Related Experiment Videos
Polymorphisms G691S/S904S of RET as genetic modifiers of MEN 2A
Mercedes Robledo1, Laura Gil, Marina Pollán
1Centro Nacional de Epidemiología, Instituto de Salud Carlos III; Centro Nacional de Investigaciones Oncológicas, Madrid, Spain.
Abstract:
Multiple endocrine neoplasia type 2A (MEN 2A) is associated with specific germ-line missense mutations in the RET proto-oncogene. Only a minor fraction of human disorders are simple monogenic diseases, and the identification of polymorphisms that increase susceptibility, including variations in pathological phenotypes, to human diseases is one of the key problems in medical genetics. To explore this idea, we analyzed the polymorphisms G691S (exon 11) and S904S (TCC-TCG, exon 15) of RET in 198 individuals corresponding to 35 unrelated Spanish MEN 2A families (104 patients with oncogenic MEN 2A mutation and 94 healthy relatives). We found strong cosegregation between both polymorphisms (100% Fisher's exact test, P < 0.001) using a control population containing 653 healthy individuals (362 females and 291 males). Interestingly, we found that the homozygous for these polymorphisms were, on average, 10 years younger at diagnosis compared with heterozygous and wild-type homozygous (P = 0.037). Taken together, all these findings could indicate that the G691S and S904S variants of RET have a modifier effect on the age at onset of MEN 2A. Moreover, compared with the control population, the homozygote status was significantly more prevalent in a series of 110 sporadic thyroid carcinoma (odds ratio = 2.36), suggesting that these polymorphisms may play a role as a low penetrance risk factor.
Insights
Genetic variations in the RET proto-oncogene, specifically G691S and S904S polymorphisms, influence the age of diagnosis for Multiple Endocrine Neoplasia type 2A (MEN 2A). These RET variants may also act as low-penetrance risk factors for sporadic thyroid carcinoma.
Area of Science:
- Genetics
- Medical Genetics
- Oncology
Background:
- Multiple Endocrine Neoplasia type 2A (MEN 2A) is linked to RET proto-oncogene mutations.
- Identifying susceptibility polymorphisms is crucial for understanding complex human diseases.
- RET gene variations can influence disease phenotypes and age of onset.
Purpose of the Study:
- To investigate the role of RET polymorphisms G691S and S904S in MEN 2A.
- To determine if these polymorphisms affect the age at diagnosis for MEN 2A.
- To assess the potential of these RET variants as risk factors for sporadic thyroid carcinoma.
Main Methods:
- Analysis of RET polymorphisms G691S and S904S in 198 individuals from Spanish MEN 2A families.
- Comparison with a control population of 653 healthy individuals.
- Statistical analysis including Fisher's exact test and assessment of age at diagnosis and prevalence in sporadic thyroid carcinoma.
Main Results:
- Strong cosegregation observed between G691S and S904S RET polymorphisms (P < 0.001).
- Individuals homozygous for these polymorphisms were diagnosed with MEN 2A approximately 10 years earlier (P = 0.037).
- Homozygous status for these polymorphisms was more prevalent in sporadic thyroid carcinoma patients (OR = 2.36).
Conclusions:
- The G691S and S904S variants of RET may act as modifier genes influencing the age of onset in MEN 2A.
- These RET polymorphisms could represent low-penetrance risk factors for sporadic thyroid carcinoma.
- Further research is warranted to elucidate the precise role of these variants in disease development.