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The molecular genetics of familial non-medullary thyroid cancer
thesisposted on 2023-05-26, 17:45 authored by McKay, James Dowling
Familial non-medullary thyroid cancer (fNMTC) has been recognised as a clinical entity. However, the susceptibility gene, or genes, that predispose patients to this form of cancer have yet to be identified. The initial genetic analysis of a large Tasmanian family (Tas 1) with eight patients affected with NMTC allowed the exclusion of the three fNMTC susceptibility loci that have been identified, MNG1,TCO and PRN1 on chromosomes 14, 19 and 1, respectively. Similarly, the candidate genes RET, NTRK1, APC, PTEN and MET were excluded using linkage analysis. As the susceptibility gene in Tasl appeared to be novel, a genome-wide search was performed. On 2q21, 7 of the 8 PTC cases in the Tas 1 family shared a haplotype. The significance of the 2q21 locus was tested in an independent set of 80 fNMTC pedigrees. Targeted linkage analysis using 13 markers positioned across this locus yielded a LOD score of 3.07 and an NPL score of 3.19 (p=0.001) with 42% of families estimated to be linked. Stratification by the phenotype over-represented in Tas 1 , fvPTC, revealed 17 families, and linkage analysis using this subgroup yielded a maximum HLOD score of 4.07, NPL=4.99 (p=0.00002) with 80% of families estimated to be linked. This data indicated the likelihood of a susceptibility locus for fNMTC at 2q21 and it was named NMTC1. Families with oxyphilia, which has been associated with the TCO locus, were stratified from the fNMTC family set. One large oxyphilic family, 103, showed suggestive evidence for linkage to TCO, LOD score of 2.0 at D19S391, and additionally at NMTC1, LOD score of 1.9 at marker D2S2215, suggesting interaction between these loci in conferring susceptibility to this trait. Four of the remaining smaller families with oxyphilia showed evidence for linkage to both loci. Under a two loci linkage analysis using a multiplicative risk model, the 103 family gave a LOD score of 3.2 and the smaller families also provided evidence for linkage, indicating the possibility of a multigenic inheritance pattern in fNMTC. Finally, recombinants in the families used in this study limited the candidate region containing the NMTCI susceptibility gene limited to approximately 200 000 bases, making its identification a realistic possibility in the near future.
Rights statementCopyright 2002 the Author - The University is continuing to endeavour to trace the copyright owner(s) and in the meantime this item has been reproduced here in good faith. We would be pleased to hear from the copyright owner(s). Thesis (Ph.D.)--University of Tasmania, 2002. Includes bibliographical references