020] [Indexed: 12/30/2022]
Abstract
In accordance with the Asian BRCA Consortium data, there is a significant difference in incidence rate of breast cancer depending on age, as well as spectrum and prevalence of BRCA1/2 mutations between Mongoloid (East Asian) and Caucasoid (European) people. However, European strategies to identify familial BC are still applied to the Asian population, including Russian Mongoloids (Khakas, Buryats, Tyvans and Yakuts and others). The main purpose of the study was to identify molecular changes associated with hereditary BC in Russian Mongoloid BC patients (Buryats). Thirty-nine patients were included in the study. Genomic DNA extracted from lymphocytes was used to prepare DNA-libraries. Target sequencing was designed to cover 27 genes, such as ATM, APC, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2 and others. Paired-end sequencing (2 × 150 bp) was conducted on a NextSeq 500 system (Illumina, USA). Three pathogenic mutations in non-BRCA genes were found (prevalence of 8%). The pathogenic mutations were found in the RAD51D and PTEN genes. The pathogenic variant in the RAD51D gene (rs137886232, NC_000017.10:g.33428366G>A, p.R141X) was observed in two unrelated individuals aged under 40. One of these patients had a family history of late-onset stomach cancer in second-degree relatives. The pathogenic mutation in the PTEN gene (rs786201044, NC_000010.10:g.89692922T>C, p.C136R) was observed in a 38 years old breast cancer patient with no family history. In our study, we first describe pathogenic mutations in RAD51D and PTEN genes found in young Buryat patients.
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Affiliation(s)
- Polina Gervas
- Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Science, 5 Kooperativny Street, Tomsk, Russia, 634009.
| | - Aleksey Molokov
- Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Science, 5 Kooperativny Street, Tomsk, Russia, 634009
| | - Anastasia Schegoleva
- Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Science, 5 Kooperativny Street, Tomsk, Russia, 634009
| | - Artem Kiselev
- Federal Almazov North-West Medical Research Centre, St. Petersburg, Russia
| | - Nataliya Babyshkina
- Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Science, 5 Kooperativny Street, Tomsk, Russia, 634009.,Tomsk State University, Tomsk, Russia
| | - Lubov Pisareva
- Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Science, 5 Kooperativny Street, Tomsk, Russia, 634009
| | - Yury Tyukalov
- Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Science, 5 Kooperativny Street, Tomsk, Russia, 634009
| | - Evgeny Choynzonov
- Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Science, 5 Kooperativny Street, Tomsk, Russia, 634009
| | - Nadezda Cherdyntseva
- Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Science, 5 Kooperativny Street, Tomsk, Russia, 634009.,Tomsk State University, Tomsk, Russia
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34
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Haddadi N, Travis G, Nassif NT, Simpson AM, Marsh DJ. Toward Systems Pathology for PTEN Diagnostics. Cold Spring Harb Perspect Med 2020; 10:cshperspect.a037127. [PMID: 31615872 DOI: 10.1101/cshperspect.a037127] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Germline alterations of the tumor suppressor PTEN have been extensively characterized in patients with PTEN hamartoma tumor syndromes, encompassing subsets of Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, Proteus and Proteus-like syndromes, as well as autism spectrum disorder. Studies have shown an increase in the risk of developing specific cancer types in the presence of a germline PTEN mutation. Furthermore, outside of the familial setting, somatic variants of PTEN occur in numerous malignancies. Here we introduce and discuss the prospect of moving toward a systems pathology approach for PTEN diagnostics, incorporating clinical and molecular pathology data with the goal of improving the clinical management of patients with a PTEN mutation. Detection of a germline PTEN mutation can inform cancer surveillance and in the case of somatic mutation, have value in predicting disease course. Given that PTEN functions in the PI3K/AKT/mTOR pathway, identification of a PTEN mutation may highlight new therapeutic opportunities and/or inform therapeutic choices.
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Affiliation(s)
- Nahal Haddadi
- School of Life Sciences, University of Technology Sydney, Ultimo, New South Wales 2007, Australia
| | - Glena Travis
- School of Life Sciences, University of Technology Sydney, Ultimo, New South Wales 2007, Australia
| | - Najah T Nassif
- School of Life Sciences, University of Technology Sydney, Ultimo, New South Wales 2007, Australia.,Centre for Health Technologies, University of Technology Sydney, Ultimo, New South Wales 2007, Australia
| | - Ann M Simpson
- School of Life Sciences, University of Technology Sydney, Ultimo, New South Wales 2007, Australia.,Centre for Health Technologies, University of Technology Sydney, Ultimo, New South Wales 2007, Australia
| | - Deborah J Marsh
- School of Life Sciences, University of Technology Sydney, Ultimo, New South Wales 2007, Australia.,Centre for Health Technologies, University of Technology Sydney, Ultimo, New South Wales 2007, Australia.,Translational Oncology Group, School of Life Sciences, Faculty of Science, University of Technology Sydney, Ultimo, New South Wales 2007, Australia.,Northern Clinical School, Kolling Institute, Faculty of Medicine and Health, University of Sydney, New South Wales 2006, Australia
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35
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Morisaki T, Kashiwagi S, Kouhashi R, Yabumoto A, Asano Y, Takashima T, Hirakawa K, Ohira M. Cowden Syndrome Diagnosed by Bilateral Breast Cancer with Lhermitte-Duclos Disease: A Case Report. Case Rep Oncol 2020; 13:419-423. [PMID: 32399010 PMCID: PMC7204884 DOI: 10.1159/000506979] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Accepted: 03/03/2020] [Indexed: 11/19/2022] Open
Abstract
Cowden syndrome is extremely rare and is characterized by multiple hamartomas in various tissues, including the skin, mucous membranes, gastrointestinal tract, breast, thyroid, and brain, and has an increased risk of breast, thyroid, and uterine cancers. Here, we report a case of Cowden syndrome diagnosed following presentation with bilateral breast cancer and provide a discussion of the relevant literature. A 47-year-old woman with a tumor in her right breast was referred to our hospital. She was diagnosed with bilateral breast cancer upon imaging and underwent a bilateral mastectomy and sentinel lymph node biopsy. Previously, she had undergone total thyroidectomy to treat a thyroid tumor. Approximately 3 years later, she was diagnosed with Lhermitte-Duclos disease affecting her left cerebellar hemisphere. As her sister and mother had also been diagnosed with breast cancer, we suspected that she might have an inherited disease. Since 80% of individuals with Cowden syndrome have a mutation in the phosphatase and tension homolog (PTEN) gene, we did not perform any genetic testing. Instead, we used the syndrome’s pathognomonic criteria and major criteria (breast cancer, thyroid tumor, and Lhermitte-Duclos disease) to diagnose our patient with Cowden syndrome. While treatment of Cowden syndrome is currently limited to strategies that can manage the symptoms, patients are at an increased risk of certain cancers and require regular screening to allow for early detection of disease.
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Affiliation(s)
- Tamami Morisaki
- Department of Breast and Endocrine Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Shinichiro Kashiwagi
- Department of Breast and Endocrine Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan
- *Shinichiro Kashiwagi, MD, PhD, Department of Breast and Endocrine Surgery, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585 (Japan),
| | - Rika Kouhashi
- Department of Breast and Endocrine Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Akimichi Yabumoto
- Department of Breast and Endocrine Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Yuka Asano
- Department of Breast and Endocrine Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Tsutomu Takashima
- Department of Breast and Endocrine Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Kosei Hirakawa
- Department of Breast and Endocrine Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan
- Department of Gastrointestinal Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Masaichi Ohira
- Department of Breast and Endocrine Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan
- Department of Gastrointestinal Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan
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36
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Smerdel MP, Skytte AB, Jelsig AM, Ebbehøj E, Stochholm K. Revised Danish guidelines for the cancer surveillance of patients with Cowden Syndrome. Eur J Med Genet 2020; 63:103873. [PMID: 32058060 DOI: 10.1016/j.ejmg.2020.103873] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Revised: 11/05/2019] [Accepted: 02/01/2020] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Cowden syndrome is a cancer predisposition syndrome caused by pathogenic variants in PTEN. The affected patients possess an increased risk of breast, thyroid, renal, colorectal, endometrial cancers as well as malignant melanoma. Thus prophylactic surveillance and follow up is crucial for these patients. METHODS A review of the literature including existing guidelines from the years 1996 until 2017 was carried out. In total, 2078 scientific papers were identified through database searches on Cowden syndrome. Among these, 11 manuscripts were included based on scientific relevance and quality. Expert consensus was reached to define management guidelines. RESULTS The literature revealed a high risk of cancer in specific organs for patients diagnosed with Cowden Syndrome. Alternative management guidelines were proposed and discussed. CONCLUSIONS Here we propose a revised set of management guidelines for patients with Cowden syndrome in Denmark to address the increased risk of various cancer types.
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Affiliation(s)
- Maja Patricia Smerdel
- Department of Clinical Genetics, Lillebaelt Hospital - University Hospital of Southern Denmark, Vejle, Denmark.
| | - Anne-Bine Skytte
- Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark.
| | - Anne Marie Jelsig
- Clinical Genetic Clinic, Kennedy Center, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
| | - Eva Ebbehøj
- Department of Internal Medicine and Diabetes, Aarhus University Hospital, Aarhus, Denmark.
| | - Kirstine Stochholm
- Department of Pediatrics, Center of Rare Diseases, Aarhus University Hospital and Department of Internal Medicine and Diabetes, Aarhus University Hospital, Aarhus, Denmark.
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37
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Griff JR, Duffy KA, Kalish JM. Characterization and Childhood Tumor Risk Assessment of Genetic and Epigenetic Syndromes Associated With Lateralized Overgrowth. Front Pediatr 2020; 8:613260. [PMID: 33392121 PMCID: PMC7773942 DOI: 10.3389/fped.2020.613260] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Accepted: 11/03/2020] [Indexed: 12/26/2022] Open
Abstract
Lateralized overgrowth (LO), or segmental overgrowth, is defined as an increase in growth of tissue (bone, muscle, connective tissue, vasculature, etc.) in any region of the body. Some overgrowth syndromes, characterized by both generalized and lateralized overgrowth, have been associated with an increased risk of tumor development. This may be due to the underlying genetic and epigenetic defects that lead to disrupted cell growth and proliferation pathways resulting in the overgrowth and tumor phenotypes. This chapter focuses on the four most common syndromes characterized by LO: Beckwith-Wiedemann spectrum (BWSp), PIK3CA-related overgrowth spectrum (PROS), Proteus syndrome (PS), and PTEN hamartoma tumor syndrome (PHTS). These syndromes demonstrate variable risks for tumor development in patients affected by LO, and we provide a comprehensive literature review of all common tumors reported in patients diagnosed with an LO-related disorder. This review summarizes the current data on tumor risk among these disorders and their associated tumor screening guidelines. Furthermore, this chapter highlights the importance of an accurate diagnosis when a patient presents with LO as similar phenotypes are associated with different tumor risks, thereby altering preventative screening protocols.
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Affiliation(s)
- Jessica R Griff
- Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, United States
| | - Kelly A Duffy
- Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, United States
| | - Jennifer M Kalish
- Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, United States.,Departments of Genetics and Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
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38
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Abstract
Background: The field of hereditary cancer syndromes and genetic testing for patients and families is a rapidly evolving discipline, with an emphasis on cancer prevention. Methods: We review the literature regarding the most common genetic syndromes associated with gynecologic malignancies and discuss the management of these conditions. We also examine the logistic process surrounding cancer genetic testing and identify some perceived barriers. Results: Five genetic syndromes are known to be associated with gynecologic malignancies: hereditary breast and ovarian cancer, Lynch, Cowden, Peutz-Jeghers, and Li-Fraumeni. Each is associated with varying risks of breast, ovarian, and uterine malignancies. The National Comprehensive Cancer Network guidelines regarding the management of these syndromes are focused primarily on reducing the risk of developing gynecologic malignancies. However, great complexity is involved with genetic testing for patients and their families, and barriers exist for the widespread use and implementation of such testing. Conclusion: Genetic testing is fundamental to primary cancer prevention and to oncologic care. Physicians, payers, and institutions must work collaboratively to maximize genetic testing with the goals of primary cancer prevention and treatment.
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Affiliation(s)
- Katrina S. Wade
- Department of Gynecologic Oncology, Ochsner Clinic Foundation, New Orleans, LA
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39
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Abstract
This article examines more uncommon thyroid entities, including anaplastic thyroid carcinoma, poorly differentiated thyroid carcinoma, rare papillary thyroid carcinoma variants, medullary thyroid carcinoma, non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), and multiple adenomatous nodules in the setting of Cowden syndrome. These entities were chosen based on their clinical significance and because they can be diagnostically challenging due to their morphologic diversity and overlap with other thyroid tumors. This article addresses the diagnostic features of each entity, focusing on how to avoid potential pitfalls and mimics while also highlighting the clinical implications of each diagnosis.
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Affiliation(s)
- Kristine S Wong
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA
| | - Justine A Barletta
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.
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40
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Macken WL, Tischkowitz M, Lachlan KL. PTEN Hamartoma tumor syndrome in childhood: A review of the clinical literature. AMERICAN JOURNAL OF MEDICAL GENETICS PART C-SEMINARS IN MEDICAL GENETICS 2019; 181:591-610. [PMID: 31609537 DOI: 10.1002/ajmg.c.31743] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Revised: 08/28/2019] [Accepted: 09/05/2019] [Indexed: 01/06/2023]
Abstract
PTEN hamartoma tumor syndrome (PHTS) is a highly variable autosomal dominant condition associated with intellectual disability, overgrowth, and tumor predisposition phenotypes, which often overlap. PHTS incorporates a number of historical clinical presentations including Bannayan-Riley-Ruvalcaba syndrome, Cowden syndrome, and a macrocephaly-autism/developmental delay syndrome. Many reviews in the literature focus on PHTS as an adult hamartoma and malignancy predisposition condition. Here, we review the current literature with a focus on pediatric presentations. The review starts with a summary of the main conditions encompassed within PHTS. We then discuss PHTS diagnostic criteria, and clinical features. We briefly address rarer PTEN associations, and the possible role of mTOR inhibitors in treatment. We acknowledge the limited understanding of the natural history of childhood-onset PHTS as a cancer predisposition syndrome and present a summary of important management considerations.
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Affiliation(s)
- William L Macken
- Wessex Clinical Genetics Service, University Hospitals Southampton NHS Trust, Southampton, United Kingdom
| | - Marc Tischkowitz
- Department of Clinical Genetics, East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom.,Department of Medical Genetics, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom
| | - Katherine L Lachlan
- Wessex Clinical Genetics Service, University Hospitals Southampton NHS Trust, Southampton, United Kingdom.,Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
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41
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Leon L, Shuen AY, Vizirakis M, McCord C. Papillomatosis of the hard palate. J Am Dent Assoc 2019; 150:788-793. [DOI: 10.1016/j.adaj.2018.12.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2018] [Revised: 11/09/2018] [Accepted: 12/07/2018] [Indexed: 11/28/2022]
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42
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Khandpur U, Huntoon K, Smith-Cohn M, Shaw A, Elder JB. Bilateral Recurrent Dysplastic Cerebellar Gangliocytoma (Lhermitte-Duclos Disease) in Cowden Syndrome: A Case Report and Literature Review. World Neurosurg 2019; 127:319-325. [DOI: 10.1016/j.wneu.2019.03.131] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Revised: 03/12/2019] [Accepted: 03/13/2019] [Indexed: 10/27/2022]
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43
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Pilarski R. PTEN Hamartoma Tumor Syndrome: A Clinical Overview. Cancers (Basel) 2019; 11:cancers11060844. [PMID: 31216739 PMCID: PMC6627214 DOI: 10.3390/cancers11060844] [Citation(s) in RCA: 99] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Revised: 06/13/2019] [Accepted: 06/14/2019] [Indexed: 12/12/2022] Open
Abstract
The phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome (PHTS) is a grouping of related genetic disorders that has been linked to germline mutations in the PTEN gene. These disorders include Cowden syndrome (CS), Bannayan–Riley–Ruvalcaba syndrome, adult Lhermitte–Duclos disease, and autism spectrum disorders associated with macrocephaly. The majority of the clinical information available on PHTS, however, is related to individuals diagnosed with CS. There is still much to be learned about this disorder, since diagnostic criteria for CS were only established in 1996, before the identification of the PTEN gene, and were based primarily on features seen in cases reported in the existing literature. More recently, however, data from several large series of patients have shown that a number of the clinical features associated with PTEN mutations are either more or less common than previously reported. In addition, we now know that only about 30–35% of patients meeting clinical diagnostic criteria for Cowden syndrome actually have a detectable PTEN mutation. Thus, our understanding of PTEN-related diseases and their management has evolved significantly over time. The United States National Comprehensive Cancer Network (NCCN) has produced and regularly updates practice guidelines which include clinical diagnostic criteria as well as guidelines for PTEN testing and management of patients with mutations. This review will summarize the overall literature on PHTS as well as recent findings which are broadening our understanding of this set of disorders.
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Affiliation(s)
- Robert Pilarski
- Division of Human Genetics, Department of Internal Medicine and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43221, USA.
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44
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Cohen-Haguenauer O. [Hereditary predisposition to breast cancer (1): genetics]. Med Sci (Paris) 2019; 35:138-151. [PMID: 30774081 DOI: 10.1051/medsci/2019003] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
The main objective of oncogenetics is to characterize a subpopulation of patients at high risk of cancer development at an early age in order to provide specific recommendations for an optimized follow-up and care path. Oncogenetic counselling helps to assess individual risk from a family history. By a family approach of formal genetics, the key issue is to identify families with a strong aggregation of cancers, and, in particular, suggesting a specific syndrome of inherited predisposition to cancer. This approach can lead to the proposal of germline genetic testing in search of causal mutations. As up to know, the search for a constitutional mutation in the BRCA genes has led to the identification of a causal deleterious mutation in less than 10% of index-cases analyzed. It is therefore important to evaluate the impact of new genes in the current panorama of inherited predisposition to breast and ovarian cancer.
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Affiliation(s)
- Odile Cohen-Haguenauer
- Unité d'Oncogénétique, Service d'oncologie médicale, pôle HI-3RO et faculté de Médecine, université Paris 7 Denis Diderot, USPC - Hôpital Saint-Louis, 1, avenue Claude Vellefaux, 75475 Paris Cedex 10, France
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45
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Boulier K, Erwin DJ, Nagamani S, Eble TN. A case report of hamartomatous polyposis in an individual with Neurofibromatosis type 1. Clin Case Rep 2019; 7:202-205. [PMID: 30656042 PMCID: PMC6333055 DOI: 10.1002/ccr3.1908] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Revised: 10/01/2018] [Accepted: 10/05/2018] [Indexed: 11/11/2022] Open
Abstract
Even in well-described genetic syndromes, such as neurofibromatosis type 1, expansion of the phenotype should be considered as a possible explanation for atypical presentations. However, it is critical to complete the evaluation for a potential dual diagnosis, as there could be significant prognostic and management implications.
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Affiliation(s)
- Kristin Boulier
- Baylor College of MedicineHoustonTexas
- Present address:
Stanford UniversityStanfordCalifornia
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46
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Chandan VS. Drugs-Induced Injury, Infections, Vascular, Congenital, and Miscellaneous Disorders. SURGICAL PATHOLOGY OF NON-NEOPLASTIC GASTROINTESTINAL DISEASES 2019:151-188. [DOI: 10.1007/978-3-030-15573-5_8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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47
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Hammer J, Seront E, Duez S, Dupont S, Van Damme A, Schmitz S, Hoyoux C, Chopinet C, Clapuyt P, Hammer F, Vikkula M, Boon LM. Sirolimus is efficacious in treatment for extensive and/or complex slow-flow vascular malformations: a monocentric prospective phase II study. Orphanet J Rare Dis 2018; 13:191. [PMID: 30373605 PMCID: PMC6206885 DOI: 10.1186/s13023-018-0934-z] [Citation(s) in RCA: 146] [Impact Index Per Article: 20.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2018] [Accepted: 10/11/2018] [Indexed: 01/19/2023] Open
Abstract
Background Extensive and complex vascular malformations often cause chronic pain and severe functional restraint. Conventional treatments, such as surgery and/or sclerotherapy, are rarely curative, underscoring the great need for new therapeutic modalities. Recent preclinical and clinical data demonstrated that sirolimus could offset the progression of vascular malformations and significantly improve quality of life of patients through inhibition of the Phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian Target of Rapamycin (mTOR) pathway. The purpose of this prospective study was to assess the efficacy and safety of this treatment in patients with extensive or complex slow-flow vascular malformations. Methods Sirolimus was administered orally on a continuous dosing schedule with pharmacokinetic-guided target serum concentration level of 10 to 15 ng/ml. Patients were seen every month for the first three months and subsequently every three months. The primary endpoints were safety and efficacy, based on clinical, biological and radiological evaluations, as well as a quality of life questionnaire. Results Nineteen patients, from 3 to 64 years old, with lymphatic (LM), venous (VM) or complex slow-flow malformations, refractory to standard care, were enrolled and received sirolimus continuously. After 12 months of follow-up, 16 patients were available for assessment of efficacy and safety: all had a significant and rapid improvement of their symptoms and quality of life. In two patients, sirolimus treatment permitted sclerotherapy and surgery, initially evaluated unfeasible. Sirolimus was well tolerated, with mucositis as the most common (10% of patients) grade 3 adverse event. Conclusions Sirolimus was efficient in extensive LM, VM and/or complex malformations that were refractory to conventional treatments and was well tolerated.
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Affiliation(s)
| | - Emmanuel Seront
- Center for Vascular Anomalies, Institut Roi Albert II, Department of Medical Oncology, Cliniques universitaires Saint Luc, University of Louvain, Brussels, Belgium
| | - Steven Duez
- Center for Vascular Anomalies, Division of Plastic Surgery, Cliniques universitaires Saint Luc, University of Louvain, 10 avenue Hippocrate, B-1200, Brussels, Belgium
| | - Sophie Dupont
- Department of Pediatric Hemato-oncology, Cliniques universitaires Saint Luc, University of Louvain, Brussels, Belgium
| | - An Van Damme
- Center for Vascular Anomalies, Department of Pediatric Hemato-oncology, Cliniques universitaires Saint Luc, University of Louvain, Brussels, Belgium
| | - Sandra Schmitz
- Center for Vascular Anomalies, Department of Head and Neck Surgery, Cliniques universitaires Saint-Luc, University of Louvain, Brussels, Belgium
| | - Claire Hoyoux
- Department of Pediatric Hemato-oncology, CHR Citadelle, Liège, Belgium
| | | | - Philippe Clapuyt
- Division of Pediatric Radiology, Cliniques universitaires Saint-Luc, University of Louvain, Brussels, Belgium
| | - Frank Hammer
- Division of Interventional Radiology, Cliniques universitaires Saint-Luc, University of Louvain, Brussels, Belgium
| | - Miikka Vikkula
- Human Molecular Genetics, de Duve Institute, University of Louvain, Brussels, Belgium
| | - Laurence M Boon
- Center for Vascular Anomalies, Division of Plastic Surgery, Cliniques universitaires Saint Luc, University of Louvain, 10 avenue Hippocrate, B-1200, Brussels, Belgium. .,Human Molecular Genetics, de Duve Institute, University of Louvain, Brussels, Belgium.
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Takei J, Tochigi S, Arai M, Tanaka T, Kajiwara I, Hatano K, Ichinose D, Sakamoto H, Hasegawa Y, Ishibashi T, Tani S, Murayama Y. Spinal Extradural Arteriovenous Fistula with Cowden Syndrome: A Case Report and Literature Review Regarding Pathogenesis and Therapeutic Strategy. NMC Case Rep J 2018; 5:83-85. [PMID: 30327747 PMCID: PMC6187262 DOI: 10.2176/nmccrj.cr.2018-0018] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2018] [Accepted: 05/02/2018] [Indexed: 11/22/2022] Open
Abstract
We report the case of a patient with a spinal extradural arteriovenous fistula (AVF) associated with Cowden syndrome (CS) that was successfully treated by endovascular surgery. CS is an autosomal dominant disorder associated with diverse symptoms caused by a deleterious mutation in the phosphatase and tensin homolog (PTEN) gene. A 67-year-old woman was diagnosed with CS based on her medical history of multiple cancers for which she underwent abdominal surgery, macrocephaly, Lhermitte-Duclos disease, and facial papules. Her genetic testing demonstrated a PTEN mutation. She presented with progressive paraparesis and her MRI of the thoracolumbar spine showed the spinal cord edema along with flow voids. A spinal angiogram demonstrated a spinal extradural AVF with the perimedullary drainage. The AVF was successfully treated by endovascular surgery. The PTEN mutation can accelerate angiogenesis; thus, vascular anomalies are one of the diagnostic criteria of CS. However, only two cases of vascular anomalies involving the spinal cord in patients with CS have been reported previously. As the present case, both cases had a history of abdominal or retroperitoneal cancer. The PTEN mutation accompanied with abdominal surgery might have caused this vascular anomaly as the consequences of venous congestion around the thoracolumbar spine. A spinal extradural AVF should be considered in patients with CS who present with myelopathy, especially when the patient has a history of abdominal or retroperitoneal surgery. Regarding the treatment strategy, endovascular surgery should be considered because surgical insult could prompt secondary vascular anomalies resulting from neovascularization due to the PTEN mutation.
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Affiliation(s)
- Jun Takei
- Department of Neurosurgery, Jikei University Kashiwa Hospital, Kashiwa, Chiba, Japan
| | - Satoru Tochigi
- Department of Neurosurgery, Jikei University Kashiwa Hospital, Kashiwa, Chiba, Japan
| | - Masami Arai
- Department of Clinical Genetic Oncology, the Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Toshihide Tanaka
- Department of Neurosurgery, Jikei University Kashiwa Hospital, Kashiwa, Chiba, Japan
| | - Ikki Kajiwara
- Department of Neurosurgery, Jikei University Kashiwa Hospital, Kashiwa, Chiba, Japan
| | - Keisuke Hatano
- Department of Neurosurgery, Jikei University Kashiwa Hospital, Kashiwa, Chiba, Japan
| | - Daisuke Ichinose
- Department of Neurosurgery, Jikei University Kashiwa Hospital, Kashiwa, Chiba, Japan
| | - Hiroki Sakamoto
- Department of Neurosurgery, Jikei University Kashiwa Hospital, Kashiwa, Chiba, Japan
| | - Yuzuru Hasegawa
- Department of Neurosurgery, Jikei University Kashiwa Hospital, Kashiwa, Chiba, Japan
| | - Toshihiro Ishibashi
- Department of Neurosurgery, Jikei University School of Medicine, Tokyo, Japan
| | - Satoshi Tani
- Department of Neurosurgery, Jikei University School of Medicine, Tokyo, Japan
| | - Yuichi Murayama
- Department of Neurosurgery, Jikei University School of Medicine, Tokyo, Japan
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Cavaillé M, Ponelle-Chachuat F, Uhrhammer N, Viala S, Gay-Bellile M, Privat M, Bidet Y, Bignon YJ. Early Onset Multiple Primary Tumors in Atypical Presentation of Cowden Syndrome Identified by Whole-Exome-Sequencing. Front Genet 2018; 9:353. [PMID: 30233642 PMCID: PMC6127642 DOI: 10.3389/fgene.2018.00353] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Accepted: 08/10/2018] [Indexed: 12/17/2022] Open
Abstract
A family with an aggregation of rare early onset multiple primary tumors has been managed in our oncogenetics department: the proband developed four early onset carcinomas between ages 31 and 33 years, including acral melanoma, bilateral clear cell renal carcinoma (RC), and follicular variant of papillary thyroid carcinoma. The proband's parent developed orbital lymphoma and small intestine mucosa-associated lymphoid tissue (MALT) lymphoma between 40 and 50 years old. Whole-exome-sequencing (WES) of the nuclear family (proband, parents, and sibling) identified in the proband a de novo deleterious heterozygous mutation c.1003C > T (p.Arg335∗) in the phosphatase and tensin homolog (PTEN) gene. Furthermore, WES allowed analysis of the nuclear family's genetic background, and identified deleterious variants in two candidate modifier genes: CEACAM1 and MIB2. CEACAM1, a tumor suppressor gene, presents loss of expression in clear cell RC and is involved in proliferation of B cells. It could explain in part the phenotype of proband's parent and the occurrence of clear cell RC in the proband. Deleterious mutations in the MIB2 gene are associated with melanoma invasion, and could explain the occurrence of melanoma in the proband. Cowden syndrome is a hereditary autosomal dominant disorder associated with increased risk of muco-cutaneous features, hamartomatous tumors, and cancer. This atypical presentation, including absence of muco-cutaneous lesions, four primary early onset tumors and bilateral clear cell RC, has not been described before. This encourages including the PTEN gene in panel testing in the context of early onset RC, whatever the histological subtype. Further studies are required to determine the implication of CEACAM1 and MIB2 in the severity of Cowden syndrome in our proband and occurrence of early onset MALT lymphoma in a parent.
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Affiliation(s)
- Mathias Cavaillé
- INSERM, U1240 Imagerie Moléculaire et Stratégies Théranostiques, Université Clermont Auvergne, Clermont-Ferrand, France.,Département d'Oncogénétique, Centre Jean Perrin, Clermont-Ferrand, France
| | - Flora Ponelle-Chachuat
- INSERM, U1240 Imagerie Moléculaire et Stratégies Théranostiques, Université Clermont Auvergne, Clermont-Ferrand, France.,Département d'Oncogénétique, Centre Jean Perrin, Clermont-Ferrand, France
| | - Nancy Uhrhammer
- INSERM, U1240 Imagerie Moléculaire et Stratégies Théranostiques, Université Clermont Auvergne, Clermont-Ferrand, France.,Département d'Oncogénétique, Centre Jean Perrin, Clermont-Ferrand, France
| | - Sandrine Viala
- INSERM, U1240 Imagerie Moléculaire et Stratégies Théranostiques, Université Clermont Auvergne, Clermont-Ferrand, France.,Département d'Oncogénétique, Centre Jean Perrin, Clermont-Ferrand, France
| | - Mathilde Gay-Bellile
- INSERM, U1240 Imagerie Moléculaire et Stratégies Théranostiques, Université Clermont Auvergne, Clermont-Ferrand, France.,Département d'Oncogénétique, Centre Jean Perrin, Clermont-Ferrand, France
| | - Maud Privat
- INSERM, U1240 Imagerie Moléculaire et Stratégies Théranostiques, Université Clermont Auvergne, Clermont-Ferrand, France.,Département d'Oncogénétique, Centre Jean Perrin, Clermont-Ferrand, France
| | - Yannick Bidet
- INSERM, U1240 Imagerie Moléculaire et Stratégies Théranostiques, Université Clermont Auvergne, Clermont-Ferrand, France.,Département d'Oncogénétique, Centre Jean Perrin, Clermont-Ferrand, France
| | - Yves-Jean Bignon
- INSERM, U1240 Imagerie Moléculaire et Stratégies Théranostiques, Université Clermont Auvergne, Clermont-Ferrand, France.,Département d'Oncogénétique, Centre Jean Perrin, Clermont-Ferrand, France
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Abstract
OBJECTIVE To describe the pulmonary imaging findings in patients with Cowden syndrome (CS). MATERIALS AND METHODS A retrospective review identified all patients with CS who underwent dedicated computed tomography examinations of the chest at our institution between January 2000 and October 2017. Patient demographics and imaging characteristics were identified through a review of the electronic medical record and relevant imaging. RESULTS Fifteen patients (6 males/9 females; mean age 53 y) with a clinical diagnosis of CS were identified. Genetic confirmation of the PTEN mutation was available in 8/15 (50%) patients. Pulmonary cysts were present in 12/15 (80%) patients and in 8/8 (100%) patients with documented PTEN mutations. The cysts ranged in size from 4 to 63 mm and were <10 in 10/12 (83%). Cysts were distributed randomly in 10/12 (83%) cases. Solid pulmonary nodules were present in 13/15 (87%) patients and were distributed randomly in all cases. CONCLUSIONS Pulmonary cysts and solid nodules are common in patients with CS. Cysts tend to be distributed randomly, few in number, and may have traversing vessels. These findings should not be interpreted as evidence of another underlying disorder in the setting of CS.
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