Document Detail

Mutation-positive and mutation-negative patients with Cowden and Bannayan-Riley-Ruvalcaba syndromes associated with distinct 10q haplotypes.
MedLine Citation:
PMID:  17033968     Owner:  NLM     Status:  MEDLINE    
Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) encodes a tumor-suppressor phosphatase frequently mutated in both sporadic and heritable forms of human cancer. Germline mutations are associated with a number of heritable cancer syndromes that are jointly referred to as the "PTEN hamartoma tumor syndrome" (PHTS) and include Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, Proteus syndrome, and Proteus-like syndrome. Germline PTEN mutations have been identified in a significant proportion of patients with PHTS; however, there are still many individuals with classic diagnostic features for whom mutations have yet to be identified. To address this, we took a haplotype-based approach and investigated the association of specific genomic regions of the PTEN locus with PHTS. We found this locus to be characterized by three distinct haplotype blocks 33 kb, 65 kb, and 43 kb in length. Comparisons of the haplotype distributions for all three blocks differed significantly among patients with PHTS and controls (P=.0098, P<.0001, and P<.0001 for blocks 1, 2, and 3, respectively). "Rare" haplotype blocks and extended haplotypes account for two-to-threefold more PHTS chromosomes than control chromosomes. PTEN mutation-negative patients are strongly associated with a haplotype block spanning a region upstream of PTEN and the gene's first intron (P=.0027). Furthermore, allelic combinations contribute to the phenotypic complexity of this syndrome. Taken together, these data suggest that specific haplotypes and rare alleles underlie the disease etiology in these sample populations; constitute low-penetrance, modifying loci; and, specifically in the case of patients with PHTS for whom traditional mutations have yet to be identified, may harbor pathogenic variant(s) that have escaped detection by standard PTEN mutation-scanning methodologies.
Marcus G Pezzolesi; Yan Li; Xiao-Ping Zhou; Robert Pilarski; Lei Shen; Charis Eng
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2006-09-29
Journal Detail:
Title:  American journal of human genetics     Volume:  79     ISSN:  0002-9297     ISO Abbreviation:  Am. J. Hum. Genet.     Publication Date:  2006 Nov 
Date Detail:
Created Date:  2006-10-11     Completed Date:  2006-12-04     Revised Date:  2013-06-07    
Medline Journal Info:
Nlm Unique ID:  0370475     Medline TA:  Am J Hum Genet     Country:  United States    
Other Details:
Languages:  eng     Pagination:  923-34     Citation Subset:  IM    
Genomic Medicine Institute, Cleveland Clinic Lerner Research Institute, Cleveland, OH, 44195, USA.
Data Bank Information
Bank Name/Acc. No.:
OMIM/153480;  158350;  176920;  601728
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MeSH Terms
Base Sequence
Case-Control Studies
Chromosomes, Human, Pair 10 / genetics*
DNA / genetics
Gene Deletion
Gene Dosage
Gene Frequency
Germ-Line Mutation*
Hamartoma Syndrome, Multiple / enzymology*,  genetics*
Linkage Disequilibrium
PTEN Phosphohydrolase / genetics*
Polymorphism, Single Nucleotide
Reg. No./Substance:
9007-49-2/DNA; EC protein, human; EC Phosphohydrolase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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