Germ line missense mutations in the RET proto-oncogene are responsible for the inherited cancer syndrome multiple endocrine neoplasia type 2A (MEN2A). The clinical presentation of the disease and the age at onset varies even within families, where patients carry the same mutation. These variations in phenotypes suggest a role for genetic modifiers, and recently, it has been reported that polymorphisms within RET (G691S/S904S) may have such a modifier effect on the age at onset. Here, we investigate whether this observed association could be confirmed in a larger set of 384 individuals from MEN2 families from four different European populations. In addition, we tested as modifiers four other single nucleotide polymorphisms (SNPs), which we have found in a previous association study of RET, its coreceptors, and ligands to be associated with the risk of developing sporadic medullary thyroid carcinoma. We could not replicate the association between G691S/S904S and modifier effects in MEN2A families in any of the four European families analyzed. Of the other SNPs tested, only RET A432A showed a positive weak effect on tumor spectrum within MEN2A, which requires replication in a larger series.

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.

Hereditary medullary thyroid carcinoma (MTC) is caused by germ-line gain of function mutations in the RET proto-oncogene, and a phenotypic variability among carriers of the same mutation has been reported. We recently observed this phenomenon in a large familial MTC (FMTC) family carrying the RET-S891A mutation. Among genetic modifiers affecting RET-driven MTC, a role has been hypothesized for RET-G691S non-synonymous polymorphism, though the issue remains controversial. Aim of this study was to define the in vitro contribution of RET-G691S to the oncogenic potential of the RET-S891A, previously shown to harbour low transforming activity.

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.