Genetic Variation in KLK2 and KLK3 Is Associated with Concentrations of hK2 and PSA in Serum and Seminal Plasma in Young Men

Sävblom, Charlotta; Halldén, Christer; Cronin, Angel M.; Säll, Torbjörn; Savage, Caroline; Vertosick, Emily; Klein, Robert J.; Giwercman, Aleksander; Lilja, Hans

doi:10.1373/clinchem.2013.211219

Cited by 23 publications

(23 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, although ongoing investigation continues into genetic risk factors for PCa, there is no clinical role for SNPs in screening protocols at this time, although investigators continue to address whether there will be a clinical role for SNPs in biomarker-encoding prostate risk loci, which strongly influence biomarker levels in blood. 50 …”

Section: Single Nucleotide Polymorphismsmentioning

confidence: 99%

Beyond prostate-specific antigen

Loeb

Lilja

2016

Current Opinion in Urology

Self Cite

View full text Add to dashboard Cite

Purpose of Review The purpose of this article is to review blood and urine tests that are currently available and under investigation for a role in prostate cancer screening and detection. Recent Findings Compared to total PSA alone, its combination with percent free-to-total PSA contributes greater specificity for prostate cancer, and is a component of 2 newer blood tests called the 4kScore and Prostate Health Index. All three tests improve the prediction of high-grade disease and are commercially available options to aid in initial or repeat prostate biopsy decisions. PCA3 is a urinary marker that is currently available for repeat prostate biopsy decisions. Although PCA3 alone has inferior prediction of clinically significant disease and requires collection of urine after digital rectal examination, it may be combined with other clinical variables or other urine markers like TMPRSS2:ERG to improve performance. Little data is available to support a role for single nucleotide polymorphisms or other investigational markers in early detection. Summary Several commercially available blood and urine tests have to been shown to improve specificity of PSA for high-grade prostate cancer. Use of such tests would decrease unnecessary biopsy and overdiagnosis of indolent disease. Biopsy of men with moderately elevated PSA without use of such a reflex test should be discouraged.

show abstract

Section: Single Nucleotide Polymorphismsmentioning

confidence: 99%

Beyond prostate-specific antigen

Loeb

Lilja

2016

Current Opinion in Urology

Self Cite

View full text Add to dashboard Cite

show abstract

“…; Savblom et al . ). The T allele results in Trp 250 ‐hK2 (hereafter W‐hK2), whereas the common C allele codes for Arg 250 ‐hK2 (hereafter R‐hK2).…”

Section: Introductionmentioning

confidence: 97%

“…A recent report showed the association of seminal plasma concentration of hK2 and rs198977 in young, healthy men (Savblom et al . ). When this function of hK2 is taken into consideration, the T allele of rs198977 may also be a risk factor of male infertility.…”

Section: Introductionmentioning

confidence: 97%

Trp²⁵⁰‐hK2 is defective in intracellular trafficking and activates the unfolded protein response

et al. 2015

View full text Add to dashboard Cite

-do 363-951, Korea hK2, a member of the kallikrein protease family encoded by KLK2, is expressed exclusively in prostate and is a putative adjunct tumor marker for prostate cancer screening. The T allele of rs198977, a single nucleotide polymorphism in exon 5 of KLK2, codes for W-hK2 and is associated with lower serum hK2 levels and higher risk of prostate cancer than the C allele encoding R-hK2. To elucidate the mechanism that underlies this SNP's function, we transfected plasmids expressing R-hK2 or W-hK2 into PC3, HeLa and HEK293A cells and measured the hK2 level in cell lysates and conditioned media. The level of W-hK2 was lower than R-hK2 in conditioned media but was not different from R-hK2 in cell lysates. W-hK2 was hardly colocalized with Golgi-targeted fluorescent protein whereas R-hK2 colocalized. Reporter assays related to the unfolded protein response (UPR) and phospho-eIF2a immunoblot showed that W-hK2 increased UPR activity more than R-hK2. These results indicated that W-hK2 had a defect in cellular trafficking from the ER to the Golgi complex due to its misfolding and that it activated the UPR, suggesting a mechanism to explain the association of the T allele with higher prostate cancer risk.

show abstract

“…SNPs have been identified [24]. These variants tend to be associated with gene expression changes in normal prostate tissue, prostate cancer, and prostatic secretions [25][26][27][28][29][30] and are found more often in prostatic regulatory regions [31,32]. For instance, the prostate cancer risk SNP rs10993994 is located in the promoter of MSMB, which encodes β -microseminoprotein (β-MSP), one of the most abundant proteins in prostate secretions.…”

mentioning

confidence: 99%

Validation of prostate cancer risk variants by CRISPR/Cas9 mediated genome editing

Wang

et al. 2018

Preprint

View full text Add to dashboard Cite

GWAS have identified numerous SNPs associated with prostate cancer risk. One such SNP is rs10993994. It is located in the MSMB promoter, associates with MSMB encoded β-microseminoprotein prostate secretion levels, and is associated with mRNA expression changes in MSMB and the adjacent gene NCOA4. In addition, our previous work showed a second SNP, rs7098889, is in LD with rs10993994 and associated with MSMB expression independent of rs10993994. Here, we generate a series of clones with single alleles removed by double guide RNA (gRNA) mediated CRISPR/Cas9 deletions, through which we demonstrate that each of these SNPs independently and greatly alters MSMB expression in an allele-specific manner. We further show that these SNPs have no substantial effect on the expression of NCOA4. These data demonstrate that a single SNP can have a large effect on gene expression and illustrate the importance of functional validation to deconvolute observed correlations. The method we have developed is generally applicable to test any SNP for which a relevant heterozygous cell line is available.Author summaryIn pursuing the underlying biological mechanism of prostate cancer pathogenesis, scientists utilized the existence of common single nucleotide polymorphisms (SNPs) in human genome as genetic markers to perform large scale genome wide association studies (GWAS) and have so far identified more than a hundred prostate cancer risk variants. Such variants provide an unbiased and systematic new venue to study the disease mechanism, and the next big challenge is to translate these genetic associations to the causal role of altered gene function in oncogenesis. The majority of these variants are waiting to be studied and lots of them may act in oncogenesis through gene expression regulation. To prove the concept, we took rs10993994 and its linked rs7098889 as an example and engineered single cell clones by allelic-specific CRISPR/Cas9 deletion to separate the effect of each allele. We observed that a single nucleotide difference would lead to surprisingly high level of MSMB gene expression change in a gene specific and tissue specific manner. Our study strongly supports the notion that differential level of gene expression caused by risk variants and their associated genetic locus play a major role in oncogenesis and also highlights the importance of studying the function of MSMB encoded β-MSP in prostate cancer pathogenesis.

show abstract

Genetic Variation in KLK2 and KLK3 Is Associated with Concentrations of hK2 and PSA in Serum and Seminal Plasma in Young Men

Cited by 23 publications

References 37 publications

Beyond prostate-specific antigen

Beyond prostate-specific antigen

Trp²⁵⁰‐hK2 is defective in intracellular trafficking and activates the unfolded protein response

Validation of prostate cancer risk variants by CRISPR/Cas9 mediated genome editing

Contact Info

Product

Resources

About

Genetic Variation in KLK2 and KLK3 Is Associated with Concentrations of hK2 and PSA in Serum and Seminal Plasma in Young Men

Cited by 23 publications

References 37 publications

Beyond prostate-specific antigen

Beyond prostate-specific antigen

Trp250‐hK2 is defective in intracellular trafficking and activates the unfolded protein response

Validation of prostate cancer risk variants by CRISPR/Cas9 mediated genome editing

Contact Info

Product

Resources

About

Trp²⁵⁰‐hK2 is defective in intracellular trafficking and activates the unfolded protein response