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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
Deletions linked to TP53 loss drive cancer through p53-independent mechanisms
Yu Liu1,2, Chong Chen1,2, Zhengmin Xu1
1Department 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.
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.
Insights
Loss of TP53 tumor suppressor gene is common in cancer. Deleting linked genes alongside TP53 accelerates lymphoma and leukemia more than TP53 loss alone.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- TP53 tumor suppressor gene mutations are frequent in human cancers.
- Cancer often involves a two-hit mechanism: missense mutation and loss of heterozygosity (LOH) deletion.
- The impact of LOH deletions on tumorigenesis beyond TP53 loss is not fully understood.
Purpose of the Study:
- To investigate whether gene deletions accompanying TP53 loss influence tumorigenesis.
- To determine the role of co-deleted genes in cancer progression.
Main Methods:
- Utilized a mouse model to study heterozygous deletion of chromosome 11B3, syntenic to human 17p13.1.
- Compared the effects of Trp53 deletion versus 11B3 deletion on lymphoma and leukemia development.
- Analyzed the impact of co-deleted genes, including Eif5a and Alox15b, on tumorigenesis.
Main Results:
- Somatic heterozygous deletion of mouse chromosome 11B3 showed a more significant effect on lymphoma and leukemia development than Trp53 deletion alone.
- Suppression of co-deleted genes Eif5a and Alox15b cooperated with Trp53 loss to promote more aggressive disease.
- The selective advantage of human chromosome 17p deletion is attributed to the combined effects of TP53 loss and reduced dosage of linked tumor suppressor genes.
Conclusions:
- Gene deletions linked to TP53 loss contribute significantly to cancer progression.
- Co-deleted genes play a crucial role in cooperating with TP53 loss to drive tumorigenesis.
- Understanding the impact of LOH on linked genes is vital for comprehending cancer development and therapeutic strategies.
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