A susceptibility locus for papillary thyroid carcinoma on chromosome 8q24.
Papillary thyroid carcinoma (PTC) displays higher heritability than most other cancers. To search for genes predisposing to PTC, we performed a genome-wide linkage analysis in a large family with PTC and melanoma. Among several peaks the highest was at 8q24, with a maximum nonparametric linkage (NPL) score of 7.03. Linkage analysis was then broadened to comprise 25 additional PTC families that produced a maximum NPL score of 3.2, P = 0.007 at the 8q24 locus. Fine mapping with microsatellite markers was compatible with linkage to the 8q24 locus in 10 of the 26 families. In the large family, a approximately 320 Kb haplotype was shared by individuals with PTC, melanoma, or benign thyroid disease, but not by unaffected individuals. A 12 Kb haplotype of 8 SNP markers within the larger haplotype was shared by 9 of the 10 families in which the 8q24 locus was compatible with linkage. The shared haplotype is located within 2 known overlapping protein-coding genes, thyroglobulin (TG) and Src-like adaptor (SLA). Resequencing of the coding and control regions of TG and SLA did not disclose putative mutations in PTC patients. Embedded in the TG-SLA region are three likely noncoding RNA genes, one of which (AK023948) harbors the 8-SNP haplotype. Resequencing of AK023948 and one of the other RNA genes did not reveal candidate mutations. Gene expression analysis indicated that AK023948 is significantly down-regulated in most PTC tumors. The putative noncoding RNA gene AK023948 is a candidate susceptibility gene for PTC.
He
Huiling
H
Human Cancer Genetics Program, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA.
Nagy
Rebecca
R
Liyanarachchi
Sandya
S
Jiao
Hong
H
Li
Wei
W
Suster
Saul
S
Kere
Juha
J
de la Chapelle
Albert
A
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D002291:Carcinoma, Papillary / Q000235:genetics*; D002898:Chromosomes, Human, Pair 8; D005260:Female; D020869:Gene Expression Profiling; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D006239:Haplotypes; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics; D005810:Multigene Family; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000235:genetics; D013954:Thyroglobulin / Q000235:genetics; D013964:Thyroid Neoplasms / Q000235:genetics*
D048868:Adaptor Proteins, Signal Transducing; C490635:SLA protein, human; D013954:Thyroglobulin; D016392:Proto-Oncogene Proteins pp60(c-src)