Been implicated in the AHS as risk factors for aggressive prostate

Been implicated in the AHS as risk factors for aggressive inhibitor prostate cancer [16]. The interactions with the OP insecticides malathion and terbufos were in one nongenic region on chromosome 17q24 and two gene regions, EHBP1 and PDLIM5. The function of the rs1859962 SNP, which is located in a nongenic region, is not known. Although the nearest protein-coding regions, KCNJ2 and SOX9, are ,1Mb away, SOX9 is involved in prostate epithelial differentiation and observed to promote prostate tumor cell proliferation when upregulated [38,39]. EHBP1 encodes an Eps15 homology domain binding protein, which is involved in clathrin-mediated endocytosis, a process fundamental to neurotransmission, signal transduction and the regulation of many plasma membrane activities. Alterations (fusions, somatic mutations, over and under-expression) of clathrin-mediated endocytosis proteins have been reported in numerous cancers, including prostate cancer [40]. PDLIM5 (PDZ and LIM domain 5, also called ENH or ENH1) is a PDZ-LIM protein. PDZ-LIM proteins can act as signal modulators, influence actin dynamics, regulate cell architecture, and control gene transcription [41]. Misregulated PDZ-LIM proteins have been shown to promote tumor cell invasion and metastasis in prostate tumors and prostate cancer cell lines [42,43]. Interestingly, the OP pesticides malathion and terbufos are acetylcholinesterase (enzyme that degrades the neurotransmitter acetylcholine) inhibitors. PDLIM5 is observed to be expressed in various brain regions and is localized in presynaptic nerve terminals where neurotransmitter vesicles are stored [44]. Although it is not clear how pesticides may interactGWAS SNPs, Pesticides and Prostate Cancerwith these variants to increase the risk of prostate cancer, it is possible that exposure to these pesticides may alter important signal transduction pathways and/or compromise cellular morphology to promote the development of carcinogenesis. Another interaction was observed for the organochlorine (OC) insecticide aldrin and SNP rs7679673 on chromosome 4. This SNP is located between two gene regions, TET2, a gene recently characterized as a tumor suppressor gene involved in the pathogenesis of several hematopoietic diseases [45], and PP2A, a gene implicated in inhibitor androgen regulation in prostate cancer cell lines [46]. Organochlorine pesticides, like aldrin, have been implicated as endocrine disrupting chemicals and may alter androgen levels to influence prostate cancer risk [47]. Although there is no direct information about the function of rs7679673, this variant has been shown to be associated with earlier onset of disease and to have a stronger association with prostate cancer among those with a family history of prostate cancer [17,48]. In the AHS, we observed a significant interaction between aldrin and family history of prostate cancer [16]. Small numbers in the current analysis preclude evaluation of the effect of family history on the aldrinrs7679673-prostate cancer association (3-way interaction). Although we observed interesting interactions, the sample size for the current study is limited. This limited sample size is reflected by the small cell counts for some gene-exposure groups and in the inability to achieve the same magnitude of effect observed in GWAS for all SNP associations. This does not negate the importance of these SNPs in our population because they are known risk variants for prostate cancer as established by GWAS. We also considered.Been implicated in the AHS as risk factors for aggressive prostate cancer [16]. The interactions with the OP insecticides malathion and terbufos were in one nongenic region on chromosome 17q24 and two gene regions, EHBP1 and PDLIM5. The function of the rs1859962 SNP, which is located in a nongenic region, is not known. Although the nearest protein-coding regions, KCNJ2 and SOX9, are ,1Mb away, SOX9 is involved in prostate epithelial differentiation and observed to promote prostate tumor cell proliferation when upregulated [38,39]. EHBP1 encodes an Eps15 homology domain binding protein, which is involved in clathrin-mediated endocytosis, a process fundamental to neurotransmission, signal transduction and the regulation of many plasma membrane activities. Alterations (fusions, somatic mutations, over and under-expression) of clathrin-mediated endocytosis proteins have been reported in numerous cancers, including prostate cancer [40]. PDLIM5 (PDZ and LIM domain 5, also called ENH or ENH1) is a PDZ-LIM protein. PDZ-LIM proteins can act as signal modulators, influence actin dynamics, regulate cell architecture, and control gene transcription [41]. Misregulated PDZ-LIM proteins have been shown to promote tumor cell invasion and metastasis in prostate tumors and prostate cancer cell lines [42,43]. Interestingly, the OP pesticides malathion and terbufos are acetylcholinesterase (enzyme that degrades the neurotransmitter acetylcholine) inhibitors. PDLIM5 is observed to be expressed in various brain regions and is localized in presynaptic nerve terminals where neurotransmitter vesicles are stored [44]. Although it is not clear how pesticides may interactGWAS SNPs, Pesticides and Prostate Cancerwith these variants to increase the risk of prostate cancer, it is possible that exposure to these pesticides may alter important signal transduction pathways and/or compromise cellular morphology to promote the development of carcinogenesis. Another interaction was observed for the organochlorine (OC) insecticide aldrin and SNP rs7679673 on chromosome 4. This SNP is located between two gene regions, TET2, a gene recently characterized as a tumor suppressor gene involved in the pathogenesis of several hematopoietic diseases [45], and PP2A, a gene implicated in androgen regulation in prostate cancer cell lines [46]. Organochlorine pesticides, like aldrin, have been implicated as endocrine disrupting chemicals and may alter androgen levels to influence prostate cancer risk [47]. Although there is no direct information about the function of rs7679673, this variant has been shown to be associated with earlier onset of disease and to have a stronger association with prostate cancer among those with a family history of prostate cancer [17,48]. In the AHS, we observed a significant interaction between aldrin and family history of prostate cancer [16]. Small numbers in the current analysis preclude evaluation of the effect of family history on the aldrinrs7679673-prostate cancer association (3-way interaction). Although we observed interesting interactions, the sample size for the current study is limited. This limited sample size is reflected by the small cell counts for some gene-exposure groups and in the inability to achieve the same magnitude of effect observed in GWAS for all SNP associations. This does not negate the importance of these SNPs in our population because they are known risk variants for prostate cancer as established by GWAS. We also considered.

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