Deletions linked to TP53 loss drive cancer through p53-independent mechanisms

Liu Yu; Chen Chong; Xu Zhengmin; Scuoppo Claudio; Rillahan Cory D.; Gao Jianjiong; Spitzer Barbara; Bosbach Benedikt; Kastenhuber Edward R.; Baslan Timour; Ackermann Sarah; Cheng Lihua; Wang Qingguo; Niu Ting; Schultz Nikolaus; Levine Ross L.; Mills Alea A.; Lowe Scott W.

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Deletions linked to TP53 loss drive cancer through p53-independent mechanisms

机译：与TP53缺失相关的缺失通过p53独立机制驱动癌症

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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.

机译：禁用TP53肿瘤抑制基因的突变代表人类癌症中最常见的事件，通常通过两次打击机制发生，这种机制涉及一个等位基因的错义突变和涵盖另一种基因的“杂合性缺失”缺失。虽然TP53错义突变也可以促进影响肿瘤进展的功能获得活性，但尚不清楚删除事件（通常包括许多基因）是否会影响肿瘤发生，而不仅仅是TP53丢失。在这里，我们显示小鼠染色体11B3的体细胞杂合缺失，这是一个与人17p13.1同源的4兆碱基区域，比Trp53缺失对淋巴瘤和白血病的发展产生更大的影响。从机理上讲，11B3缺失对肿瘤发生的影响涉及共同缺失的基因，例如Eif5a和Alox15b（也称为Alox8），其抑制与Trp53缺失协同作用，从而产生更具侵略性的疾病。我们的结果暗示，由人类17p染色体缺失产生的选择性优势反映了TP53缺失和相关肿瘤抑制基因剂量降低的综合影响。

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《Nature》 |2016年第7595期|471-475|共5页
作者
Liu Yu; Chen Chong; Xu Zhengmin; Scuoppo Claudio; Rillahan Cory D.; Gao Jianjiong; Spitzer Barbara; Bosbach Benedikt; Kastenhuber Edward R.; Baslan Timour; Ackermann Sarah; Cheng Lihua; Wang Qingguo; Niu Ting; Schultz Nikolaus; Levine Ross L.; Mills Alea A.; Lowe Scott W.;
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作者单位

Sichuan Univ, West China Hosp, Dept Hematol, Chengdu 610041, Peoples R China|Sichuan Univ, West China Hosp, Dept Liver Surg, State Key Lab Biotherapy, Chengdu 610041, Peoples R China|Sichuan Univ, West China Hosp, Ctr Canc, Chengdu 610041, Peoples R China|Natl Collaborat Innovat Ctr, Chengdu 610041, Peoples R China|Mem Sloan Kettering Canc Ctr, Dept Canc Biol & Genet, New York, NY 10065 USA;

Sichuan Univ, West China Hosp, Dept Hematol, Chengdu 610041, Peoples R China|Sichuan Univ, West China Hosp, Dept Liver Surg, State Key Lab Biotherapy, Chengdu 610041, Peoples R China|Sichuan Univ, West China Hosp, Ctr Canc, Chengdu 610041, Peoples R China|Natl Collaborat Innovat Ctr, Chengdu 610041, Peoples R China|Mem Sloan Kettering Canc Ctr, Dept Canc Biol & Genet, New York, NY 10065 USA;

Sichuan Univ, West China Hosp, Dept Hematol, Chengdu 610041, Peoples R China|Sichuan Univ, West China Hosp, Dept Liver Surg, State Key Lab Biotherapy, Chengdu 610041, Peoples R China|Sichuan Univ, West China Hosp, Ctr Canc, Chengdu 610041, Peoples R China|Natl Collaborat Innovat Ctr, Chengdu 610041, Peoples R China;

Columbia Univ, Inst Canc Genet, Med Ctr, New York, NY 10032 USA;

Mem Sloan Kettering Canc Ctr, Dept Canc Biol & Genet, New York, NY 10065 USA;

Mem Sloan Kettering Canc Ctr, Kravis Ctr Mol Oncol, New York, NY 10065 USA;

Mem Sloan Kettering Canc Ctr, Dept Pediat, New York, NY 10065 USA|Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA|Mem Sloan Kettering Canc Ctr, Leukemia Serv, New York, NY 10065 USA;

Mem Sloan Kettering Canc Ctr, Dept Canc Biol & Genet, New York, NY 10065 USA;

Mem Sloan Kettering Canc Ctr, Dept Canc Biol & Genet, New York, NY 10065 USA;

Mem Sloan Kettering Canc Ctr, Dept Canc Biol & Genet, New York, NY 10065 USA;

Mem Sloan Kettering Canc Ctr, Dept Canc Biol & Genet, New York, NY 10065 USA;

Sichuan Univ, West China Hosp, Dept Hematol, Chengdu 610041, Peoples R China|Sichuan Univ, West China Hosp, Res Lab Hematol, Chengdu 610041, Peoples R China;

Mem Sloan Kettering Canc Ctr, Kravis Ctr Mol Oncol, New York, NY 10065 USA;

Sichuan Univ, West China Hosp, Dept Hematol, Chengdu 610041, Peoples R China|Sichuan Univ, West China Hosp, Res Lab Hematol, Chengdu 610041, Peoples R China;

Mem Sloan Kettering Canc Ctr, Kravis Ctr Mol Oncol, New York, NY 10065 USA;

Mem Sloan Kettering Canc Ctr, Leukemia Serv, New York, NY 10065 USA;

Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA;

Mem Sloan Kettering Canc Ctr, Dept Canc Biol & Genet, New York, NY 10065 USA|Howard Hughes Med Inst, New York, NY 10065 USA;

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收录信息美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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Deletions linked to TP53 loss drive cancer through p53-independent mechanisms

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