title: Deletions linked to TP53 loss drive cancer through p53-independent mechanisms.
abstract: Mutations disabling the TP53 tumour suppressor gene represent the most frequent events in human cancer and typically occur through a two-hit mechanism involving a missense mutation in one allele and a 'loss of heterozygosity' deletion encompassing the other. While TP53 missense mutations can also contribute gain-of-function activities that impact tumour progression, it remains unclear whether the deletion event, which frequently includes many genes, impacts tumorigenesis beyond TP53 loss alone. Here we show that somatic heterozygous deletion of mouse chromosome 11B3, a 4-megabase region syntenic to human 17p13.1, produces a greater effect on lymphoma and leukaemia development than Trp53 deletion. Mechanistically, the effect of 11B3 loss on tumorigenesis involves co-deleted genes such as Eif5a and Alox15b (also known as Alox8), the suppression of which cooperates with Trp53 loss to produce more aggressive disease. Our results imply that the selective advantage produced by human chromosome 17p deletion reflects the combined impact of TP53 loss and the reduced dosage of linked tumour suppressor genes.
authors.affiliation: Department of Hematology and Department of Liver Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and National Collaborative Innovation Center, Chengdu 610041, China.|Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Hematology and Department of Liver Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and National Collaborative Innovation Center, Chengdu 610041, China.|Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Chong
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Hematology and Department of Liver Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and National Collaborative Innovation Center, Chengdu 610041, China.
authors.forename: Zhengmin
authors.initials: Z
authors.lastname: Xu
authors.affiliation: institute for Cancer Genetics, Columbia University Medical Center, New York, New York 10032, USA.
authors.forename: Claudio
authors.initials: C
authors.lastname: Scuoppo
authors.affiliation: Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Cory D
authors.initials: CD
authors.lastname: Rillahan
authors.affiliation: Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Jianjiong
authors.initials: J
authors.lastname: Gao
authors.affiliation: Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.|Human Oncology & Pathogenesis Program and Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Spitzer
authors.affiliation: Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Bosbach
authors.affiliation: Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Edward R
authors.initials: ER
authors.lastname: Kastenhuber
authors.affiliation: Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Timour
authors.initials: T
authors.lastname: Baslan
authors.affiliation: Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Ackermann
authors.affiliation: Department of Hematology & Research Laboratory of Hematology, West China Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Lihua
authors.initials: L
authors.lastname: Cheng
authors.affiliation: Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Qingguo
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Hematology & Research Laboratory of Hematology, West China Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Niu
authors.affiliation: Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Schultz
authors.affiliation: Human Oncology & Pathogenesis Program and Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Ross L
authors.initials: RL
authors.lastname: Levine
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
authors.forename: Alea A
authors.initials: AA
authors.lastname: Mills
authors.affiliation: Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.|Howard Hughes Medical Institute, New York, New York 10065, USA.
authors.forename: Scott W
authors.initials: SW
authors.lastname: Lowe
mesh_terms: D000483:Alleles; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D033481:Chromosomes, Mammalian / Q000235:genetics; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D016158:Genes, p53 / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000473:pathology; D008223:Lymphoma / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology*; D010448:Peptide Initiation Factors / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion / Q000235:genetics*; D026801:Synteny / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency*; D000097574:Eukaryotic Translation Initiation Factor 5A
chemical_list: D010448:Peptide Initiation Factors; D016601:RNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; D000097574:Eukaryotic Translation Initiation Factor 5A