Deletion of the MAD2L1 spindle assembly checkpoint gene is tolerated in mouse models of acute T-cell lymphoma and hepatocellular carcinoma
- University Medical Center Groningen, Netherlands
- Harvard Medical School, United States
- University Health Network, Canada
- Vertex Pharmaceuticals Incorporated, United States
- BC Cancer Agency, Canada
- Wellcome Trust Sanger Institute, United Kingdom
Abstract
Chromosome instability (CIN) is deleterious to normal cells because of the burden of aneuploidy. However, most human solid tumors have an abnormal karyotype implying that gain and loss of chromosomes by cancer cells confers a selective advantage. CIN can be induced in the mouse by inactivating the spindle assembly checkpoint. This is lethal in the germline but we show here that adult T cells and hepatocytes can survive conditional inactivation of the Mad2l1 SAC gene and resulting CIN. This causes rapid onset of acute lymphoblastic leukemia (T-ALL) and progressive development of hepatocellular carcinoma (HCC), both lethal diseases. The resulting DNA copy number variation and patterns of chromosome loss and gain are tumor-type specific, suggesting differential selective pressures on the two tumor cell types.
Data availability
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Copy number changes (average and single cell) and matching transcriptomes of HCCs and T-ALLs isolated from Mad2 p53 conditional double knockout micePublicly available at the NCBI Gene Expression Omnibus (accession no: GSE63689).
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Cytogenetic aberrations in Hepatocellular adenoma and carcinomaPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE63100).
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Hepatocellular adenoma/carcinoma from Mad2 deficient hepatocytesPublicly available at the NCBI Sequence Read Archive (accession no: SRA191233).
Article and author information
Author details
Funding
National Institute for Health Research (CA084179)
- Lee A Albacker
- Ying Yue
- Stephanie H Davis
- Peter K Sorger
National Institute for Health Research (CA139980)
- Lee A Albacker
- Ying Yue
- Stephanie H Davis
- Peter K Sorger
KWF Kankerbestrijding (2012-RUG-5549)
- Floris Foijer
- Bjorn Bakker
H2020 European Research Council (ERC advanced ROOTS)
- Diana C Spierings
- Peter M Lansdorp
European Molecular Biology Organization (Longterm fellowship)
- Floris Foijer
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Angelika Amon, Howard Hughes Medical Institute, Massachusetts Institute of Technology, United States
Ethics
Animal experimentation: All animals were kept in pathogen-free housing under guidelines approved by the Center for Animal Resources and Comparative Medicine at Harvard Medical School or at the Wellcome Trust Sanger Institute. Animal protocols were approved by the Massachusetts Institute of Technology, Harvard Medical School Committees on Animal Care (IACUC numbers I04272 and IS00000178), UK Home Office, and UMCG animal facility (DEC 6369).
Version history
- Received: August 23, 2016
- Accepted: March 18, 2017
- Accepted Manuscript published: March 20, 2017 (version 1)
- Version of Record published: April 21, 2017 (version 2)
Copyright
© 2017, Foijer et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Deletion of the MAD2L1 spindle assembly checkpoint gene is tolerated in mouse models of acute T-cell lymphoma and hepatocellular carcinoma
eLife 6:e20873.
https://doi.org/10.7554/eLife.20873
Further reading
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- Cancer Biology
- Genetics and Genomics
Enhancers are critical for regulating tissue-specific gene expression, and genetic variants within enhancer regions have been suggested to contribute to various cancer-related processes, including therapeutic resistance. However, the precise mechanisms remain elusive. Using a well-defined drug-gene pair, we identified an enhancer region for dihydropyrimidine dehydrogenase (DPD, DPYD gene) expression that is relevant to the metabolism of the anti-cancer drug 5-fluorouracil (5-FU). Using reporter systems, CRISPR genome-edited cell models, and human liver specimens, we demonstrated in vitro and vivo that genotype status for the common germline variant (rs4294451; 27% global minor allele frequency) located within this novel enhancer controls DPYD transcription and alters resistance to 5-FU. The variant genotype increases recruitment of the transcription factor CEBPB to the enhancer and alters the level of direct interactions between the enhancer and DPYD promoter. Our data provide insight into the regulatory mechanisms controlling sensitivity and resistance to 5-FU.
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- Cancer Biology
- Epidemiology and Global Health
Background:
Age is the most important risk factor for cancer, but aging rates are heterogeneous across individuals. We explored a new measure of aging-Phenotypic Age (PhenoAge)-in the risk prediction of site-specific and overall cancer.
Methods:
Using Cox regression models, we examined the association of Phenotypic Age Acceleration (PhenoAgeAccel) with cancer incidence by genetic risk group among 374,463 participants from the UK Biobank. We generated PhenoAge using chronological age and nine biomarkers, PhenoAgeAccel after subtracting the effect of chronological age by regression residual, and an incidence-weighted overall cancer polygenic risk score (CPRS) based on 20 cancer site-specific polygenic risk scores (PRSs).
Results:
Compared with biologically younger participants, those older had a significantly higher risk of overall cancer, with hazard ratios (HRs) of 1.22 (95% confidence interval, 1.18–1.27) in men, and 1.26 (1.22–1.31) in women, respectively. A joint effect of genetic risk and PhenoAgeAccel was observed on overall cancer risk, with HRs of 2.29 (2.10–2.51) for men and 1.94 (1.78–2.11) for women with high genetic risk and older PhenoAge compared with those with low genetic risk and younger PhenoAge. PhenoAgeAccel was negatively associated with the number of healthy lifestyle factors (Beta = –1.01 in men, p<0.001; Beta = –0.98 in women, p<0.001).
Conclusions:
Within and across genetic risk groups, older PhenoAge was consistently related to an increased risk of incident cancer with adjustment for chronological age and the aging process could be retarded by adherence to a healthy lifestyle.
Funding:
This work was supported by the National Natural Science Foundation of China (82230110, 82125033, 82388102 to GJ; 82273714 to MZ); and the Excellent Youth Foundation of Jiangsu Province (BK20220100 to MZ).
