title: Exome sequencing reveals novel mutation targets in diffuse large B-cell lymphomas derived from Chinese patients.
abstract: Next-generation sequencing studies on diffuse large B-cell lymphomas (DLBCLs) have revealed novel targets of genetic aberrations but also high intercohort heterogeneity. Previous studies have suggested that the prevalence of disease subgroups and cytogenetic profiles differ between Western and Asian patients. To characterize the coding genome of Chinese DLBCL, we performed whole-exome sequencing of DNA derived from 31 tumors and respective peripheral blood samples. The mutation prevalence of B2M, CD70, DTX1, LYN, TMSB4X, and UBE2A was investigated in an additional 105 tumor samples. We discovered 11 novel targets of recurrent mutations in DLBCL that included functionally relevant genes such as LYN and TMSB4X. Additional genes were found mutated at high frequency (≥10%) in the Chinese cohort including DTX1, which was the most prevalent mutation target in the Notch pathway. We furthermore demonstrated that mutations in DTX1 impair its function as a negative regulator of Notch. Novel and previous unappreciated targets of somatic mutations in DLBCL identified in this study support the existence of additional/alternative tumorigenic pathways in these tumors. The observed differences with previous reports might be explained by the genetic heterogeneity of DLBCL, the germline genetic makeup of Chinese individuals, and/or exposure to distinct etiological agents.
authors.affiliation: Clinical Immunology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital, Huddinge, Sweden;
authors.forename: Noel F C C
authors.initials: NF
authors.lastname: de Miranda
authors.affiliation: Clinical Immunology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital, Huddinge, Sweden;
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Georgiou
authors.affiliation: Department of Medical Sciences Research, Beijing Genomics Institute-Shenzhen, Shenzhen, China;
authors.forename: Longyun
authors.initials: L
authors.lastname: Chen
authors.affiliation: Clinical Immunology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital, Huddinge, Sweden;
authors.forename: Chenglin
authors.initials: C
authors.lastname: Wu
authors.affiliation: Department of Medical Sciences Research, Beijing Genomics Institute-Shenzhen, Shenzhen, China;
authors.forename: Zhibo
authors.initials: Z
authors.lastname: Gao
authors.affiliation: Clinical Immunology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital, Huddinge, Sweden;
authors.forename: Apostolos
authors.initials: A
authors.lastname: Zaravinos
authors.affiliation: Department of Genetics, Portuguese Oncology Institute, and Abel Salazar Biomedical Sciences Institute, Porto University, Porto, Portugal;
authors.forename: Susana
authors.initials: S
authors.lastname: Lisboa
authors.affiliation: Department of Radiology, Oncology and Radiation Science, Uppsala University, Uppsala, Sweden;
authors.forename: Gunilla
authors.initials: G
authors.lastname: Enblad
authors.affiliation: Department of Genetics, Portuguese Oncology Institute, and Abel Salazar Biomedical Sciences Institute, Porto University, Porto, Portugal;
authors.forename: Manuel R
authors.initials: MR
authors.lastname: Teixeira
authors.affiliation: Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, and Collaborative Innovation Center of Cancer Medicine, Guangzhou, China; and.
authors.forename: Yixin
authors.initials: Y
authors.lastname: Zeng
authors.affiliation: Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, and Collaborative Innovation Center of Cancer Medicine, Guangzhou, China; and.
authors.forename: Roujun
authors.initials: R
authors.lastname: Peng
authors.affiliation: Clinical Immunology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital, Huddinge, Sweden; Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, and Collaborative Innovation Center of Cancer Medicine, Guangzhou, China; and Guangzhou Institute of Respiratory Disease and China State Key Laboratory of Respiratory Disease, Guangzhou, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Pan-Hammarström
mesh_terms: D044466:Asian People / Q000235:genetics; D002681:China / Q000453:epidemiology; D059472:Exome; D005260:Female; D018740:Genetic Heterogeneity; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000235:genetics
chemical_list: D051880:Receptors, Notch; C583410:DTX1 protein, human; D044767:Ubiquitin-Protein Ligases