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Polymorphisms in RET and its coreceptors and ligands as genetic modifiers of multiple endocrine neoplasia type 2A

Fabienne Lesueur1, Arancha Cebrian, Mercedes Robledo

  • 1Strangeways Research Laboratory, Cancer Research UK Department of Oncology, University of Cambridge,Worts Causeway, Cambridge CB1 8RN, UK.

Cancer Research
|January 21, 2006
PubMed

Insights

Genetic variations in the RET proto-oncogene influence multiple endocrine neoplasia type 2A (MEN2A) presentation. This study found no significant modifier effect for RET polymorphisms G691S/S904S on MEN2A onset age, but identified a potential link for RET A432A with tumor spectrum.

Area of Science:

  • Oncology
  • Genetics
  • Endocrinology

Background:

  • Germ line mutations in the RET proto-oncogene cause multiple endocrine neoplasia type 2A (MEN2A), an inherited cancer syndrome.
  • Phenotypic variability in MEN2A, even within families with identical mutations, suggests the influence of genetic modifiers.
  • Previous studies indicated that RET polymorphisms (G691S/S904S) might affect the age of onset in MEN2A.

Purpose of the Study:

  • To validate the association of RET polymorphisms (G691S/S904S) as modifiers of age at onset in a larger cohort of MEN2A families.
  • To investigate the potential modifier effects of four additional single nucleotide polymorphisms (SNPs) in RET, its coreceptors, and ligands on MEN2A phenotypes.
  • To assess the association of these SNPs with the risk of sporadic medullary thyroid carcinoma.

Main Methods:

  • Genotyping of 384 individuals from four European MEN2A families to analyze RET polymorphisms.
  • Statistical analysis to evaluate the association between specific RET SNPs and clinical parameters like age at onset and tumor spectrum.
  • Comparison of findings with previous association studies on RET and medullary thyroid carcinoma risk.

Main Results:

  • The association between RET polymorphisms G691S/S904S and modifier effects on age at onset in MEN2A families could not be replicated across the four analyzed European populations.
  • Among the tested SNPs, only RET A432A demonstrated a weak, positive association with the tumor spectrum in MEN2A patients.
  • No significant modifier effects were confirmed for G691S/S904S, and the effect of A432A requires further validation.

Conclusions:

  • The studied RET polymorphisms G691S/S904S do not appear to significantly modify the age of onset in MEN2A patients across European populations.
  • The RET A432A polymorphism may have a role in influencing the tumor spectrum within MEN2A, warranting further investigation.
  • Identifying genetic modifiers is crucial for understanding MEN2A variability and requires larger, diverse cohorts for robust confirmation.

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