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Recurrent Patterns of Single Nucleotide Polymorphism in the MAPK-pathway of Papillary Thyroid Carcinoma Patients.
*Jill Rubinstein, *Taylor Brown, *Reju Korah, Tobias Carling
Yale School of Medicine, New Haven, CT

Objective: To identify single nucleotide polymorphism (SNP) signatures within the MAPK-pathway that differ between the genomes of papillary thyroid carcinoma (PTC) patients and that of healthy controls.
Design: Whole exome sequencing was performed on 53 PTC samples and matched non-tumor thyroid tissues. Exome data from 53 healthy, race-matched blood samples were downloaded from the 1000 Genomes project. SNPs were called using SAMtools, those present in dbSNP flagged using ANNOVAR, and functional effect predicted with PolyPhen-2. SNPs present in both PTC and matched non-tumor thyroid were considered germline.
Setting: Academic medical center
Patients: Fifty-three patients who underwent total thyroidectomy for PTC.
Interventions: -
Main Outcome Measures: MAPK-pathway SNP signatures.
Results: Nine non-synonymous MAPK-pathway SNPs were found to occur in at least 85% of the PTC samples' germlines and fewer than 20% of the 1000 Genomes control samples. The mean minor allele frequency (MAF) for these SNPs in the PTC cohort was 0.76 (range 0.5-0.99), significantly higher than their mean MAF of 0.198 in the dbSNP database (p-value: 1.8e-5). Two SNPs, in the MAP2K3 and CACNA1B genes, were present in 100% of PTCs and no control samples and both were predicted to have a damaging impact on protein function.
Conclusions: There is a small subset of germline MAPK SNPs that occur with significantly greater frequency in the genomes of PTC patients than in the greater population. These SNPs result in non-synonymous changes to the amino acid sequence, potentially causing increased PTC risk by serving as a first hit within a pathway where subsequent somatic mutations (ex. BRAF, RAS) are strongly correlated with more aggressive disease and higher rates of recurrence.


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