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Novel Pheochromocytoma Susceptibility Loci Identified by Integrative Genomics

Departments of ¹ Cancer Biology and ² Biostatistics, Dana-Farber Cancer Institute, Harvard Medical School; ³ Department of Biostatistics, Harvard School of Public Health, Research Division, Joslin Diabetes Center, Boston, Massachusetts; ⁴ Interleukin Genetics, Waltham, Massachusetts; Schools of ⁵ Medicine and ⁶ Chemistry, University of São Paulo, São Paulo, São Paulo, Brazil; ⁷ Translational Research Laboratory, Catalan Institute of Oncology, L'Hospitalet, Barcelona, Spain; ⁸ Broad Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts; ⁹ Division of Endocrinology, University of Massachusetts Memorial Medical Center, Worcester, Massachusetts; and ¹⁰ Molecular Pathology Program, National Center for Oncological Investigation, Madrid, Spain

Requests for reprints: Patricia L.M. Dahia, Departments of Medicine and Cellular and Structural Biology, University of Texas Health Science Center, 7703 Floyd Curl Drive, Room 5053-R3, MC 7880, San Antonio, TX 78229-3900. Phone: 210-567-4866; Fax: 210-567-1956; E-mail: dahia{at}uthscsa.edu.

Pheochromocytomas are catecholamine-secreting tumors that result from mutations of at least six different genes as components of distinct autosomal dominant disorders. However, there remain familial occurrences of pheochromocytoma without a known genetic defect. We describe here a familial pheochromocytoma syndrome consistent with digenic inheritance identified through a combination of global genomics strategies. Multipoint parametric linkage analysis revealed identical LOD scores of 2.97 for chromosome 2cen and 16p13 loci. A two-locus parametric linkage analysis produced maximum LOD score of 5.16 under a double recessive multiplicative model, suggesting that both loci are required to develop the disease. Allele-specific loss of heterozygosity (LOH) was detected only at the chromosome 2 locus in all tumors from this family, consistent with a tumor suppressor gene. Four additional pheochromocytomas with a similar genetic pattern were identified through transcription profiling and helped refine the chromosome 2 locus. High-density LOH mapping with single nucleotide polymorphism–based array identified a total of 18 of 62 pheochromocytomas with LOH within the chromosome 2 region, which further narrowed down the locus to <2 cM. This finding provides evidence for two novel susceptibility loci for pheochromocytoma and adds a recessive digenic trait to the increasingly broad genetic heterogeneity of these tumors. Similarly, complex traits may also be involved in other familial cancer syndromes.

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