Related Experiment Video
Updated: Aug 9, 2026
Spontaneous Murine Model of Anaplastic Thyroid Cancer
Published on: February 3, 2023
Analysis of RET polymorphisms and haplotypes in the context of sporadic medullary thyroid carcinoma
Raquel M Fernández1, Ana Peciña, Guillermo Antiñolo
1Unidad Clínica de Genética y Reproducción, Hospitales Universitarios Virgen del Rocío, Sevilla, Spain.
Context:
Little is known about the etiology of sporadic medullary thyroid carcinoma (sMTC). While germline gain-of-function mutations in the RET proto-oncogene cause hereditary MTC, the molecular mechanisms leading to the sporadic forms remain obscure. Our group had evidence about the existence of a low-penetrance susceptibility locus for sMTC in linkage disequilibrium with RET variants S836S/IVS1-126G>T, and probably in 5' with respect to both variants. In this study we sought to identify such locus. On the other hand, because an overrepresentation of G691S/S904S variants in patients with sMTC had been previously reported, we sought to determine if such association was present in our series.
Design:
We performed a case-control study analysing a wide spectrum of RET variants in the 5' region of the gene, as well as the variants G691S/S904S. Haplotype distribution were also analyzed. A total of 58 patients with sMTC were included in the study. In addition, 100 unselected, unrelated race-, age-, and gender-matched normal controls were also evaluated.
Main Outcome:
Although the overrepresentation of IVS1-126G>T remains present in our current sMTC series, thus supporting our previous hypothesis, no differences were obtained among cases and controls in the distribution of the variants tested upstream this position. On the other hand, the frequency and distribution of G691S/S904S variants were similar in both groups of study, leading to exclude their role in sMTC in our series.
Conclusions:
These findings would suggest that the major genetic events contributing to the appearance of sMTC may reside in several different RET loci. In this way, we could hypothesize about the existence of at least two sMTC loci, linked to S836S-IVS1-126G>T, or to G691S-S904S, respectively.
Insights
The study investigated genetic factors in sporadic medullary thyroid carcinoma (sMTC), finding evidence for a susceptibility locus linked to RET variants S836S/IVS1-126G>T. Other RET variants (G691S/S904S) were not associated with sMTC in this series.
Area of Science:
- Genetics
- Oncology
- Molecular Biology
Background:
- The etiology of sporadic medullary thyroid carcinoma (sMTC) is largely unknown.
- Germline mutations in the RET proto-oncogene cause hereditary MTC, but sporadic forms lack clear genetic drivers.
- Previous work suggested a low-penetrance susceptibility locus for sMTC linked to RET variants S836S/IVS1-126G>T.
Purpose of the Study:
- To identify the genetic locus associated with sMTC susceptibility.
- To investigate the role of RET variants G691S/S904S in sMTC etiology, as previously suggested.
- To analyze RET variants in the 5' region and specific MTC-associated variants.
Main Methods:
- Case-control study design.
- Analysis of a wide spectrum of RET variants in the 5' region and G691S/S904S variants.
- Inclusion of 58 sMTC patients and 100 matched controls.
- Haplotype distribution analysis.
Main Results:
- The overrepresentation of the IVS1-126G>T variant in sMTC patients was confirmed, supporting the hypothesis of a linked susceptibility locus.
- No significant differences in variants upstream of IVS1-126G>T were found between sMTC cases and controls.
- The frequency and distribution of G691S/S904S variants were similar in cases and controls, excluding their role in this sMTC series.
Conclusions:
- The findings suggest that major genetic contributors to sMTC may involve multiple RET loci.
- Hypothesize the existence of at least two distinct sMTC susceptibility loci.
- One locus is linked to S836S-IVS1-126G>T, while another potential locus is linked to G691S-S904S.
