title: Novel pheochromocytoma susceptibility loci identified by integrative genomics.
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.
authors.affiliation: Department of Cancer Biology and Biostatistics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA. dahia@uthsca.edu
authors.forename: Patricia L M
authors.initials: PL
authors.lastname: Dahia
authors.forename: Ke
authors.initials: K
authors.lastname: Hao
authors.forename: John
authors.initials: J
authors.lastname: Rogus
authors.forename: Christian
authors.initials: C
authors.lastname: Colin
authors.forename: Miguel A G
authors.initials: MA
authors.lastname: Pujana
authors.forename: Ken
authors.initials: K
authors.lastname: Ross
authors.forename: Danielle
authors.initials: D
authors.lastname: Magoffin
authors.forename: Neil
authors.initials: N
authors.lastname: Aronin
authors.forename: Alberto
authors.initials: A
authors.lastname: Cascon
authors.forename: César Y
authors.initials: CY
authors.lastname: Hayashida
authors.forename: Cheng
authors.initials: C
authors.lastname: Li
authors.forename: Sérgio P A
authors.initials: SP
authors.lastname: Toledo
authors.forename: Charles D
authors.initials: CD
authors.lastname: Stiles
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000235:genetics*; D000328:Adult; D002885:Chromosomes, Human, Pair 16; D002889:Chromosomes, Human, Pair 2; D005260:Female; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D023281:Genomics / Q000379:methods; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D010673:Pheochromocytoma / Q000235:genetics*