Whole Exome Sequencing Identifies a Novel Hedgehog-Interacting Protein G516R Mutation in Locally Advanced Papillary Thyroid Cancer

International Journal of Molecular Sciences
Woo Kyung LeeJandee Lee

Abstract

Locally advanced thyroid cancer exhibits aggressive clinical features requiring extensive neck dissection. Therefore, it is important to identify changes in the tumor biology before local progression. Here, whole exome sequencing (WES) using tissues from locally advanced papillary thyroid cancer (PTC) presented a large number of single nucleotide variants (SNVs) in the metastatic lymph node (MLN), but not in normal tissues and primary tumors. Among those MLN-specific SNVs, a novel HHIP G516R (G1546A) mutation was also observed. Interestingly, in-depth analysis for exome sequencing data from the primary tumor presented altered nucleotide 'A' at a very low frequency indicating intra-tumor heterogeneity between the primary tumor and MLN. Computational prediction models such as PROVEAN and Polyphen suggested that HHIP G516R might affect protein function and stability. In vitro, HHIP G516R increased cell proliferation and promoted cell migration in thyroid cancer cells. HHIP G516R, a missense mutation, could be a representative example for the intra-tumor heterogeneity of locally advanced thyroid cancer, which can be a potential future therapeutic target for this disease.

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Methods Mentioned

BETA
biopsy
dissection
Phenotyping
co-immunoprecipitation
transfection
co-IP
PCR
electrophoresis
Assay

Software Mentioned

SPSS
Mutect
PROVEAN
GraphPad Prism
PolyPhen2
Samtools
SIFT
SNVmix2
Annovar
Clustalw2

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