Tohoku J. Exp. Med., 2017 April, 241(4)

A SLC24A2 Gene Variant Uncovered in Pancreatic Ductal Adenocarcinoma by Whole Exome Sequencing

LEI WANG,¹ ZHUO SHAO,² SHIYUE CHEN,³ LU SHI⁴ and ZHAOSHEN LI¹

¹Digestive Endoscopy Center, Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai, China
²Department of General Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China
³Department of Radiology, Changhai Hospital, Second Military Medical University, Shanghai, China
⁴Department of Public Health Sciences, Clemson University, SC, USA

Pancreatic ductal adenocarcinoma (PDAC) presents as an aggressive malignancy caused by environmental and genetic factors. In order to identify causal genes for PDAC, we performed whole exome sequencing (WES) to detect gene mutations in seven pairs of PDAC tissue and adjacent non-tumor tissue samples. Finally, we found a new nonsynonymous single nucleotide variant (nsSNV) in solute carrier 24 family member 2 (SLC24A2) gene resulting in the substitution of native glutamic acid (E) into aspartic acid (D) at position of 287 amino acid (E287D) in SLC24A2 protein, and confirmed this variant by Sanger gene sequencing. SLC24A2 is a potassium-dependent sodium-calcium exchanger and can transport metal ion across cell membrane. Multiple in silico variants' effects analyses methods including SIFT, PolyPhen, PROVEAN, and PANTHER demonstrated this variant had probably damaging effects, which was consistent with the results obtained from Mutation Taster software analysis with a probability of 0.99999997 to be “disease causing.” The three dimension (3D) structure analysis results suggested this variant had little effects on the solubility and hydrophobicity of the protein; but it could decrease the protein stability by increasing the total protein structure energy (&minos;8874.33 kJ/mol for the mutant and &minos;8963.54 kJ/mol for the native) and by causing the mutant protein decreasing three stabilizing residues. Less stability of the mutant 287D protein than the native E287 protein was also supported by I-Mutant and Western-blotting analysis results. Overall, a new mutation in SLC24A2 gene was identified to decrease the stability of SLC24A2, which may have potential clinical usages.

keywords —— next-generation sequencing; nonsynonymous single nucleotide variant; pancreatic ductal adenocarcinoma; SLC24A2; whole exome sequencing

© 2017 Tohoku University Medical Press

===============================

Tohoku J. Exp. Med., 2017, 241, 287-295

Correspondence: Zhaoshen Li, Digestive Endoscopy Center, Department of Gastroenterology, Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai 200433, China.

e-mail: zsl2001@yeah.net