title: GSTT1 deletion is related to polycyclic aromatic hydrocarbons-induced DNA damage and lymphoma progression.
abstract: The interrelationship between genetic susceptibility and carcinogenic exposure is important in cancer development. Polymorphisms in detoxification enzymes of the glutathione-S-transferases (GST) family are associated with an increased incidence of lymphoma. Here we investigated the molecular connection of the genetic polymorphism of GSTT1 to the response of lymphocytes to polycyclic aromatic hydrocarbons (PAH). In neoplastic situation, GSTT1 deletions were more frequently observed in lymphoma patients (54.9%) than in normal controls (42.0%, P = 0.009), resulting in an increased risk for lymphoma in individuals with GSTT1-null genotype (Odds ratio = 1.698, 95% confidence interval = 1.145-2.518). GSTT1 gene and protein expression were accordingly decreased in GSTT1-deleting patients, consistent with activated profile of cell cycle regulation genes. Mimicking environmental exposure using long-term repeat culture with low-dose PAH metabolite Hydroquinone, malignant B- and T-lymphocytes presented increased DNA damage, pCHK1/MYC expression and cell proliferation, which were counteracted by ectopic expression of GSTT1. Moreover, GSTT1 expression retarded xenograft tumor formation of Hydroquinone-treated lymphoma cells in nude mice. In non-neoplastic situation, when zebrafish was exposed to PAH Benzo(a)pyrene, molecular silencing of gstt1 enhanced the proliferation of normal lymphocytes and upregulated myca expression. Collectively, these findings suggested that GSTT1 deletion is related to genetic predisposition to lymphoma, particularly interacting with environmental pollutants containing PAH.
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Shanghai Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China ; Pôle de Recherches Sino-Français en Science du Vivant et Génomique, Laboratory of Molecular Pathology, Shanghai, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Shanghai Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Xiong
authors.affiliation: Institute of Health Sciences, Shanghai Institutes for Biological Sciences and Graduate University, Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Xiao-E
authors.initials: XE
authors.lastname: Jia
authors.affiliation: Shanghai Centre for Systems biomedicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Zhao-Hui
authors.initials: ZH
authors.lastname: Gu
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Shanghai Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Jing-Yi
authors.initials: JY
authors.lastname: Shi
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Shanghai Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Shanghai Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Jun-Min
authors.initials: JM
authors.lastname: Li
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Shanghai Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China ; Pôle de Recherches Sino-Français en Science du Vivant et Génomique, Laboratory of Molecular Pathology, Shanghai, China.
authors.forename: Sai-Juan
authors.initials: SJ
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Shanghai Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China ; Pôle de Recherches Sino-Français en Science du Vivant et Génomique, Laboratory of Molecular Pathology, Shanghai, China.
authors.forename: Wei-Li
authors.initials: WL
authors.lastname: Zhao
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D018736:DNA Adducts; D056915:DNA Copy Number Variations / Q000235:genetics; D004249:DNA Damage / Q000187:drug effects* / Q000235:genetics; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D007124:Immunoenzyme Techniques; D017403:In Situ Hybridization; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy / Q000209:etiology / Q000473:pathology*; D016399:Lymphoma, T-Cell / Q000188:drug therapy / Q000209:etiology / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D011084:Polycyclic Aromatic Hydrocarbons / Q000633:toxicity*; D011110:Polymorphism, Genetic / Q000235:genetics*; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017384:Sequence Deletion / Q000235:genetics*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D055815:Young Adult; D015027:Zebrafish / Q000235:genetics / Q000254:growth & development
chemical_list: D018736:DNA Adducts; D011084:Polycyclic Aromatic Hydrocarbons; D012333:RNA, Messenger; C413545:glutathione S-transferase T1; D005982:Glutathione Transferase