Novel pheochromocytoma susceptibility loci identified by integrative genomics

Patricia L.M. Dahia, Ke Hao, John Rogus, Christian Colin, Miguel A.G. Pujana, Ken Ross, Danielle Magoffin, Neil Aronin, Alberto Cascon, César Y. Hayashida, Cheng Li, Sérgio P.A. Toledo, Charles D. Stiles

Research output: Contribution to journalArticlepeer-review

76 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)9651-9658
Number of pages8
JournalCancer Research
Volume65
Issue number21
DOIs
StatePublished - Nov 1 2005

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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