Potential association between the functional variant RS2043556 in MIR605 gene and development of multiple primary tumors in TP53 P.ARG337HIS mutation carriers pacientes do Rio Grande do Sul

Li-Fraumeni and Li-Fraumeni-like syndromes (LFS/LFL) are cancer predisposition syndromes associated with TP53 germline mutations and characterized by high risk for multiple early-onset cancers.In Southern and Southeastern Brazil, a founder germline mutation located in the oligomerization domain of the TP53 gene and with incomplete penetrance, c.1010G>A (p.Arg337His), has been detected in many families showing a predisposition to at least some of the cancers of the LFS/LFL spectrum.Recently, the functional variant rs2043556 (A>G), located in MIR605 gene, was identified as a novel genetic modifier of the LFS phenotype in families with classical hotspot TP53 mutations (DNA binding domain mutations).Indeed, miR-605 is a component in the p53 regulatory network, being transcriptionally activated by p53 and post-transcriptionally repressing Mdm2 (a well-known negative regulator of p53 expression levels and activity).Here, we determined the frequency and explored possible effects of the SNP rs2043556 on clinical manifestations of Brazilian individuals carrying TP53 p.Arg337His mutation.Genotyping was performed by allelic discrimination using TaqMan assay and statistical analyzes were conducted on SPSS V.18.0 software.Among 233 patients harboring the founder TP53 mutation, the variant G-allele was detected in 132 (56.7%), of which 23 in homozygosis (GG genotype, 9.9%).Although this SNP was associated with an earlier mean age of tumor onset in LFS patients (classic phenotype) from a Canadian population, this effect was not replicated in our cohort (P = 0.6).A possible reason for this conflicting result is because there were no LFS/LFL families with this highly-prevalent Brazilian mutation evaluated in the previous study.The MIR605 rs204356 genotype was also not associated with the tumor type diagnosed in TP53 p.Arg337His mutation carriers (P = 0.4).However, the GG genotype showed a borderline modifier effect (P = 0.049) to the manifestation of multiple primary tumors in the same group.Among these TP53 p.Arg337His and rs204356[GG]-positive patients with tumor diagnosis in multiple primary sites, a female patient developed very early-onset breast and thyroid cancers (at 23 and 25 years, respectively).To our knowledge, this is the first description of LFS/LFL patients with the variant G-allele of MIR605 rs204356 in homozygosis.Further functional studies are necessary to clarify the effects of this variant in cancer pathways.Uniterms

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