Genetic polymorphisms in the human tissue kallikrein (KLK) locus and their implication in various malignant and non-malignant diseases

Abstract

Abstract:The Kallikrein ( KLK ) gene locus encodes a family of serine proteases and is the largest contiguous cluster of protease-encoding genes attributed an evolutionary age of 330 million years. The KLK locus has been implicated as a high susceptibility risk loci in numerous cancer studies through the last decade. The KLK3 gene already has established clinical relevance as a biomarker in prostate cancer prognosis through its encoded protein, prostate-specific antigen. Data mined through genome-wide association studies (GWAS) and next-generation sequencing point to many important candidate single nucleotide polymorphisms (SNPs) in KLK3 and other KLK genes. SNPs in the KLK locus have been found to be associated with several diseases including cancer, hypertension, cardiovascular disease and atopic dermatitis. Moreover, introducing a model incorporating SNPs to improve the efficiency of prostate-specific antigen in detecting malignant states of prostate cancer has been recently suggested. Establishing the functional relevance of these newly-discovered SNPs, and their interactions with each other, through in silico investigations followed by experimental validation, can accelerate the discovery of diagnostic and prognostic biomarkers. In this review, we discuss the various genetic association studies on the KLK loci identified either through candidate gene association studies or at the GWAS and post-GWAS front to aid researchers in streamlining their search for the most significant, relevant and therapeutically promising candidate KLK gene and/or SNP for future investigations.

Sweet and Sour: The Impact of Differential Glycosylation in Cancer Cells Undergoing Epithelial–Mesenchymal Transition

“…Basic Local Alignment Search Tool (BLAST) analysis (118) revealed that human kallikrein 12 (h-klk12), a serine protease expressed by adult and fetal tissues (119), share the same VTHPGY sequence that is O -glycosylated in the IIICS domain of human onfFN. It has been well described that h-klk12 modulates many physiological processes (120, 121), as well tumor cell invasion and metastasis (122, 123). Previous studies have shown that cancer cells express kallikreins with atypical glycophenotypes (124).…”

Kallikreins as Biomarkers in Human Malignancies

“…Regarding KLK3, two SNPs located within the gene and the KLK2-KLK3 intergenic region are strongly associated with CaP patients' survival; also, a functional SNP located at one of the androgen response elements of KLK3 was found to be associated with increased serum PSA levels. Finally, two individual SNPs at KLK3 and KLK15 are strongly related to poorer OC patients' survival (Batra et al 2013;Mavridis et al 2012). …”

Mining for single nucleotide variants (SNVs) at the kallikrein locus with predicted functional consequences

“…More SNVs were noted in KLKs 2, 3, 5, 7, and 13, while fewer were found in KLK9. Compared to prior studies (Goard et al, 2007;Batra et al, 2012), we expanded the number of identified SNVs, as a result of the availability of sequencing information from larger cohorts of individuals. The total number of our identified SNVs is similar to that recently described by Batra et al,who identified 4331 KLK SNVs. Older studies, such as the one by Goard et al, reported on 1856 KLK SNVs in 2007.…”

“…As part of the general extracellular web of proteases, KLK activity is tightly regulated by endogenous inhibitors, activating proteolytic cascades and regulatory feedback that maintain balanced KLK activity . Disruption of this balance and concomitant dysregulation of KLK function has been linked to several diseases, including skin diseases (Eissa and Diamandis, 2008), neurodegenerative diseases, chronic inflammation, diabetes mellitus (Paliouras and Diamandis, 2006;Batra et al, 2012), and cancer (Bharaj et al, 2002;Ahn et al, 2008;Antoniou et al, 2010;Batra et al, 2011). The recent advances in sequencing technologies have brought to light numerous variations, such as single nucleotide variants (SNVs), of several KLK genes, as major contributors to KLK dysregulation in vivo.…”

“…Previous studies have examined SNVs in the KLK locus (Goard et al, 2007;Batra et al, 2012). These studies mined databases such as dbSNP and 1000 Genomes to discover SNVs at the KLK locus and contributed valuable information.…”