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

Cancers (Sep 2020)

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

Affiliations

Ramona A. Eiholzer: Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin 9016, New Zealand
Sunali Mehta: Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin 9016, New Zealand
Marina Kazantseva: Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin 9016, New Zealand
Catherine J. Drummond: Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin 9016, New Zealand
Cushla McKinney: Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin 9016, New Zealand
Katie Young: Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin 9016, New Zealand
David Slater: 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
Brianna C. Morten: 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
Kelly A. Avery-Kiejda: 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
Annette Lasham: Department of Molecular Medicine and Pathology, University of Auckland, Auckland 1023, New Zealand
Nicholas Fleming: Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin 9016, New Zealand
Helen R. Morrin: Department of Pathology and Biomedical Science, University of Otago, Christchurch 8140, New Zealand
Karen Reader: Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin 9016, New Zealand
Janice A. Royds: Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin 9016, New Zealand
Michael Landmann: Department of Surgical Sciences, Dunedin School of Medicine, University of Otago, Dunedin 9054, New Zealand
Simone Petrich: Department of Surgical Sciences, Dunedin School of Medicine, University of Otago, Dunedin 9054, New Zealand
Roger Reddel: Children’s Medical Research Institute, University of Sydney, Westmead, New South Wales 2145, Australia
Lily Huschtscha: Children’s Medical Research Institute, University of Sydney, Westmead, New South Wales 2145, Australia
Ahmad Taha: Department of Neurosurgery, Southern District Heath Board, Dunedin 9016, New Zealand
Noelyn A. Hung: Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin 9016, New Zealand
Tania L. Slatter: Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin 9016, New Zealand
Antony W. Braithwaite: Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin 9016, New Zealand

DOI: https://doi.org/10.3390/cancers12092472
Journal volume & issue: Vol. 12, no. 9
p. 2472

Abstract

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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.

Published in Cancers

ISSN: 2072-6694 (Online)
Publisher: MDPI AG
Country of publisher: Switzerland
LCC subjects: Medicine: Internal medicine: Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Website: https://www.mdpi.com/journal/cancers/

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