title: Exome sequencing reveals mutant genes with low penetrance involved in MEN2A-associated tumorigenesis.
abstract: Activating rearranged during transfection (RET) mutations function as the initiating causative mutation for multiple endocrine neoplasia type 2A (MEN2A). However, no conclusive findings regarding the non-RET genetic events have been reported. This is the first study, to our knowledge, examining genomic alterations in matched MEN2A-associated tumors. We performed exome sequencing and SNP array analysis of matched MEN2A tumors and germline DNA. Somatic alterations were validated in an independent set of patients using Sanger sequencing. Genes of functional interest were further evaluated. The germline RET mutation was found in all MEN2A-component tumors. Thirty-two somatic mutations were identified in the nine MEN2A-associated tumors, of which 28 (87.5%) were point mutations and 4 (12.5%) were small insertions, duplications, or deletions. We sequenced all the mutations as well as coding sequence regions of the 12 genes in an independent sample set including 35 medullary thyroid cancers (20 MEN2A) and 34 PCCs (22 MEN2A), but found no recurrent mutations. Recurrent alterations were found in 13 genes with either mutations or alterations in copy number, including an EIF4G1 mutation (p. E1147V). Mutation of EIF4G1 led to increased cell proliferation and RET/MAPK phosphorylation, while knockdown of EIF4G1 led to reduced cell proliferation and RET/MAPK phosphorylation in TT, MZ-CRC1, and PC-12 cells. We found fewer somatic mutations in endocrine tumors compared with non-endocrine tumors. RET was the primary driver in MEN2A-associated tumors. However, low-frequency alterations such as EIF4G1 might participate in MEN2A-associated tumorigenesis, possibly by regulating the activity of the RET pathway.
authors.affiliation: School of MedicineShanghai Clinical Center for Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University, #197 Ruijin 2nd Road, Shanghai 200025 People's Republic of ChinaBGI-ShenzhenShenzhen 518083, ChinaLaboratory for Endocrine and Metabolic Diseases of Institute of Health ScienceShanghai Jiao Tong University School of Medicine and Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, #227 South Chongqing Road, Shanghai 200025, People's Republic of China.
authors.forename: Jie
authors.initials: J
authors.lastname: Cai
authors.affiliation: School of MedicineShanghai Clinical Center for Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University, #197 Ruijin 2nd Road, Shanghai 200025 People's Republic of ChinaBGI-ShenzhenShenzhen 518083, ChinaLaboratory for Endocrine and Metabolic Diseases of Institute of Health ScienceShanghai Jiao Tong University School of Medicine and Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, #227 South Chongqing Road, Shanghai 200025, People's Republic of China.
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.affiliation: School of MedicineShanghai Clinical Center for Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University, #197 Ruijin 2nd Road, Shanghai 200025 People's Republic of ChinaBGI-ShenzhenShenzhen 518083, ChinaLaboratory for Endocrine and Metabolic Diseases of Institute of Health ScienceShanghai Jiao Tong University School of Medicine and Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, #227 South Chongqing Road, Shanghai 200025, People's Republic of China.
authors.forename: Lei
authors.initials: L
authors.lastname: Ye
authors.affiliation: School of MedicineShanghai Clinical Center for Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University, #197 Ruijin 2nd Road, Shanghai 200025 People's Republic of ChinaBGI-ShenzhenShenzhen 518083, ChinaLaboratory for Endocrine and Metabolic Diseases of Institute of Health ScienceShanghai Jiao Tong University School of Medicine and Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, #227 South Chongqing Road, Shanghai 200025, People's Republic of China.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Jiang
authors.affiliation: School of MedicineShanghai Clinical Center for Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University, #197 Ruijin 2nd Road, Shanghai 200025 People's Republic of ChinaBGI-ShenzhenShenzhen 518083, ChinaLaboratory for Endocrine and Metabolic Diseases of Institute of Health ScienceShanghai Jiao Tong University School of Medicine and Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, #227 South Chongqing Road, Shanghai 200025, People's Republic of China.
authors.forename: Liyun
authors.initials: L
authors.lastname: Shen
authors.affiliation: School of MedicineShanghai Clinical Center for Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University, #197 Ruijin 2nd Road, Shanghai 200025 People's Republic of ChinaBGI-ShenzhenShenzhen 518083, ChinaLaboratory for Endocrine and Metabolic Diseases of Institute of Health ScienceShanghai Jiao Tong University School of Medicine and Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, #227 South Chongqing Road, Shanghai 200025, People's Republic of China.
authors.forename: Zhibo
authors.initials: Z
authors.lastname: Gao
authors.affiliation: School of MedicineShanghai Clinical Center for Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University, #197 Ruijin 2nd Road, Shanghai 200025 People's Republic of ChinaBGI-ShenzhenShenzhen 518083, ChinaLaboratory for Endocrine and Metabolic Diseases of Institute of Health ScienceShanghai Jiao Tong University School of Medicine and Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, #227 South Chongqing Road, Shanghai 200025, People's Republic of China.
authors.forename: Weiyuan
authors.initials: W
authors.lastname: Fang
authors.affiliation: School of MedicineShanghai Clinical Center for Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University, #197 Ruijin 2nd Road, Shanghai 200025 People's Republic of ChinaBGI-ShenzhenShenzhen 518083, ChinaLaboratory for Endocrine and Metabolic Diseases of Institute of Health ScienceShanghai Jiao Tong University School of Medicine and Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, #227 South Chongqing Road, Shanghai 200025, People's Republic of China.
authors.forename: Fengjiao
authors.initials: F
authors.lastname: Huang
authors.affiliation: School of MedicineShanghai Clinical Center for Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University, #197 Ruijin 2nd Road, Shanghai 200025 People's Republic of ChinaBGI-ShenzhenShenzhen 518083, ChinaLaboratory for Endocrine and Metabolic Diseases of Institute of Health ScienceShanghai Jiao Tong University School of Medicine and Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, #227 South Chongqing Road, Shanghai 200025, People's Republic of China.
authors.forename: Tingwei
authors.initials: T
authors.lastname: Su
authors.affiliation: School of MedicineShanghai Clinical Center for Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University, #197 Ruijin 2nd Road, Shanghai 200025 People's Republic of ChinaBGI-ShenzhenShenzhen 518083, ChinaLaboratory for Endocrine and Metabolic Diseases of Institute of Health ScienceShanghai Jiao Tong University School of Medicine and Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, #227 South Chongqing Road, Shanghai 200025, People's Republic of China.
authors.forename: Yulin
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: School of MedicineShanghai Clinical Center for Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University, #197 Ruijin 2nd Road, Shanghai 200025 People's Republic of ChinaBGI-ShenzhenShenzhen 518083, ChinaLaboratory for Endocrine and Metabolic Diseases of Institute of Health ScienceShanghai Jiao Tong University School of Medicine and Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, #227 South Chongqing Road, Shanghai 200025, People's Republic of China.
authors.forename: Weiqing
authors.initials: W
authors.lastname: Wang
authors.affiliation: School of MedicineShanghai Clinical Center for Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University, #197 Ruijin 2nd Road, Shanghai 200025 People's Republic of ChinaBGI-ShenzhenShenzhen 518083, ChinaLaboratory for Endocrine and Metabolic Diseases of Institute of Health ScienceShanghai Jiao Tong University School of Medicine and Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, #227 South Chongqing Road, Shanghai 200025, People's Republic of China School of MedicineShanghai Clinical Center for Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University, #197 Ruijin 2nd Road, Shanghai 200025 People's Republic of ChinaBGI-ShenzhenShenzhen 518083, ChinaLaboratory for Endocrine and Metabolic Diseases of Institute of Health ScienceShanghai Jiao Tong University School of Medicine and Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, #227 South Chongqing Road, Shanghai 200025, People's Republic of China gning@sibs.ac.cn.
authors.forename: Guang
authors.initials: G
authors.lastname: Ning
mesh_terms: D000328:Adult; D063646:Carcinogenesis / Q000235:genetics / Q000473:pathology; D048708:Cell Growth Processes / Q000235:genetics; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000097:blood / Q000235:genetics; D059472:Exome; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D018813:Multiple Endocrine Neoplasia Type 2a / Q000097:blood / Q000235:genetics* / Q000473:pathology; D019683:Penetrance; D017354:Point Mutation; D020641:Polymorphism, Single Nucleotide; D014162:Transfection
chemical_list: D004273:DNA, Neoplasm
keywords: EIF4G1; MEN2A; RET; exome sequencing