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Good Cop, Bad Cop: Defining the Roles of Δ40p53 in Cancer and Aging
Open AccessFeature PaperArticle

Intronic TP53 Polymorphisms Are Associated with Increased Δ133TP53 Transcript, Immune Infiltration and Cancer Risk

1
Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin 9016, New Zealand
2
Maurice Wilkins Centre for Molecular Biodiscovery, Dunedin 9016, New Zealand
3
Priority Research Centre for Cancer Research, Innovation and Translation and the Hunter Cancer Research Alliance, School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, New South Wales 2305, Australia
4
Hunter Medical Research Institute, New South Wales 2305, Australia
5
Department of Molecular Medicine and Pathology, University of Auckland, Auckland 1023, New Zealand
6
Department of Pathology and Biomedical Science, University of Otago, Christchurch 8140, New Zealand
7
Department of Surgical Sciences, Dunedin School of Medicine, University of Otago, Dunedin 9054, New Zealand
8
Children’s Medical Research Institute, University of Sydney, Westmead, New South Wales 2145, Australia
9
Department of Neurosurgery, Southern District Heath Board, Dunedin 9016, New Zealand
10
Malaghan Institute of Medical Research, Wellington 6242, New Zealand
*
Author to whom correspondence should be addressed.
Contributed equally to the work.
Joint last authors.
Cancers 2020, 12(9), 2472; https://doi.org/10.3390/cancers12092472
Received: 7 August 2020 / Revised: 26 August 2020 / Accepted: 28 August 2020 / Published: 1 September 2020
We investigated the influence of genetic variants, called single nucleotide polymorphisms (SNP) in the TP53 tumour suppressor gene, on cancer risk, clinical features and TP53 isoform levels. These SNPs were significantly over-represented in cohorts of mixed cancers versus controls, suggesting they confer increased cancer risk. Heterozygosity at rs1042522(GC) and either of the two SNPs rs9895829(TC) and rs2909430(AG) confer up to a 5-fold greater risk of developing cancer. The SNP combinations were associated with high Δ133TP53 and TP53β messenger RNA levels, elevated infiltrating immune cells and shorter patient survival for glioblastoma and prostate cancer. The data suggest that ∆133p53β protein levels are increased by the SNPs resulting in increased inflammation which contributes to more aggressive cancers.
We investigated the influence of selected TP53 SNPs in exon 4 and intron 4 on cancer risk, clinicopathological features and expression of TP53 isoforms. The intron 4 SNPs were significantly over-represented in cohorts of mixed cancers compared to three ethnically matched controls, suggesting they confer increased cancer risk. Further analysis showed that heterozygosity at rs1042522(GC) and either of the two intronic SNPs rs9895829(TC) and rs2909430(AG) confer a 2.34–5.35-fold greater risk of developing cancer. These SNP combinations were found to be associated with shorter patient survival for glioblastoma and prostate cancer. Additionally, these SNPs were associated with tumor-promoting inflammation as evidenced by high levels of infiltrating immune cells and expression of the Δ133TP53 and TP53β transcripts. We propose that these SNP combinations allow increased expression of the Δ133p53 isoforms to promote the recruitment of immune cells that create an immunosuppressive environment leading to cancer progression. View Full-Text
Keywords: single nucleotide polymorphism; TP53; glioblastoma; prostate cancer; Δ133p53; rs1042522; rs9895829 and rs2909430 single nucleotide polymorphism; TP53; glioblastoma; prostate cancer; Δ133p53; rs1042522; rs9895829 and rs2909430
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Eiholzer, R.A.; Mehta, S.; Kazantseva, M.; Drummond, C.J.; McKinney, C.; Young, K.; Slater, D.; Morten, B.C.; Avery-Kiejda, K.A.; Lasham, A.; Fleming, N.; Morrin, H.R.; Reader, K.; Royds, J.A.; Landmann, M.; Petrich, S.; Reddel, R.; Huschtscha, L.; Taha, A.; Hung, N.A.; Slatter, T.L.; Braithwaite, A.W. Intronic TP53 Polymorphisms Are Associated with Increased Δ133TP53 Transcript, Immune Infiltration and Cancer Risk. Cancers 2020, 12, 2472.

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