Blood biomarker levels to aid discovery of cancer-related single-nucleotide polymorphisms: Kallikreins and prostate cancer Journal Article
| Authors: | Klein, R. J.; Halldén, C.; Cronin, A. M.; Ploner, A.; Wiklund, F.; Bjartell, A. S.; Stattin, P.; Xu, J.; Scardino, P. T.; Offit, K.; Vickers, A. J.; Grönberg, H.; Lilja, H. |
| Article Title: | Blood biomarker levels to aid discovery of cancer-related single-nucleotide polymorphisms: Kallikreins and prostate cancer |
| Abstract: | Polymorphisms associated with prostate cancer include those in three genes encoding major secretory products of the prostate: KLK2 (encoding kallikrein-related peptidase 2; hK2), KLK3 (encoding prostate-specific antigen; PSA), and MSMB (encoding β-microseminoprotein). PSA and hK2, members of the kallikrein family, are elevated in sera of men with prostate cancer. In a comprehensive analysis that included sequencing of all coding, flanking, and 2 kb of putative promoter regions of all 15 kallikrein (KLK) genes spanning ≈280 kb on chromosome 19q, we identified novel single-nucleotide polymorphisms (SNP) and genotyped 104 SNPs in 1,419 cancer cases and 736 controls in Cancer Prostate in Sweden 1, with independent replication in 1,267 cases and 901 controls in Cancer Prostate in Sweden 2. This verified prior associations of SNPs in KLK2 and in MSMB (but not in KLK3) with prostate cancer. Twelve SNPs in KLK2 and KLK3 were associated with levels of PSA forms or hK2 in plasma of control subjects. Based on our comprehensive approach, this is likely to represent all common KLK variants associated with these phenotypes. A T allele at rs198977 in KLK2 was associated with increased cancer risk and a striking decrease of hK2 levels in blood. We also found a strong interaction between rs198977 genotype and hK2 levels in blood in predicting cancer risk. Based on this strong association, we developed a model for predicting prostate cancer risk from standard biomarkers, rs198977 genotype, and rs198977 x hK2 interaction; this model had greater accuracy than did biomarkers alone (area under the receiver operating characteristic curve, 0.874 versus 0.866), providing proof in principle to clinical application for our findings. ©2010 American Association for Cancer Research. |
| Keywords: | adult; controlled study; aged; unclassified drug; major clinical study; single nucleotide polymorphism; case-control studies; polymorphism, single nucleotide; cancer risk; polymerase chain reaction; prostate specific antigen; cancer susceptibility; genetic predisposition to disease; tumor markers, biological; gene locus; genotype; risk factors; prostate cancer; sweden; prostate-specific antigen; prostatic neoplasms; serine proteinase; genetic susceptibility; dna flanking region; area under curve; genetic risk; genetic marker; kallikrein related peptidase 2; kallikreins; roc curve; beta microseminoprotein; genotype phenotype correlation; chromosome 19q |
| Journal Title: | Cancer Prevention Research |
| Volume: | 3 |
| Issue: | 5 |
| ISSN: | 1940-6207 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2010-05-01 |
| Start Page: | 611 |
| End Page: | 619 |
| Language: | English |
| DOI: | 10.1158/1940-6207.capr-09-0206 |
| PUBMED: | 20424135 |
| PROVIDER: | scopus |
| PMCID: | PMC2865570 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 6" - "Export Date: 20 April 2011" - "Source: Scopus" |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work