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Hum Mol Genet. 2016 May 1;25(9):1875-84. doi: 10.1093/hmg/ddw056. Epub 2016 Mar 2.

Whole exome sequencing identifies lncRNA GAS8-AS1 and LPAR4 as novel papillary thyroid carcinoma driver alternations.

Author information

1
Beijing Laboratory of Biomedical Materials, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China.
2
Department of Radiation Oncology, Huaian No. 2 Hospital, Huaian 223002, Jiangsu Province, China.
3
Department of Head and Neck Surgery, Zhejiang Province Cancer Hospital, Hangzhou 310022, Zhejiang Province, China.
4
Department of Head and Neck Surgical Oncology and.
5
Department of Oncology, Provincial Hospital affiliated to Shandong University, Jinan 250021, Shandong Province, China.
6
Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China.
7
State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences, Beijing 100021, China.
8
State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences, Beijing 100021, China, aaryoung@yeah.net chenwu@cicams.ac.cn.
9
Beijing Laboratory of Biomedical Materials, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China, Shandong Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Jinan 250117, Shandong Province, China aaryoung@yeah.net chenwu@cicams.ac.cn.

Abstract

Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. However, we know little of mutational spectrum in the Chinese population. Thus, here we report the identification of somatic mutations for Chinese PTC using 402 tumor-normal pairs (Discovery: 91 pairs via exome sequencing; validation: 311 pairs via Sanger sequencing). We observed three distinct mutational signatures, evidently different from the two mutational signatures among Caucasian PTCs. Ten significantly mutated genes were identified, most previously uncharacterized. Notably, we found that long non-coding RNA (lncRNA) GAS8-AS1 is the secondary most frequently altered gene and acts as a novel tumor suppressor in PTC. As a mutation hotspot, the c.713A>G/714T>C dinucleotide substitution was found among 89.1% patients with GAS8-AS1 mutations and associated with advanced PTC disease (P = 0.009). Interestingly, the wild-type lncRNA GAS8-AS1 (A713T714) showed consistently higher capability to inhibit cancer cell growth compared to the mutated lncRNA (G713C714). Further studies also elucidated the oncogene nature of the G protein-coupled receptor LPAR4 and its c.872T>G (p.Ile291Ser) mutation in PTC malignant transformation. The BRAF c.1799T>A (p.Val600Glu) substitution was present in 59.0% Chinese PTCs, more frequently observed in patients with lymph node metastasis (P = 1.6 × 10(-4)). Together our study defines a exome mutational spectrum of PTC in the Chinese population and highlights lncRNA GAS8-AS1 and LPAR4 as potential diagnostics and therapeutic targets.

PMID:
26941397
DOI:
10.1093/hmg/ddw056
[Indexed for MEDLINE]

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