Identification of a novel prostate cancer susceptibility variant in the KLK3 gene transcript

Kóte-Jarai, Zsofia; Olama, Ali Amin Al; Leongamornlert, Daniel; Tymrakiewicz, Malgorzata; Saunders, Ed; Guy, Michelle; Giles, Graham G.; Severi, Gianluca; Southey, Melissa C.; Hopper, John L.; Sit, Kei Chun; Harris, Jonathan M.; Batra, Jyotsna; Spurdle, Amanda B.; Clements, Judith A.; Hamdy, Freddie C.; Neal, David E.; Donovan, Jenny; Muir, Ken; Pharoah, Paul D.P.; Chanock, Stephen J.; Brown, Nathan; Benlloch, Sara; Castro, Elena; Mahmud, Nadiya; O'Brien, Lynne T.; Hall, Amanda L.; Sawyer, Emma; Wilkinson, Rosemary; Easton, Douglas F.; Eeles, Rosalind

doi:10.1007/s00439-011-0981-1

Cited by 84 publications

(73 citation statements)

References 20 publications

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“…6,[8][9][10][11][12][13][14][15][16] For some cancers, these splicing alterations create functionally significant biomarkers. 9,12,14,[17][18][19][20][21] In light of these studies and the results presented here, we believe that NOTCH2 and FLT3 splicing events are associated with pathogenesis in AML and that identification of the causes and consequences of these splicing alterations will provide a better understanding of the biology of this disease. Because it is well known that splicing alterations can result from mutations and/or could be due to modulated expression of splicing factors, we evaluated whether expression of NOTCH2 and FLT3 splice variants correlated with mutations detected on commonly mutated genes such as U2AF1 and SF3B1 in patients with AML (supplemental Figure 4).…”

Section: Discussionsupporting

confidence: 52%

“…6,[8][9][10][11][12][13][14][15][16] For some cancers, these splicing alterations create functionally significant biomarkers. 9,12,14,[17][18][19][20][21] Using exome sequencing, frequent mutations in genes involved in regulating splicing were identified in myelodysplasia (MDS) and in some AML patients. 22 Recently, using a single nucleotide polymorphism (SNP) array and targeted sequencing of 1000 genes, novel somatic mutations of splicing factor SFPQ and splicing regulator CTCF were identified in 10% of AML patients.…”

Section: Introductionmentioning

confidence: 99%

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NOTCH2 and FLT3 gene mis-splicings are common events in patients with acute myeloid leukemia (AML): new potential targets in AML

Adamia

Bar-Natan

Haibe‐Kains

et al. 2014

Blood

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• Overall, our results suggest that NOTCH2 and FLT3 aberrant splicing is a common event in AML that correlates with disease status and may correlate with disease outcomes. • Selected variants of NOTCH2and FLT3 transcripts were detected in a significant number of AML patients and could be useful as disease markers.Our previous studies revealed an increase in alternative splicing of multiple RNAs in cells from patients with acute myeloid leukemia (AML) compared with CD34 1 bone marrow cells from normal donors. Aberrantly spliced genes included a number of oncogenes, tumor suppressor genes, and genes involved in regulation of apoptosis, cell cycle, and cell differentiation. Among the most commonly mis-spliced genes (>70% of AML patients) were 2, NOTCH2 and FLT3, that encode myeloid cell surface proteins. The splice variants of NOTCH2 and FLT3 resulted from complete or partial exon skipping and utilization of cryptic splice sites. Longitudinal analyses suggested that NOTCH2 and FLT3 aberrant splicing correlated with disease status. Correlation analyses between splice variants of these genes and clinical features of patients showed an association between NOTCH2-Va splice variant and overall survival of patients. Our results suggest that NOTCH2 and FLT3 mis-splicing is a common characteristic of AML and has the potential to generate transcripts encoding proteins with altered function. Thus, splice variants of these genes might provide disease markers and targets for novel therapeutics. (Blood. 2014;123(18):2816-2825

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Section: Discussionsupporting

confidence: 52%

Section: Introductionmentioning

confidence: 99%

NOTCH2 and FLT3 gene mis-splicings are common events in patients with acute myeloid leukemia (AML): new potential targets in AML

Adamia

Bar-Natan

Haibe‐Kains

et al. 2014

Blood

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“…This is consistent with the reporter assay result, indicating that this SNP is negatively modulating androgen regulation of MLPH expression. Previous GWAS studies have identified 2 prostate cancer susceptibility loci at 2q37.3 with the 2 SNPs rs2292884:A>G and rs7584330:A>G located either within or next to the MLPH gene (Haiman, et al, 2011; Kote-Jarai, et al, 2011a; Kote-Jarai, et al, 2011b; Schumacher, et al, 2011). The risk G allele of rs2292884:A>G, which has a stronger linkage disequilibrium with rs11891426:T>G compared to rs7584330:A>G, also strongly correlated with reduced MLPH gene expression in human prostates.…”

Section: Discussionmentioning

confidence: 99%

Putative Prostate Cancer Risk SNP in an Androgen Receptor‐Binding Site of the Melanophilin Gene Illustrates Enrichment of Risk SNPs in Androgen Receptor Target Sites

Narisu

Schlick

et al. 2015

Human Mutation

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Genome-wide association studies have identified genomic loci, whose single nucleotide polymorphisms (SNPs) predispose to prostate cancer (PCa). However, the mechanisms of most of these variants are largely unknown. We integrated chromatin-IP coupled sequencing and microarray expression profiling in TMPRSS2-ERG gene rearrangement positive DUCaP cells with the GWAS PCa risk SNPs catalog to identify disease susceptibility SNPs localized within functional androgen receptor binding sites (ARBSs). Among the 48 GWAS index risk SNPs and 3,917 linked SNPs, 80 were found located in ARBSs. Of these, rs11891426:T>G in an intron of the melanophilin gene (MLPH), was within a novel putative auxiliary AR binding motif, which is enriched in the neighborhood of canonical androgen responsive elements. T→G exchange attenuated the transcriptional activity of the ARBS in an AR reporter gene assay. The expression of melanophilin in primary prostate tumors was significantly lower in those with the G compared to the T allele and correlated significantly with AR protein. Higher melanophilin level in prostate tissue of patients with a favourable PCa risk profile points out a tumor suppressive effect. These results unravel a hidden link between AR and a functional putative PCa risk SNP, whose allele alteration affects androgen regulation of its host gene MLPH.

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“…A recent paper by Kote -Jarai et al (2011a) undertook an imputation approach to refine the association between SNPs in the KLK3 GWAS-identified region and prostate cancer. Using genotyping data from a two-stage GWAS using British and Australian samples (Eeles et al , 2009 ) and the Cancer Genetic Markers of Susceptibility study ( http://www.cgems.cancer.gov/ ), genotypes were imputed for 197 and 312 SNPs from HapMap Phase II and the 1000 Genomes project, respectively.…”

Section: Imputation: a New Tool For Fine-mapping Studiesmentioning

confidence: 99%

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

Batra

O’Mara²,

Patnala

et al. 2012

Biological Chemistry

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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.

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Identification of a novel prostate cancer susceptibility variant in the KLK3 gene transcript

Cited by 84 publications

References 20 publications

NOTCH2 and FLT3 gene mis-splicings are common events in patients with acute myeloid leukemia (AML): new potential targets in AML

NOTCH2 and FLT3 gene mis-splicings are common events in patients with acute myeloid leukemia (AML): new potential targets in AML

Putative Prostate Cancer Risk SNP in an Androgen Receptor‐Binding Site of the Melanophilin Gene Illustrates Enrichment of Risk SNPs in Androgen Receptor Target Sites

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

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