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

The Practical Consortium - Centre for Cancer Genetic Epidemiology; The Australian Prostate Cancer BioResource - Translational Research Institute; Srilakshmi Srinivasan; Thomas Kryza; Nathalie Bock; Carson Stephens; Ying Dong; Janaththani Panchadsaram; Leire Moya; Joan Rohl; Joanna L Perry-Keene; Katie Buzacott; Tokhir Dadaev; Mark N Brook; Hans Lilja; Amanda Spurdle; Hannu Koistinen; Ulf-Hakan Stenman; Zsofia Kote-Jarai; Rosalind Eeles; Jyotsna Batra

doi:10.1530/oncolabs.1.p004

Abstract

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.

Original language	English
Pages	9-10
Number of pages	2
DOIs	https://doi.org/10.1530/oncolabs.1.p004
Publication status	Published - 26 Sept 2019
Externally published	Yes
Event	7th International Pacific Rim (PacRim) Breast and Prostate Cancer Meeting - Barossa Valley, Australia Duration: 17 Mar 2019 → 20 Mar 2019 https://pacrimmeeting.com/2018/

Conference

Conference	7th International Pacific Rim (PacRim) Breast and Prostate Cancer Meeting
Country/Territory	Australia
Period	17/03/19 → 20/03/19
Internet address	https://pacrimmeeting.com/2018/

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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Cite this

The Practical Consortium - Centre for Cancer Genetic Epidemiology, The Australian Prostate Cancer BioResource - Translational Research Institute, Srinivasan, S., Kryza, T., Bock, N., Stephens, C., Dong, Y., Panchadsaram, J., Moya, L., Rohl, J., Perry-Keene, J. L., Buzacott, K., Dadaev, T., Brook, M. N., Lilja, H., Spurdle, A., Koistinen, H., Stenman, U.-H., Kote-Jarai, Z., ... Batra, J. (2019). 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. 9-10. Abstract from 7th International Pacific Rim (PacRim)
Breast and Prostate Cancer Meeting, South Australia, Australia. https://doi.org/10.1530/oncolabs.1.p004

The Practical Consortium - Centre for Cancer Genetic Epidemiology ; The Australian Prostate Cancer BioResource - Translational Research Institute ; Srinivasan, Srilakshmi et al. / 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. Abstract from 7th International Pacific Rim (PacRim)
Breast and Prostate Cancer Meeting, South Australia, Australia.2 p.

@conference{c11c2373156e482a8421e7d1c912f591,

title = "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",

abstract = "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 {\textquoteleft}Thr{\textquoteright} PSA protein variant displayed significant functional differences in the tumour microenvironment and thus may play a multifunctional role in tumourigenesis and metastasis. The minor {\textquoteleft}C{\textquoteright} 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.",

author = "{The Practical Consortium - Centre for Cancer Genetic Epidemiology} and {The Australian Prostate Cancer BioResource - Translational Research Institute} and Srilakshmi Srinivasan and Thomas Kryza and Nathalie Bock and Carson Stephens and Ying Dong and Janaththani Panchadsaram and Leire Moya and Joan Rohl and Perry-Keene, {Joanna L} and Katie Buzacott and Tokhir Dadaev and Brook, {Mark N} and Hans Lilja and Amanda Spurdle and Hannu Koistinen and Ulf-Hakan Stenman and Zsofia Kote-Jarai and Rosalind Eeles and Judith Clements and Jyotsna Batra",

year = "2019",

month = sep,

day = "26",

doi = "10.1530/oncolabs.1.p004",

language = "English",

pages = "9--10",

note = "7th International Pacific Rim (PacRim)<br/>Breast and Prostate Cancer Meeting ; Conference date: 17-03-2019 Through 20-03-2019",

url = "https://pacrimmeeting.com/2018/",

}

The Practical Consortium - Centre for Cancer Genetic Epidemiology, The Australian Prostate Cancer BioResource - Translational Research Institute, Srinivasan, S, Kryza, T, Bock, N, Stephens, C, Dong, Y, Panchadsaram, J, Moya, L, Rohl, J, Perry-Keene, JL, Buzacott, K, Dadaev, T, Brook, MN, Lilja, H, Spurdle, A, Koistinen, H, Stenman, U-H, Kote-Jarai, Z, Eeles, R & Batra, J 2019, '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', 7th International Pacific Rim (PacRim)
Breast and Prostate Cancer Meeting, Australia, 17/03/19 - 20/03/19 pp. 9-10. https://doi.org/10.1530/oncolabs.1.p004

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. / The Practical Consortium - Centre for Cancer Genetic Epidemiology; The Australian Prostate Cancer BioResource - Translational Research Institute; Srinivasan, Srilakshmi et al.
2019. 9-10 Abstract from 7th International Pacific Rim (PacRim)
Breast and Prostate Cancer Meeting, South Australia, Australia.

Research output: Contribution to conference › Abstract › Research

TY - CONF

T1 - 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

AU - The Practical Consortium - Centre for Cancer Genetic Epidemiology

AU - The Australian Prostate Cancer BioResource - Translational Research Institute

AU - Srinivasan, Srilakshmi

AU - Kryza, Thomas

AU - Bock, Nathalie

AU - Stephens, Carson

AU - Dong, Ying

AU - Panchadsaram, Janaththani

AU - Moya, Leire

AU - Rohl, Joan

AU - Perry-Keene, Joanna L

AU - Buzacott, Katie

AU - Dadaev, Tokhir

AU - Brook, Mark N

AU - Lilja, Hans

AU - Spurdle, Amanda

AU - Koistinen, Hannu

AU - Stenman, Ulf-Hakan

AU - Kote-Jarai, Zsofia

AU - Eeles, Rosalind

AU - Clements, Judith

AU - Batra, Jyotsna

PY - 2019/9/26

Y1 - 2019/9/26

N2 - 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.

AB - 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.

U2 - 10.1530/oncolabs.1.p004

DO - 10.1530/oncolabs.1.p004

M3 - Abstract

SP - 9

EP - 10

T2 - 7th International Pacific Rim (PacRim)<br/>Breast and Prostate Cancer Meeting

Y2 - 17 March 2019 through 20 March 2019

ER -

The Practical Consortium - Centre for Cancer Genetic Epidemiology, The Australian Prostate Cancer BioResource - Translational Research Institute, Srinivasan S, Kryza T, Bock N, Stephens C et al.. 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. 2019. Abstract from 7th International Pacific Rim (PacRim)
Breast and Prostate Cancer Meeting, South Australia, Australia. doi: 10.1530/oncolabs.1.p004