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Papillary thyroid carcinoma (PTC) is the most common thyroid malignancy and an estimated 5-10% of PTC cases display familial aggregation. Despite the fact that genetic factors contribute to PTC, no predisposing gene has been found. We performed a genomic search on a single large family that included 8 individuals with PTC, 2 of whom also had melanoma. An additional 10 individuals had benign thyroid disease (nodules or goiter), including one individual with goiter who also had both cutaneous and ocular melanoma, as well as breast cancer. Among the remaining family members, 2 had melanoma only and 2 had chronic lymphocytic leukemia (CLL). Genome-wide genotyping was conducted using GeneChip Human Mapping 50K and 500K Arrays. Multipoint linkage analyses were undertaken using selected SNPs with nonparametric and parametric methods. We obtained a maximum nonparametric linkage (NPL) score of 7.03 on chromosome 8q24. In addition, at least 3 other chromosomal loci, 6q27, 12q21 and 14q11, displayed NPL scores from 6.5 to 6.9. To evaluate the significance of the 8q24 locus, we performed linkage analysis in a set of 25 additional PTC families of variable size and informativity. The combined linkage analysis with all 26 families produced a maximum NPL score of 3.2, p value 0.007. Fine mapping with microsatellite markers were compatible with linkage to the 8q24 locus in 10 families. Haplotypes in the 8q24 locus were constructed. In the large PTC and melanoma family, a ~320 Kb haplotype in the thyroglobulin (TG) gene region was shared by 7 individuals affected with PTC and 3 individuals with benign thyroid disease, but not by any of the unaffected individuals whom we genotyped. Further haplotype sharing analysis identified a smaller ~27 Kb haplotype within the larger haplotype; this small haplotype was shared by 9 out of the 10 families in which the 8q24 locus was compatible with linkage. The shared haplotype is located within 2 known coding genes, TG and Src-like adaptor (SLA), and also covers 3 putative non-coding RNA genes, AK023948, AK023852and AK024366. SLA is encoded by the antisense strand of three introns of the TG gene. The 3 putative non-coding RNA genes reside in the introns of the SLA gene. Gene expression analysis indicated that AK023948 and AK023852 were significantly down-expressed in some PTC tumors, as compared to normal thyroid tissue. Moreover, allelic variation in AK023948 expression in unaffected thyroid tissue was observed in 6 out of 21 sporadic PTC cases, but not in any of 10 controls. The putative non-coding RNA gene AK023948 is a strong candidate susceptibility gene for PTC.

99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA