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

Ramona A Eiholzer; Sunali Mehta; Marina Kazantseva; Catherine J Drummond; Cushla McKinney; Katie Young; David Slater; Brianna C Morten; Kelly A Avery-Kiejda; Annette Lasham; Nicholas Fleming; Helen R Morrin; Karen Reader; Janice A Royds; Michael Landmann; Simone Petrich; Roger Reddel; Lily Huschtscha; Ahmad Taha; Noelyn A Hung; Tania L Slatter; Antony W Braithwaite

doi:10.3390/cancers12092472

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

Cancers (Basel). 2020 Sep 1;12(9):2472. doi: 10.3390/cancers12092472.

Authors

Ramona A Eiholzer¹, Sunali Mehta^{1

2}, Marina Kazantseva^{1

2}, Catherine J Drummond^{1

2}, Cushla McKinney¹, Katie Young¹, David Slater^{3

4}, Brianna C Morten^{3

4}, Kelly A Avery-Kiejda^{3

4}, Annette Lasham⁵, Nicholas Fleming¹, Helen R Morrin⁶, Karen Reader¹, Janice A Royds¹, Michael Landmann⁷, Simone Petrich⁷, Roger Reddel⁸, Lily Huschtscha⁸, Ahmad Taha⁹, Noelyn A Hung¹, Tania L Slatter^{1

2}, Antony W Braithwaite^{1

2

10}

Affiliations

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.

Abstract

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.

Keywords: TP53; glioblastoma; prostate cancer; rs1042522; rs9895829 and rs2909430; single nucleotide polymorphism; Δ133p53.

Abstract

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