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      Cancer risk in patients with Noonan syndrome carrying a PTPN11 mutation

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          Abstract

          Noonan syndrome (NS) is characterized by short stature, facial dysmorphisms and congenital heart defects. PTPN11 mutations are the most common cause of NS. Patients with NS have a predisposition for leukemia and certain solid tumors. Data on the incidence of malignancies in NS are lacking. Our objective was to estimate the cancer risk and spectrum in patients with NS carrying a PTPN11 mutation. In addition, we have investigated whether specific PTPN11 mutations result in an increased malignancy risk. We have performed a cohort study among 297 Dutch NS patients with a PTPN11 mutation (mean age 18 years). The cancer histories were collected from the referral forms for DNA diagnostics, and by consulting the Dutch national registry of pathology and the Netherlands Cancer Registry. The reported frequencies of cancer among NS patients were compared with the expected frequencies using population-based incidence rates. In total, 12 patients with NS developed a malignancy, providing a cumulative risk for developing cancer of 23% (95% confidence interval (CI), 8–38%) up to age 55 years, which represents a 3.5-fold (95% CI, 2.0–5.9) increased risk compared with that in the general population. Hematological malignancies occurred most frequently. Two malignancies, not previously observed in NS, were found: a malignant mastocytosis and malignant epithelioid angiosarcoma. No correlation was found between specific PTPN11 mutations and cancer occurrence. In conclusion, this study provides first evidence of an increased risk of cancer in patients with NS and a PTPN11 mutation, compared with that in the general population. Our data do not warrant specific cancer surveillance.

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          Most cited references40

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          Pathology Databanking and Biobanking in The Netherlands, a Central Role for PALGA, the Nationwide Histopathology and Cytopathology Data Network and Archive

          Since 1991, a nationwide histopathology and cytopathology network and archive is in operation in The Netherlands under the name PALGA, encompassing all sixty-four pathology laboratories in The Netherlands. The overall system comprises decentralized systems at the participating laboratories, a central databank, and a dedicated communication and information exchange tool. Excerpts of all histopathology and cytopathology reports are generated automatically at the participating laboratories and transferred to the central databank. Both the decentralized systems and the central system perform checks on the quality and completeness of excerpts. Currently, about 42 million records on almost 10 million patients are stored in the central databank. Each excerpt contains patient identifiers, including demographic data and the so-called PALGA diagnosis. The latter is structured along five classification axes: topography, morphology, function, procedure, and diseases. All data transfer and communication occurs electronically with encryption of patient and laboratory identifiers. All excerpts are continuously available to all participating pathology laboratories, thus contributing to the quality of daily patient care. In addition, external parties may obtain permission to use data from the PALGA system, either on an ongoing basis or on the basis of a specific permission. Annually, 40 to 60 applications for permission to use PALGA data are submitted. Among external users are the Dutch cancer registry, population-based screening programs for cancer of the uterine cervix and breast cancer in The Netherlands, and individual investigators addressing a range of research questions. Many scientific papers and theses incorporating PALGA data have been published already. In conclusion, the PALGA system is a unique system that requires a minimal effort on the part of the participating laboratories, while providing them a powerful tool in their daily practices.
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            Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia.

            We report here that individuals with Noonan syndrome and juvenile myelomonocytic leukemia (JMML) have germline mutations in PTPN11 and that somatic mutations in PTPN11 account for 34% of non-syndromic JMML. Furthermore, we found mutations in PTPN11 in a small percentage of individuals with myelodysplastic syndrome (MDS) and de novo acute myeloid leukemia (AML). Functional analyses documented that the two most common mutations in PTPN11 associated with JMML caused a gain of function.
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              The RAS/MAPK syndromes: novel roles of the RAS pathway in human genetic disorders.

              The RAS proteins and their downstream pathways play pivotal roles in cell proliferation, differentiation, survival and cell death, but their physiological roles in human development had remained unknown. Noonan syndrome, Costello syndrome, and cardio-facio-cutaneous (CFC) syndrome are autosomal dominant multiple congenital anomaly syndromes characterized by a distinctive facial appearance, heart defects, musculocutaneous abnormalities, and mental retardation. A variety of mutations in protein tyrosine phosphatase, non-receptor type 11(PTPN11) has been identified in 50% of Noonan patients. Specific mutations in PTPN11 have been identified in LEOPARD (multiple lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness) syndrome. In 2005, we discovered Harvey-RAS (HRAS) germline mutations in patients with Costello syndrome. This discovery provided a clue to identification of germline mutations in Kirsten-RAS (KRAS), BRAF and mitogen-activated protein kinase kinase 1 and 2 (MAP2K1/MAP2K2) in patients with CFC syndrome. These genes encode molecules in the RAS/RAF/MEK/extracellular signal-regulated kinase (ERK) pathway, leading to a new concept that clinically related disorders, i.e., Noonan, Costello, and CFC syndromes are caused by dysregulation of the RAS/mitogen activated protein kinase (MAPK) pathway. In the present review, we summarize mutations in HRAS, KRAS, BRAF, MAP2K1/2, and PTPN11, the phenotypes of patients with these mutations, the functional properties of mutants and animal models. Finally we suggest that disorders with mutations of molecules in the RAS/MAPK cascade (Noonan, LEOPARD, Costello, and CFC syndromes and neurofibromatosis type I) may be comprehensively termed "the RAS/MAPK syndromes." Details on mutations will be updated in the RAS/MAPK Syndromes Homepage (www.medgen.med.tohoku.ac.jp/RasMapk syndromes.html).
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                Author and article information

                Journal
                Eur J Hum Genet
                European Journal of Human Genetics
                Nature Publishing Group
                1018-4813
                1476-5438
                August 2011
                16 March 2011
                1 August 2011
                : 19
                : 8
                : 870-874
                Affiliations
                [1 ]Department of Human Genetics, Radboud University Nijmegen Medical Center , Nijmegen, The Netherlands
                [2 ]Departments of Pediatric Hemato-oncology, Radboud University Nijmegen Medical Center , Nijmegen, The Netherlands
                [3 ]Department of Pediatric Endocrinology, Radboud University Nijmegen Medical Center , Nijmegen, The Netherlands
                [4 ]Department of Pathology, Radboud University Nijmegen Medical Center , Nijmegen, The Netherlands
                [5 ]Departments of Epidemiology, Biostatistics and HTA, Radboud University Nijmegen Medical Center , Nijmegen, The Netherlands
                [6 ]Department of Urology, Radboud University Nijmegen Medical Center , Nijmegen, The Netherlands
                Author notes
                [* ]Department of Human Genetics, Radboud University Nijmegen Medical Center , PO Box 9101, 6500 HB Nijmegen, The Netherlands. Tel: +31 24 3613946; Fax: +31 24 3668774; E-mail: m.jongmans@ 123456antrg.umcn.nl
                Article
                ejhg201137
                10.1038/ejhg.2011.37
                3172922
                21407260
                24e66ebe-a9ea-415b-ba39-f35b901af430
                Copyright © 2011 Macmillan Publishers Limited

                This work is licensed under the Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/

                Categories
                Article

                Genetics
                noonan syndrome,ptpn11 gene,cumulative risk,cancer incidence
                Genetics
                noonan syndrome, ptpn11 gene, cumulative risk, cancer incidence

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