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The molecular genetics of familial non-medullary thyroid cancer


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McKay, James Dowling 2002 , 'The molecular genetics of familial non-medullary thyroid cancer', PhD thesis, University of Tasmania.

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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
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.

Item Type: Thesis - PhD
Authors/Creators:McKay, James Dowling
Keywords: Thyroid gland
Copyright Holders: The Author
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Copyright 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).

Additional Information:

Thesis (Ph.D.)--University of Tasmania, 2002. Includes bibliographical references

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