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Clinical Predictors for Germline Mutations in Head and Neck Paraganglioma Patients: Cost Reduction Strategy in Genetic Diagnostic Process as Fall-Out

¹ Department of Nephrology, Section of Preventive Medicine, ² Department of Otorhinolaryngology, and ³ Department of Laboratory Medicine, Albert-Ludwigs University, Freiburg, Germany; ⁴ Department of Quantitative Health Sciences, ⁵ Taussig Cancer Institute, ⁶ Genomic Medicine Institute, Lerner Research Institute, and ⁷ Head and Neck Institute, Cleveland Clinic, Cleveland, Ohio; ⁸ Hereditary Endocrine Cancer Group, Spanish National Cancer Center, Madrid and ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain; ⁹ Instituto Universitario de Oncologia del Principado de Asturias and ¹⁰ Department of Otolaryngology, Hospital U. Central de Asturias, University of Oviedo, Oviedo, Spain; ¹¹ Veneto Institute of Oncology (IRCCS) and ¹² Department of Medical and Surgical Sciences, University of Padova, Padova, Italy; ¹³ Gruppo Otologico, Piacenza-Rome, Italy; ¹⁴ Department of Otorhinolaryngology, University of Regensburg, Regensburg, Germany; ¹⁵ Department of Endocrinology and Biochemistry, University Hospital, CHRU, Lille, France; ¹⁶ Department of Ear, Nose and Throat Diseases, Head and Neck Surgery, International Neuroscience Institute, Otto-von-Guericke University, Magdeburg, Germany; ¹⁷ Department of Otorhinolaryngology, University of Duisburg-Essen, Essen, Germany; ¹⁸ Cancer Genetics, Kolling Institute of Medical Research & Department of Endocrinology, Royal North Shore Hospital and University of Sydney and ¹⁹ Faculty of Medicine, University of New South Wales, Sydney, Australia; ²⁰ Department of Otorhinolaryngology, Carl-Gustav-Carus University, Dresden, Germany; ²¹ Department of Otorhinolaryngology, Katharinenhospital, Stuttgart, Germany; ²² Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Mannheim, Mannheim, Germany; ²³ Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands; ²⁴ Department of Hypertension, Institute of Cardiology, Warsaw, Poland; ²⁵ Department of Endocrinology, Greenlane Clinical Centre, Auckland, New Zealand; ²⁶ Institute of Otolaryngology AMS of Ukraine, Kiev, Ukraine; ²⁷ Department of Otorhinolaryngology, Städtische Kliniken, Fulda, Germany; ²⁸ Department of Endocrinology, Hospital Adultes Brabois, Nancy, France; ²⁹ Department of Otorhinolaryngology, Head and Neck Surgery of the Martin Luther University Halle-Wittenberg, Halle, Germany; ³⁰ Department of Otorhinolaryngology, University Hospital Karlsruhe, Karlsruhe, Germany; ³¹ Department of Otorhinolaryngology, Head and Neck Surgery, University of Heidelberg, Heidelberg, Germany; ³² Department of Otorhinolaryngology, University of München-Grosshadern; ³³ Endocrinology and Metabolism, Medizinische Klinik-Innenstadt, University Hospital Munich, München, Germany; ³⁴ Department of Otorhinolaryngology, University of Köln, Köln, Germany; ³⁵ Department of Otorhinolaryngology, Helios-Kliniken, Erfurt, Germany; ³⁶ Institute of Nuclear Medicine, University Hospital, Basel, Switzerland; ³⁷ Department of Otorhinolaryngology, Head and Neck Surgery, Ernst-Moritz-Arndt-University, Greifswald, Germany; ³⁸ Department of Otorhinolaryngology, Medizinische Hochschule, Hannover, Germany; ³⁹ Department of Endocrinology, Mainz, Germany; ⁴⁰ Department of Otorhinolaryngology, Katholisches Klinikum Koblenz, Koblenz, Germany; ⁴¹ Department of Otorhinolaryngology, Amir Alam Hospital, Tehran University of Medical Sciences, Tehran, Iran; ⁴² Department of Otorhinolaryngology, Heinrich-Heine-University, Düsseldorf, Germany; ⁴³ Department of Otorhinolaryngology, University of Erlangen, Erlangen, Germany; ⁴⁴ Department of Otorhinolaryngology, Friedrich-Wilhelm University, Bonn, Germany; ⁴⁵ Department of Otorhinolaryngology, Institute of Phoniatry and Pedaudiology, Friedrich-Schiller University Jena, Jena, Germany; ⁴⁶ Department of Otorhinolaryngology, Krankenhaus der Borromäerinnen, Trier, Germany; ⁴⁷ Division of Endocrinology, Helsinki University Central Hospital, Helsinki, Finland; ⁴⁸ Department of Otolaryngology, Pozna'n University of Medical Sciences, Poznan, Poland; ⁴⁹ Eberhard Institute of Laboratory Medicine, Dortmund, Germany; and ⁵⁰ Department of Human Genetics, University Medical Center, Rheinisch Westfälische Technische Hochschule, Aachen, Germany

Requests for reprints: Hartmut P.H. Neumann, Medizinische Universitätsklinik, Abteilung Innere Medizin 4, Hugstetter Str. 55, D 79106 Freiburg, Germany. Phone: 0761-270-3578, Fax: 0761-270-3778; E-mail: hartmut.neumann{at}uniklinik-freiburg.de.

Key Words: paraganglioma • pheochromocytoma • genetic diagnosis • molecular genetics • hereditary cancer disease

Multiple genes and their variants that lend susceptibility to many diseases will play a major role in clinical routine. Genetics-based cost reduction strategies in diagnostic processes are important in the setting of multiple susceptibility genes for a single disease. Head and neck paraganglioma (HNP) is caused by germline mutations of at least three succinate dehydrogenase subunit genes (SDHx). Mutation analysis for all 3 costs US$2,700 per patient. Genetic classification is essential for downstream management of the patient and preemptive management of family members. Utilizing HNP as a model, we wanted to determine predictors to prioritize the most heritable clinical presentations and which gene to begin testing in HNP presentations, to reduce costs of genetic screening. Patients were tested for SDHB, SDHC, and SDHD intragenic mutations and large deletions. Clinical parameters were analyzed as potential predictors for finding germline mutations. Cost reduction was calculated between prioritized gene testing compared with that for all genes. Of 598 patients, 30.6% had SDHx germline mutations: 34.4% in SDHB, 14.2% SDHC, and 51.4% SDHD. Predictors for an SDHx mutation are family history [odds ratio (OR), 37.9], previous pheochromocytoma (OR, 10.9), multiple HNP (OR, 10.6), age 40 years (OR, 4.0), and male gender (OR, 3.5). By screening only preselected cases and a stepwise approach, 60% cost reduction can be achieved, with 91.8% sensitivity and 94.5% negative predictive value. Our data give evidence that clinical parameters can predict for mutation and help prioritize gene testing to reduce costs in HNP. Such strategy is cost-saving in the practice of genetics-based personalized health care. [Cancer Res 2009;69(8):3650–6]

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