A Susceptibility Locus for Papillary Thyroid Carcinoma on Chromosome 8q24

Abstract

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 f320 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 suseptibility gene for PTC.

Hidden treasures in unspliced EST data

“…Together with MENβ, which is located in the same genomic region, it belongs to a class of long nuclear retained transcripts involved in the organization of nuclear speckles [16,35], see also [17] and the references therein. Other examples, such as KCNQ1OT1 [20] and PTCSC [36] are clearly visible in our data, albeit with moderate coverage.…”

Cumulative Risk Impact of Five Genetic Variants Associated with Papillary Thyroid Carcinoma

“…As stated in the Introduction, only a few genes or candidate genes have so far been detected in PTC even though several researchers have done extensive linkage analyses and analyzed functionally plausible candidate genes (34)(35)(36)(37)(38)(39). All of these facts are compatible with the genetic predisposition to PTC being multifactorial and mostly of low penetrance.…”

Thyroid cancer GWAS identifies 10q26.12 and 6q14.1 as novel susceptibility loci and reveals genetic heterogeneity among populations

“…Tumor histology was assessed by pathologists at each participating institution. The median time from diagnosis to recruitment was 4 years (range [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. Personal and clinical data, such as family history of thyroid cancer and What's new?…”

“…Linkage analyses have only identified putative genomic loci, but most of these findings have not been consistently replicated. [4][5][6][7][8] Therefore, it has become generally accepted that genetic predisposition to DTC is likely due to common lowpenetrance or rare moderate-penetrance variants. 9 Moreover, there is evidence that gene-gene 10,11 and gene-environment interactions 12,13 modulate individual susceptibility.…”