Abstract
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.
Highlights
IntroductionCatecholamine-secreting tumors derive from the neural crest and are known as pheochromocytomas if located in the adrenalNote: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).P.L.M
Catecholamine-secreting tumors derive from the neural crest and are known as pheochromocytomas if located in the adrenalNote: Supplementary data for this article are available at Cancer Research Online.P.L.M
The oligonucleotide array used for DNA analysis contains 11,500 single nucleotide polymorphism (SNP) distributed throughout the genome at an average density of 0.2-Mb interval. 10K SNP genotypes were generated from all six affected individuals and two siblings without clinical disease for linkage analysis
Summary
Catecholamine-secreting tumors derive from the neural crest and are known as pheochromocytomas if located in the adrenalNote: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).P.L.M. Catecholamine-secreting tumors derive from the neural crest and are known as pheochromocytomas if located in the adrenal. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). P.L.M. Dahia is currently at the Department of Medicine and Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, 5053-R3, MC 7880, San Antonio, TX 78229-3900. D. Magoffin is currently at Commonwealth Scientific and Industrial Research Organisation Livestock Industries, Australian Animal Health Laboratory, Geelong, Victoria, Australia. Familial Pheochromocytoma Consortium members and their affiliations are listed in the Appendix
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
