Novel pheochromocytoma susceptibility loci identified by integrative genomics.
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.
Dahia
Patricia L M
PL
Department of Cancer Biology and Biostatistics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA. dahia@uthsca.edu
Hao
Ke
K
Rogus
John
J
Colin
Christian
C
Pujana
Miguel A G
MA
Ross
Ken
K
Magoffin
Danielle
D
Aronin
Neil
N
Cascon
Alberto
A
Hayashida
César Y
CY
Li
Cheng
C
Toledo
Sérgio P A
SP
Stiles
Charles D
CD
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*