PacRim7 7th PacRim Meeting Poster Presentations (1) (52 abstracts)
A GWAS identified functional variation in PSA (KLK3) gene that confers lower risk is also associated with more aggressive disease and lower survival in men with prostate cancer
Srilakshmi Srinivasan 1, , Thomas Kryza 1, , Nathalie Bock 1, , Carson Stephens 1, , Ying Dong 1 , Janaththani Panchadsaram 1, , Leire Moya 1, , Joan Röhl 1, , Joanna L Perry-Keene 3 , Katie Buzacott 3 , Tokhir Dadaev 4 , Mark N Brook 4 , Hans Lilja 5 , Amanda Spurdle 6 , Hannu Koistinen 7 , Ulf-Håkan Stenman 7 , Zsofia Kote-Jarai 4, , Rosalind Eeles 4, , The Practical Consortium 9 , The Australian Prostate Cancer BioResource 2 , Judith Clements 1, & Jyotsna Batra 1,
1Cancer Program, Institute of Health and Biomedical Innovation and School of Biomedical Sciences, Queensland University of Technology, Brisbane, Queensland, Australia; 2Australian Prostate Cancer Research Centre – Queensland, Translational Research Institute, 37 Kent Street, Woolloongabba, Queensland, Australia; 3Anatomical Pathology, Pathology Queensland, Queensland, Australia; 4Department of Genetics and Epidemiology, The Institute of Cancer Research, London, UK; 5Departments of Laboratory Medicine, Surgery (Urology Service) and Medicine (Genitourinary Oncology), Memorial Sloan Kettering Cancer Center, New York, USA; 6Molecular Cancer Epidemiology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; 7Department of Clinical Chemistry, Biomedicum Helsinki, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland; 8Royal Marsden NHS Foundation Trust, London, UK; 9Centre for Cancer Genetic Epidemiology, Cambridge, UK.
Objective: Prostate cancer susceptibility is influenced by common variants at multiple loci, however, the mechanisms by which these germline variants influence prostate cancer risk remain largely unknown. A single nucleotide polymorphism (SNP) rs17632542 in the PSA gene has been identified to be associated with prostate cancer risk using large scale genome-wide associate studies. This SNP was previously questioned for its association with prostate cancer due to its association with PSA levels as well. We aimed to verify that this SNP plays a functional role in mediating prostate cancer risk and progression.
Methods: We conducted in silico and functional analysis in several prostate cancer cell models and in clinical samples to identify the biological role of the rs17632542 SNP.
Results: The non-synonymous rs17632542 SNP (c.536T>C), in exon 4 of the PSA-encoding KLK3 gene was associated with disease risk, and aggressiveness and survival in opposite directions. The prostate cancer associated rs17632542 SNP leads to amino acid change Ile to Thr at position 161, which lowers the proteolytic activity of PSA towards extracellular matrix proteins and diminishes the proliferation and migration of prostate cancer cells. In addition, we show that the ‘Thr’ PSA protein variant displayed significant functional differences in the tumour microenvironment and thus may play a multifunctional role in tumourigenesis and metastasis. The minor ‘C’ allele leads to lower levels of serum PSA-inhibitor complexes and is associated with higher free PSA levels. Furthermore, the c.536 T>C change leads to altered KLK3 splicing and reduced mRNA levels of KLK3 in an allele-specific manner.
Conclusions: Genetic correction of the rs17632542 variant with PSA levels; and/or the free-to-total PSA ratio may reduce the inaccuracies for prostate cancer diagnosis based on PSA levels alone.
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Oncology Abstracts
ISSN 2631-4657 (online)
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