title: Whole exome sequencing identifies lncRNA GAS8-AS1 and LPAR4 as novel papillary thyroid carcinoma driver alternations.
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.
authors.affiliation: Beijing Laboratory of Biomedical Materials, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China.
authors.forename: Wenting
authors.initials: W
authors.lastname: Pan
authors.affiliation: Department of Radiation Oncology, Huaian No. 2 Hospital, Huaian 223002, Jiangsu Province, China.
authors.forename: Liqing
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Head and Neck Surgery, Zhejiang Province Cancer Hospital, Hangzhou 310022, Zhejiang Province, China.
authors.forename: Minghua
authors.initials: M
authors.lastname: Ge
authors.affiliation: Department of Head and Neck Surgical Oncology and.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Beijing Laboratory of Biomedical Materials, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China.
authors.forename: Xinyu
authors.initials: X
authors.lastname: Yang
authors.affiliation: Beijing Laboratory of Biomedical Materials, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China.
authors.forename: Xiangyu
authors.initials: X
authors.lastname: Xiong
authors.affiliation: Department of Oncology, Provincial Hospital affiliated to Shandong University, Jinan 250021, Shandong Province, China.
authors.forename: Guobin
authors.initials: G
authors.lastname: Fu
authors.affiliation: Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Head and Neck Surgery, Zhejiang Province Cancer Hospital, Hangzhou 310022, Zhejiang Province, China.
authors.forename: Xilin
authors.initials: X
authors.lastname: Nie
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences, Beijing 100021, China.
authors.forename: Hongmin
authors.initials: H
authors.lastname: Li
authors.affiliation: Beijing Laboratory of Biomedical Materials, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China.
authors.forename: Xiaohu
authors.initials: X
authors.lastname: Tang
authors.affiliation: Beijing Laboratory of Biomedical Materials, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China.
authors.forename: Jinyu
authors.initials: J
authors.lastname: Wei
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences, Beijing 100021, China.
authors.forename: Mingming
authors.initials: M
authors.lastname: Shao
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences, Beijing 100021, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Beijing Laboratory of Biomedical Materials, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China.
authors.forename: Qipeng
authors.initials: Q
authors.lastname: Yuan
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences, Beijing 100021, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Tan
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences, Beijing 100021, China, aaryoung@yeah.net chenwu@cicams.ac.cn.
authors.forename: Chen
authors.initials: C
authors.lastname: Wu
authors.affiliation: 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.
authors.forename: Ming
authors.initials: M
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences, Beijing 100021, China.
authors.forename: Dongxin
authors.initials: D
authors.lastname: Lin
mesh_terms: D002291:Carcinoma, Papillary / Q000235:genetics* / Q000556:secondary; D016022:Case-Control Studies; D059472:Exome / Q000235:genetics*; D005260:Female; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics*; D009367:Neoplasm Staging; D011379:Prognosis; D062085:RNA, Long Noncoding / Q000235:genetics*; D018048:Receptors, Purinergic P2 / Q000235:genetics*; D013961:Thyroid Gland / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000473:pathology; D049368:Receptors, Lysophosphatidic Acid
chemical_list: D009363:Neoplasm Proteins; D062085:RNA, Long Noncoding; D018048:Receptors, Purinergic P2; C115743:GAS8-AS1 protein, human; C082320:LPAR4 protein, human; D049368:Receptors, Lysophosphatidic Acid