Evidence for interaction between the TCO and NMTC1 loci in familial non-medullary thyroid cancer

Abstract

Background: Familial non-medullary thyroid cancer (fNMTC) is a complex genetic disorder that is more aggressive than its sporadic counterpart. Thus far, three genetic loci have been implicated in susceptibility to fNMTC by linkage analysis. Methods: We used linkage analysis to test the significance of two of the known susceptibility loci for fNMTC, TCO on 19p13 and NMTC1 on 2q21 in 10 fNMTC families, nine of which present with cell oxyphilia, a rare histological phenotype associated with TCO. Furthermore, we used two-locus linkage analysis to examine the possibility that the TCO and NMTC1 loci interact to increase the risk of NMTC. Results: The 10 families provided evidence for linkage at both TCO and NMTC, with LOD scores of 1.56 and 2.85, respectively. Two-locus linkage analysis, using a multiplicative risk model for the development of NMTC, achieved a maximum LOD of 3.92, with an LOD of 4.51 when assuming 70% of families were linked, indicating that the segregation in these families is consistent with an interaction model. Most of this evidence came from a large Tyrolean family that singularly achieved a two-locus LOD of 3.21. Conclusions: These results provide further evidence that susceptibility genes for fNMTC exist at 19p13 and 2q21, and furthermore, raise the possibility that in a subset of fNMTC pedigrees, these loci interact resulting in significantly increased risk of NMTC for patients that carry both susceptibility loci.

Genetic Predisposition to Familial Neuroblastoma: Identification of Two Novel Genomic Regions at 2p and 12p

“…The presence of two candidate predisposing regions on distinct chromosomes in the same family supports the hypothesis of an oligogenic model of inheritance. Such interaction model may imply two or more genes having a synergistic effect as for familial non-medullary thyroid cancer [32] , or one gene acting as the main one and the other/s as a modifier/s of the disease-phenotype modulating penetrance, expressivity or severity of the disease [33] , or multiple genes capable of assuming either a causal or a modifying role in different families as for some developmental syndromes [34] . Since in family IGG-E we observe unaffected individuals carrying the 'predisposing' haplotypes, one hypothesis should include at least one recessive gene (TSG or modifier) and some additional 'hits' (somatic mutations or epigenetic modifications) required to promote tumor initiation.…”

Novel germline variants identified in the inner mitochondrial membrane transporter TIMM44 and their role in predisposition to oncocytic thyroid carcinomas

“…Familial clustering of oncocytic tumours has been reported and our group has previously mapped a predisposing locus on chromosome 19p13.2, which is associated in families with the transmission of an autosomal dominant trait with reduced penetrance (Canzian et al, 1998;McKay et al, 2004). It has been recently pointed out by Sobrinho-Simoes et al (2005) that every type of thyroid neoplasm has its oncocytic counterpart; however the complex interplay between genetic and environmental factors that gives rise to this tumour phenotype is not clear.…”

“…The eight families with thyroid oncocytic tumours included in the study were the same as described previously (McKay et al, 2004). Healthy donors of Caucasian origin were included as controls.…”

“…The advantage of having several multigenerational pedigrees with multiple affected individuals led us to refine the TCO region on chr19 to a 1.6 Mb interval (McKay et al, 2004). We focused on this interval in order to identify the TCO predisposing gene.…”

A new form of familial multi-nodular goitre with progression to differentiated thyroid cancer

“…More recently, a study of ten families with FNMTC found interaction between the 2q21 and 19p13.2 loci. Interestingly, the tumours in 9 of the 10 families showed cell oxyphilia (McKay et al 2004). The linkage to the locus at 19p13.2 is not necessarily to the TCO gene, as a second gene (GRIM 19) at this locus has been found to be mutated in some sporadic oxyphil tumours (Maximo et al 2005).…”