A comprehensive resequence analysis of the KLK15–KLK3–KLK2 locus on chromosome 19q13.33

Parikh, Hemang; Deng, Zuoming; Yeager, Meredith; Boland, Joseph F.; Matthews, Casey; Jia, Jinping; Collins, Irene; White, A.; Burdett, Laura; Hutchinson, Amy; Qi, Liqun; Bacior, Jennifer; Lonsberry, Victor; Rodesch, Matthew J.; Jeddeloh, Jeffrey A.; Albert, Thomas; Halvensleben, Heather; Harkins, Timothy T.; Ahn, Jiyoung; Berndt, Sonja I.; Chatterjee, Nilanjan; Hoover, Robert N.; Thomas, Gilles; Hunter, David J.; Hayes, Richard B.; Chanock, Stephen J.; Ámundadóttir, Laufey T.

doi:10.1007/s00439-009-0751-5

Cited by 28 publications

(36 citation statements)

References 35 publications

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“…Only 2 variants in our resequencing data were significantly different in frequency from those in both the dbSNP database and the findings of Parikh et al (12 ): the intronic SNP rs174776 (T to C) and the 3Ј untranslated region SNP rs1058205 (C to T). The minor allele in the latter SNP was significantly overrepresented in our sample (P ϭ 0.007, compared with the dbSNP data; P ϭ 0.003, compared with the data of Parikh et al (12 ); P ϭ 0.002, compared with the 2 data sets combined).…”

Section: Comparison Of Allele Frequenciescontrasting

confidence: 88%

Section: Comparison Of Allele Frequenciesmentioning

confidence: 44%

“…The minor allele in the latter SNP was significantly overrepresented in our sample (P ϭ 0.007, compared with the dbSNP data; P ϭ 0.003, compared with the data of Parikh et al (12 ); P ϭ 0.002, compared with the 2 data sets combined). The allele frequencies of 2 additional SNPs [the intronic SNP rs1810020 (A to G) and the 3Ј untranslated region SNP rs2659122 (C to T)] were significantly different from frequencies reported by Parikh et al (12 ) but not from those reported in the dbSNP database. When data from both sets were combined, the resulting frequencies were statistically different from the allele frequencies for these 2 loci in our sample (Table 4); however, none of these significant differences withstand the Bonferroni correction for multiple testing (␣ Bonferroni ϭ 0.05/71 ϭ 0.0007).…”

Section: Comparison Of Allele Frequenciesmentioning

confidence: 44%

“…Table 4 presents the P values obtained for comparisons of our allele counts with European data from the dbSNP database, with data from Parikh et al (12 ), and with both data sets combined. Comparisons were not possible for 3 polymorphisms that no frequency data reported in either dbSNP or Parikh et al (12 ). These polymorphisms are the far-upstream indel rs57268074, the novel C-to-T variant in the ARE II region, and the novel C-to-T variant encoding the Arg77Trp substitution.…”

Section: Phenotypic Consequences Of Nonsynonymous Variantsmentioning

confidence: 99%

“…Two recent studies have resequenced KLK3 and neighboring genes from samples obtained from PCa patients and control individuals (12,13 ). Parikh et al (12 ) identified 555 polymorphic loci within the region containing KLK3 and the neighboring genes KLK15 and KLK2, including 116 novel SNPs, 182 novel insertion-deletion (indel) polymorphisms, and 257 previously described loci.…”

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confidence: 99%

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Very Low PSA Concentrations and Deletions of the KLK3 Gene

et al. 2013

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BACKGROUND Prostate-specific antigen (PSA), a widely used biomarker for prostate cancer (PCa), is encoded by a kallikrein gene (KLK3, kallikrein-related peptidase 3). Serum PSA concentrations vary in the population, with PCa patients generally showing higher PSA concentrations than control individuals, although a small proportion of individuals in the population display very low PSA concentrations. We hypothesized that very low PSA concentrations might reflect gene-inactivating mutations in KLK3 that lead to abnormally reduced gene expression. METHODS We have sequenced all KLK3 exons and the promoter and searched for gross deletions or duplications in KLK3 in the 30 individuals with the lowest observed PSA concentrations in a sample of approximately 85 000 men from the Prostate Testing for Cancer and Treatment (ProtecT) study. The ProtecT study examines a community-based population of men from across the UK with little prior PSA testing. RESULTS We observed no stop codons or frameshift mutations, but we did find 30 single-base genetic variants, including 3 variants not described previously. These variants included missense variants that could be functionally inactivating and splicing variants. At this stage, however, we cannot confidently conclude whether these variants markedly lower PSA concentration or activity. More importantly, we identified 3 individuals with different large heterozygous deletions that encompass all KLK3 exons. The absence of a functional copy of KLK3 in these individuals is consistent with their reduced serum PSA concentrations. CONCLUSIONS The clinical interpretation of the PSA test for individuals with KLK3 gene inactivation could lead to false-negative PSA findings used for screening, diagnosis, or monitoring of PCa.

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Section: Comparison Of Allele Frequenciescontrasting

confidence: 88%

Section: Comparison Of Allele Frequenciesmentioning

confidence: 44%

Section: Comparison Of Allele Frequenciesmentioning

confidence: 44%

Section: Phenotypic Consequences Of Nonsynonymous Variantsmentioning

confidence: 99%

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confidence: 99%

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Very Low PSA Concentrations and Deletions of the KLK3 Gene

et al. 2013

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Kallikarein‐related peptidase 3 common genetic variant and the risk of prostate cancer

Motamedi

Sarhangi

Afshari

et al. 2019

J of Cellular Biochemistry

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Kallikarein‐related peptidase 3 (KLK3) gene polymorphisms seem to play a role in susceptibility to prostate cancer (PC). The purpose of this study was to investigate the association between rs2735839 polymorphism of KLK3 gene and risk of PC in an Iranian population. In this case‐control study, rs2735839 was genotyped in 532 patients with PC and 602 controls with benign prostate hyperplasia (BPH) using polymerase chain reaction‐restriction fragment length polymorphism assay. The frequency of GG, AG, and AA genotypes of KLK3 polymorphism was 24.6% and 76.2%, 46.6% and 21.7%, and 28.8% and 2.1%, in patients with BPH and PC, respectively (P < 0.001). The frequency of G allele in patients with BPH and PC was 47.9% and 87%, respectively (odds ratio: 7.31; confidence interval: 5.88‐9.10; P < 0.001). Patients with AG and GG genotypes had a higher total serum level of prostate‐specific antigen (PSA) compared to those with AA genotype (P < 0.001). Patients with this polymorphism had higher risk of tumor with higher grade (P = 0.23), advanced stage (P = 0.11), perineural invasion (P = 0.07), and vascular invasion (P = 0.07) compared to those without it but this difference was not statistically significant. Based on our results, KLK3 gene polymorphism was associated with the risk of PC. Higher levels of PSA in the presence of KLK3 polymorphism in patients with PC indicated that rs2735839 polymorphism could be a risk factor for increased levels of PSA.

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Targeted Bisulfite Sequencing Using the SeqCap Epi Enrichment System

Wendt¹,

Rosenbaum²,

Richmond³

et al. 2017

Methods in Molecular Biology

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Cytosine methylation has been shown to have a role in a host of biological processes. In mammalian biology these include stem cell differentiation, embryonic development, genomic imprinting, inflammation, and silencing of transposable elements. Given the central importance of these processes, it is not surprising to find aberrant cytosine methylation patterns associated with many disorders in humans, including cancer, cardiovascular disease, and neurological disease. While whole genome shotgun bisulfite sequencing (WGBS) has recently become feasible, generating high sequence coverage data for the entire genome is expensive, both in terms of money and analysis time, when generally only a small subset of the genome is of interest to most researchers. This report details a procedure for the targeted enrichment of bisulfite treated DNA via SeqCap Epi, allowing high resolution focus of next generation sequencing onto a subset of the genome for high resolution cytosine methylation analysis. Regions ranging in size from only a few kb up to over 200 Mb may be targeted, including the use of the SeqCap Epi CpGiant design which is designed to target 5.5 million CpGs in the human genome. Finally, multiple samples may be multiplexed and sequenced together to provide an inexpensive method of generating methylation data for a large number of samples in a high throughput fashion.

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A comprehensive resequence analysis of the KLK15–KLK3–KLK2 locus on chromosome 19q13.33

Cited by 28 publications

References 35 publications

Very Low PSA Concentrations and Deletions of the KLK3 Gene

Very Low PSA Concentrations and Deletions of the KLK3 Gene

Kallikarein‐related peptidase 3 common genetic variant and the risk of prostate cancer

Targeted Bisulfite Sequencing Using the SeqCap Epi Enrichment System

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