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

Hartmut P.H. Neumann ^1*, Zoran Erlic ¹, Carsten C. Boedeker ², Lisa A. Rybicki ^{4, 5}, Mercedes Robledo ⁸, Mario Hermsen ⁹, Francesca Schiavi ¹¹, Maurizio Falcioni ¹³, Pingling Kwok ¹⁴, Catherine Bauters ¹⁵, Karen Lampe ¹⁶, Markus Fischer ¹⁷, Emily Edelman ⁶, Diana E. Benn ¹⁸, Bruce G. Robinson ¹⁸, Stefanie Wiegand ²⁰, Gerd Rasp ²¹, Boris A. Stuck ²², Michael M. Hoffmann ³, Maren Sullivan ¹, Maria A. Sevilla ¹⁰, Marjan M. Weiss ²³, Mariola Peczkowska ²⁴, Agata Kubaszek ²⁴, Pascal Pigny ¹⁵, Robyn L. Ward ¹⁹, Diana Learoyd ¹⁸, Michael Croxson ²⁵, Dmitry Zabolotny ²⁶, Svetlana Yaremchuk ²⁶, Wolfgang Draf ²⁷, Mihaela Muresan ²⁸, Robert R. Lorenz ^{5, 7}, Stephan Knipping ²⁹, Michael Strohm ³⁰, Gerhard Dyckhoff ³¹, Christoph Matthias ³², Nicole Reisch ³³, Simon F. Preuss ³⁴, Dirk Eer ³⁵, Martin A. Walter ³⁶, Holger Kaftan ³⁷, Timo Stöver ³⁸, Christian Fottner ³⁹, Harald Gorgulla ⁴⁰, Mahdi Malekpour ⁴¹, Masoud Motasaddi Zarandy ⁴¹, Jörg Schipper ⁴², Christoph Brase ⁴³, Alexander Glien ⁴⁴, Matthias Kühnemund ⁴⁴, Sven Koscielny ⁴⁵, Peter Schwerdtfeger ⁴⁶, Matti Välimäki ⁴⁷, Witold Szyfter ⁴⁸, Ulrich Finckh ⁴⁹, Klaus Zerres ⁵⁰, Alberto Cascon ⁸, Giuseppe Opocher ^{11, 12}, Gerd J. Ridder ², Andrzej Januszewicz ²⁴, Carlos Suarez ⁹, and Charis Eng ^{5, 6}

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

^* To whom correspondence should be addressed. E-mail: hartmut.neumann{at}uniklinik-freiburg.de.

	Abstract

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]

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

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