Pub Date : 2018-12-31DOI: 10.23937/2378-3648/1410037
Yan Ruicheng, Lu Jianfei, L. Fusheng, H. Chao, Shen Shi-qiang
Aim: Vitamin K2 and phosphatidylcholine are two common drugs in clinical treatment. Studies carried out in the past several years demonstrated vitamin K2 and phosphatidylcholine could separately inhibit hepatocarcinogenesis. In this study, we sought to investigate the synergy of vitamin K2 and phosphatidylcholine and the potential mechanism. Methods: Multiple assays were performed to evaluate the effect of combination administration in vitro and in vivo. Then microRNA microarray, bioinformatics analysis and western blot were performed to explore the potential mechanism of drug action. Results: In vitro, combined administration of vitamin K2 and phosphatidylcholine for 72 hours showed significant anti-tumor effect in four HCC cell lines (Hep-3B, Hep-G2, Huh-7 and SMMC-7721). In vivo, tumor growth was significantly suppressed in the treated group. According to microRNA microarray and bioinformatics analysis, miR-16 was significantly up-regulated and WNT signaling pathway was strongly correlated with the process of anti-tumor. Then western blot analysis indicated that low-expression of WNT3A, p-β-catenin and Bcl-2 accorded with the assumption of miR-16’s function. Conclusions: At last we inferred, given together, vitamin K2 and phosphatidylcholine exhibited synergy against hepatocarcinogenesis via miR-16 regulating. However, further study is needed to confirm these regulatory relationships.
{"title":"Combination of Vitamin K2 and Phosphatidylcholine Inhibits Hepatocarcinogenesis via Mir-16 Regulating","authors":"Yan Ruicheng, Lu Jianfei, L. Fusheng, H. Chao, Shen Shi-qiang","doi":"10.23937/2378-3648/1410037","DOIUrl":"https://doi.org/10.23937/2378-3648/1410037","url":null,"abstract":"Aim: Vitamin K2 and phosphatidylcholine are two common drugs in clinical treatment. Studies carried out in the past several years demonstrated vitamin K2 and phosphatidylcholine could separately inhibit hepatocarcinogenesis. In this study, we sought to investigate the synergy of vitamin K2 and phosphatidylcholine and the potential mechanism. Methods: Multiple assays were performed to evaluate the effect of combination administration in vitro and in vivo. Then microRNA microarray, bioinformatics analysis and western blot were performed to explore the potential mechanism of drug action. Results: In vitro, combined administration of vitamin K2 and phosphatidylcholine for 72 hours showed significant anti-tumor effect in four HCC cell lines (Hep-3B, Hep-G2, Huh-7 and SMMC-7721). In vivo, tumor growth was significantly suppressed in the treated group. According to microRNA microarray and bioinformatics analysis, miR-16 was significantly up-regulated and WNT signaling pathway was strongly correlated with the process of anti-tumor. Then western blot analysis indicated that low-expression of WNT3A, p-β-catenin and Bcl-2 accorded with the assumption of miR-16’s function. Conclusions: At last we inferred, given together, vitamin K2 and phosphatidylcholine exhibited synergy against hepatocarcinogenesis via miR-16 regulating. However, further study is needed to confirm these regulatory relationships.","PeriodicalId":91313,"journal":{"name":"Journal of genetics and genome research","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43507916","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2018-12-31DOI: 10.23937/2378-3648/1410039
D Hettiaracchchi, K Weththasigha, N Nethikumara, S. Pathirana, Dissanayaka Whv
Background: Mutations in mitofusin 2 gene have been reported in Charcot-Marie-Tooth type 2 disease also known as Hereditary Sensory and Motor Neuropathy. With its cytogenetic location: 1p36.22. Case presentation: A 43-year-old female with a family history of neuropathy was experiencing gradual deterioration and proximal weakness of the bilateral lower limb for the past 3 years. Her MRI scan (Brain and whole Spinal) was normal and Electromyography (EMG) report was suggestive of motor & sensory demyelinating polyneuropathy with features of segmental involvement. Her Creatine phosphokinase (CPK) levels were marginally elevated. However, all other investigations were within normal range. Conclusions: A heterozygous missense variant denoted as c.701T > A at level of cDNA in exon 7 of the MFN2 gene was discovered which resulted in the substitution of Methionine by Lysine at position 234 [p.Met234Lys] of the amino acid sequence which was confirmed by Sanger sequence.
{"title":"A Novel Mutation in the MFN2 Gene Associated with Hereditary Sensory and Motor Neuropathy with Proximal Predominance (HMSN-P)- A Case Report","authors":"D Hettiaracchchi, K Weththasigha, N Nethikumara, S. Pathirana, Dissanayaka Whv","doi":"10.23937/2378-3648/1410039","DOIUrl":"https://doi.org/10.23937/2378-3648/1410039","url":null,"abstract":"Background: Mutations in mitofusin 2 gene have been reported in Charcot-Marie-Tooth type 2 disease also known as Hereditary Sensory and Motor Neuropathy. With its cytogenetic location: 1p36.22. Case presentation: A 43-year-old female with a family history of neuropathy was experiencing gradual deterioration and proximal weakness of the bilateral lower limb for the past 3 years. Her MRI scan (Brain and whole Spinal) was normal and Electromyography (EMG) report was suggestive of motor & sensory demyelinating polyneuropathy with features of segmental involvement. Her Creatine phosphokinase (CPK) levels were marginally elevated. However, all other investigations were within normal range. Conclusions: A heterozygous missense variant denoted as c.701T > A at level of cDNA in exon 7 of the MFN2 gene was discovered which resulted in the substitution of Methionine by Lysine at position 234 [p.Met234Lys] of the amino acid sequence which was confirmed by Sanger sequence.","PeriodicalId":91313,"journal":{"name":"Journal of genetics and genome research","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44475823","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2018-12-31DOI: 10.23937/2378-3648/1410034
Yegin Zeynep, Avsar Cumhur
The genus Aeromonas is widely distributed in aquatic environments and certain strains are serious pathogens in poikilothermic animals and humans. Human infections related with this pathogen include gastroenteritis, urinary tract infections, pneumonia, wound infections and septicemia. In this study, both the correct medical diagnosis with taking advantages of molecular approaches and a brief investigation of the enzymatic activity potential of Aeromonas were aimed. Aeromonas spp. isolates were collected from different stream samples of Sinop, Turkey and were identified according to morphological, physiological and biochemical tests based on API 20NE (Biomeriux, France). The evaluation of total cell protein profiles and molecular identification based on 16S rRNA sequencing were conducted. Amylase, cellulase and protease enzyme activities of strains were also determined. The strains were separated into two clusters of 73% and over according to the SDS-PAGE total cell protein profiles reflecting a less discriminative power for this method in the strain identification. On the other hand, according to the 16S rRNA sequence analysis results, two isolates were identified as Aeromonas tecta and the other two as Aeromonas veronii at 99% similarity level reflecting the superiority of this approach when compared with SDSPAGE profile. Enzyme assays showed that; three of the isolates were able to produce the amylase and only one could produce the cellulase but none produced the protease enzyme. Though our results are based on limited samples, enzyme activity potential of Aeromonas is recommended to be further investigated in detail in future studies. Pollution of the water by organic materials is a serious environment and health problem and thus bacterial extracellular enzyme activities degrading these pollutants in aquatic environments may reflect a bioremediation strategy in terms of a biotechnological perspective. Taking into consideration of Aeromonas in human infections, the realiable identification based on molecular techniques is an obligatory for medical practice. Besides, exploiting this pathogen in search of enzyme activities may broaden our biotechnology perspective.
{"title":"Investigation of Aeromonas: A Medical and Biotechnological Perspective","authors":"Yegin Zeynep, Avsar Cumhur","doi":"10.23937/2378-3648/1410034","DOIUrl":"https://doi.org/10.23937/2378-3648/1410034","url":null,"abstract":"The genus Aeromonas is widely distributed in aquatic environments and certain strains are serious pathogens in poikilothermic animals and humans. Human infections related with this pathogen include gastroenteritis, urinary tract infections, pneumonia, wound infections and septicemia. In this study, both the correct medical diagnosis with taking advantages of molecular approaches and a brief investigation of the enzymatic activity potential of Aeromonas were aimed. Aeromonas spp. isolates were collected from different stream samples of Sinop, Turkey and were identified according to morphological, physiological and biochemical tests based on API 20NE (Biomeriux, France). The evaluation of total cell protein profiles and molecular identification based on 16S rRNA sequencing were conducted. Amylase, cellulase and protease enzyme activities of strains were also determined. The strains were separated into two clusters of 73% and over according to the SDS-PAGE total cell protein profiles reflecting a less discriminative power for this method in the strain identification. On the other hand, according to the 16S rRNA sequence analysis results, two isolates were identified as Aeromonas tecta and the other two as Aeromonas veronii at 99% similarity level reflecting the superiority of this approach when compared with SDSPAGE profile. Enzyme assays showed that; three of the isolates were able to produce the amylase and only one could produce the cellulase but none produced the protease enzyme. Though our results are based on limited samples, enzyme activity potential of Aeromonas is recommended to be further investigated in detail in future studies. Pollution of the water by organic materials is a serious environment and health problem and thus bacterial extracellular enzyme activities degrading these pollutants in aquatic environments may reflect a bioremediation strategy in terms of a biotechnological perspective. Taking into consideration of Aeromonas in human infections, the realiable identification based on molecular techniques is an obligatory for medical practice. Besides, exploiting this pathogen in search of enzyme activities may broaden our biotechnology perspective.","PeriodicalId":91313,"journal":{"name":"Journal of genetics and genome research","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44621809","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2018-12-31DOI: 10.23937/2378-3648/1410038
S. Ricardo, Paciello María Liz, Ayala Rosa M, Lorza Leyre, Cedena Teresa, Martínez M Pilar, Martínez-López Joaquín
Systemic mastocytosis is a rare disorder characterized by clonal proliferation, which results in abnormally high numbers of mast cells in the skin, bone marrow, and internal organs, such as liver, spleen, or lymph nodes. Mast cell leukemia and subvariants were stratified by the World Health Organization in 2016, as a subtype of systemic mastocytosis. Here, we present a case of acute mast cell leukemia that was imatinib-sensitive, with well-known mutations in the oncogene, KIT (c.1565 T > G p.Phe522Cys), and in the splicing factor gene, SF3B1 (c.2098 A > G, p.Lys700Glu). Molecular cytogenetic studies showed that 26% of cells harbored the 46,XX,der(5)t(5;6)(q35;q24),t(10;16)(q26;q23) karyotype abnormality, confirmed with the fluorescence in-situ hybridization technique. Additionally, the patient showed severe hepatosplenomegaly with multiple retroperitoneal, mesenteric, and axillary adenopathies. Although the prognostic survival of patients with mast cell leukemia is around 6 months, this rare case, with a low-frequency (< 5%) p.Phe522Cys KIT mutation, was associated with complete remission and negative minimal residual disease, which lasted for 2.5 years; moreover, the mutation was not detectable after imatinib treatment. When the patient relapsed, the two mutations studied in KIT and SF3B1 genes reappeared, and a new clone emerged with the variant c.2465 A > C p.Asn822Thr, located in the activation loop of the KIT protein. Molecular analyses of the KIT gene were essential for selecting the appropriate tyrosine-kinase inhibitor. Accurate drug selection can prevent possible resistance and facilitate adequate treatment of subsequent relapses.
{"title":"Molecular Landscape and Clonal Evolution of Acute Mast Cell Leukemia: Case Study","authors":"S. Ricardo, Paciello María Liz, Ayala Rosa M, Lorza Leyre, Cedena Teresa, Martínez M Pilar, Martínez-López Joaquín","doi":"10.23937/2378-3648/1410038","DOIUrl":"https://doi.org/10.23937/2378-3648/1410038","url":null,"abstract":"Systemic mastocytosis is a rare disorder characterized by clonal proliferation, which results in abnormally high numbers of mast cells in the skin, bone marrow, and internal organs, such as liver, spleen, or lymph nodes. Mast cell leukemia and subvariants were stratified by the World Health Organization in 2016, as a subtype of systemic mastocytosis. Here, we present a case of acute mast cell leukemia that was imatinib-sensitive, with well-known mutations in the oncogene, KIT (c.1565 T > G p.Phe522Cys), and in the splicing factor gene, SF3B1 (c.2098 A > G, p.Lys700Glu). Molecular cytogenetic studies showed that 26% of cells harbored the 46,XX,der(5)t(5;6)(q35;q24),t(10;16)(q26;q23) karyotype abnormality, confirmed with the fluorescence in-situ hybridization technique. Additionally, the patient showed severe hepatosplenomegaly with multiple retroperitoneal, mesenteric, and axillary adenopathies. Although the prognostic survival of patients with mast cell leukemia is around 6 months, this rare case, with a low-frequency (< 5%) p.Phe522Cys KIT mutation, was associated with complete remission and negative minimal residual disease, which lasted for 2.5 years; moreover, the mutation was not detectable after imatinib treatment. When the patient relapsed, the two mutations studied in KIT and SF3B1 genes reappeared, and a new clone emerged with the variant c.2465 A > C p.Asn822Thr, located in the activation loop of the KIT protein. Molecular analyses of the KIT gene were essential for selecting the appropriate tyrosine-kinase inhibitor. Accurate drug selection can prevent possible resistance and facilitate adequate treatment of subsequent relapses.","PeriodicalId":91313,"journal":{"name":"Journal of genetics and genome research","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41541743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2018-05-11DOI: 10.23937/2378-3648/1410046
pS, ra P Smieszekp
Autism Spectrum Disorder (ASD) comprises a complex of neurodevelopmental disorders primarily characterized by deficits in verbal communication, impaired social interaction and repetitive behaviors. The complex genetic architecture of ASD encompasses profound clinical heterogeneity, which poses huge challenges in understanding its pathophysiology. We conducted a large scale association analysis of the MSSNG whole genome sequencing data to elucidate potential modifiers of ASD severity. Using linear regression, we have directly tested the association between 6,198,166 SNPs and Vineland Adaptive Behavior Scale Scores a standardized metric for measuring severity across multiple ASD spectra. The most significant variants direct us to a significant haplostretch chr3p21 (pval 3.68e-12) of SNPs, n = 132) containing variants on chromosome 3 including a highly interesting nonsynonymous SNV rs11539148 within the QARS gene (NM_001272073:c.A821G:p.N274S MAF = 0.0391) a glutaminyl-tRNA synthetase coding gene crucial in brain development. Furthermore, we analyzed eQTLs for QARS, and found decreased expression across several datasets, a result consistent with the observed effect. The effect further potentially explains differences in significant changes in head circumference. To leverage the size of the region we conducted a pathway enrichment analysis of the set of highly significant loci. The most significant categories include brain development and structural component of the myelin sheath. Genes categorized as neurological, developmental and immune-related constitute 65% of all the genes contributing to these pathways. Our analysis has detected a region that may be a hallmark of severity in ASD. As the genetic predisposition may be different for almost every ASD individual, understanding the common mechanisms for endophenotypes may help elucidate ASD causal mechanisms.
{"title":"Modifiers of Severity in Autism Spectrum Disorder","authors":"pS, ra P Smieszekp","doi":"10.23937/2378-3648/1410046","DOIUrl":"https://doi.org/10.23937/2378-3648/1410046","url":null,"abstract":"Autism Spectrum Disorder (ASD) comprises a complex of neurodevelopmental disorders primarily characterized by deficits in verbal communication, impaired social interaction and repetitive behaviors. The complex genetic architecture of ASD encompasses profound clinical heterogeneity, which poses huge challenges in understanding its pathophysiology. We conducted a large scale association analysis of the MSSNG whole genome sequencing data to elucidate potential modifiers of ASD severity. Using linear regression, we have directly tested the association between 6,198,166 SNPs and Vineland Adaptive Behavior Scale Scores a standardized metric for measuring severity across multiple ASD spectra. The most significant variants direct us to a significant haplostretch chr3p21 (pval 3.68e-12) of SNPs, n = 132) containing variants on chromosome 3 including a highly interesting nonsynonymous SNV rs11539148 within the QARS gene (NM_001272073:c.A821G:p.N274S MAF = 0.0391) a glutaminyl-tRNA synthetase coding gene crucial in brain development. Furthermore, we analyzed eQTLs for QARS, and found decreased expression across several datasets, a result consistent with the observed effect. The effect further potentially explains differences in significant changes in head circumference. To leverage the size of the region we conducted a pathway enrichment analysis of the set of highly significant loci. The most significant categories include brain development and structural component of the myelin sheath. Genes categorized as neurological, developmental and immune-related constitute 65% of all the genes contributing to these pathways. Our analysis has detected a region that may be a hallmark of severity in ASD. As the genetic predisposition may be different for almost every ASD individual, understanding the common mechanisms for endophenotypes may help elucidate ASD causal mechanisms.","PeriodicalId":91313,"journal":{"name":"Journal of genetics and genome research","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44053385","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2015-01-01Epub Date: 2015-09-15DOI: 10.23937/2378-3648/1410017
Heather S L Jim, Hui-Yi Lin, Jonathan P Tyrer, Kate Lawrenson, Joe Dennis, Ganna Chornokur, Zhihua Chen, Ann Y Chen, Jennifer Permuth-Wey, Katja Kh Aben, Hoda Anton-Culver, Natalia Antonenkova, Fiona Bruinsma, Elisa V Bandera, Yukie T Bean, Matthias W Beckmann, Maria Bisogna, Line Bjorge, Natalia Bogdanova, Louise A Brinton, Angela Brooks-Wilson, Clareann H Bunker, Ralf Butzow, Ian G Campbell, Karen Carty, Jenny Chang-Claude, Linda S Cook, Daniel W Cramer, Julie M Cunningham, Cezary Cybulski, Agnieszka Dansonka-Mieszkowska, Andreas du Bois, Evelyn Despierre, Weiva Sieh, Jennifer A Doherty, Thilo Dörk, Matthias Dürst, Douglas F Easton, Diana M Eccles, Robert P Edwards, Arif B Ekici, Peter A Fasching, Brooke L Fridley, Yu-Tang Gao, Aleksandra Gentry-Maharaj, Graham G Giles, Rosalind Glasspool, Marc T Goodman, Jacek Gronwald, Philipp Harter, Hanis N Hasmad, Alexander Hein, Florian Heitz, Michelle A T Hildebrandt, Peter Hillemanns, Claus K Hogdall, Estrid Hogdall, Satoyo Hosono, Edwin S Iversen, Anna Jakubowska, Allan Jensen, Bu-Tian Ji, Beth Y Karlan, Melissa Kellar, Lambertus A Kiemeney, Camilla Krakstad, Susanne K Kjaer, Jolanta Kupryjanczyk, Robert A Vierkant, Diether Lambrechts, Sandrina Lambrechts, Nhu D Le, Alice W Lee, Shashi Lele, Arto Leminen, Jenny Lester, Douglas A Levine, Dong Liang, Boon Kiong Lim, Jolanta Lissowska, Karen Lu, Jan Lubinski, Lene Lundvall, Leon F A G Massuger, Keitaro Matsuo, Valerie McGuire, John R McLaughlin, Ian McNeish, Usha Menon, Roger L Milne, Francesmary Modugno, Lotte Thomsen, Kirsten B Moysich, Roberta B Ness, Heli Nevanlinna, Ursula Eilber, Kunle Odunsi, Sara H Olson, Irene Orlow, Sandra Orsulic, Rachel Palmieri Weber, James Paul, Celeste L Pearce, Tanja Pejovic, Liisa M Pelttari, Malcolm C Pike, Elizabeth M Poole, Eva Schernhammer, Harvey A Risch, Barry Rosen, Mary Anne Rossing, Joseph H Rothstein, Anja Rudolph, Ingo B Runnebaum, Iwona K Rzepecka, Helga B Salvesen, Ira Schwaab, Xiao-Ou Shu, Yurii B Shvetsov, Nadeem Siddiqui, Honglin Song, Melissa C Southey, Beata Spiewankiewicz, Lara Sucheston-Campbell, Soo-Hwang Teo, Kathryn L Terry, Pamela J Thompson, Ingvild L Tangen, Shelley S Tworoger, Anne M van Altena, Ignace Vergote, Christine S Walsh, Shan Wang-Gohrke, Nicolas Wentzensen, Alice S Whittemore, Kristine G Wicklund, Lynne R Wilkens, Anna H Wu, Xifeng Wu, Yin-Ling Woo, Hannah Yang, Wei Zheng, Argyrios Ziogas, Ernest Amankwah, Andrew Berchuck, Joellen M Schildkraut, Linda E Kelemen, Susan J Ramus, Alvaro N A Monteiro, Ellen L Goode, Steven A Narod, Simon A Gayther, Paul D P Pharoah, Thomas A Sellers, Catherine M Phelan
Disruption in circadian gene expression, whether due to genetic variation or environmental factors (e.g., light at night, shiftwork), is associated with increased incidence of breast, prostate, gastrointestinal and hematologic cancers and gliomas. Circadian genes are highly expressed in the ovaries where they regulate ovulation; circadian disruption is associated with several ovarian cancer risk factors (e.g., endometriosis). However, no studies have examined variation in germline circadian genes as predictors of ovarian cancer risk and invasiveness. The goal of the current study was to examine single nucleotide polymorphisms (SNPs) in circadian genes BMAL1, CRY2, CSNK1E, NPAS2, PER3, REV1 and TIMELESS and downstream transcription factors KLF10 and SENP3 as predictors of risk of epithelial ovarian cancer (EOC) and histopathologic subtypes. The study included a test set of 3,761 EOC cases and 2,722 controls and a validation set of 44,308 samples including 18,174 (10,316 serous) cases and 26,134 controls from 43 studies participating in the Ovarian Cancer Association Consortium (OCAC). Analysis of genotype data from 36 genotyped SNPs and 4600 imputed SNPs indicated that the most significant association was rs117104877 in BMAL1 (OR = 0.79, 95% CI = 0.68-0.90, p = 5.59 × 10-4]. Functional analysis revealed a significant down regulation of BMAL1 expression following cMYC overexpression and increasing transformation in ovarian surface epithelial (OSE) cells as well as alternative splicing of BMAL1 exons in ovarian and granulosa cells. These results suggest that variation in circadian genes, and specifically BMAL1, may be associated with risk of ovarian cancer, likely through disruption of hormonal pathways.
{"title":"Common Genetic Variation in Circadian Rhythm Genes and Risk of Epithelial Ovarian Cancer (EOC).","authors":"Heather S L Jim, Hui-Yi Lin, Jonathan P Tyrer, Kate Lawrenson, Joe Dennis, Ganna Chornokur, Zhihua Chen, Ann Y Chen, Jennifer Permuth-Wey, Katja Kh Aben, Hoda Anton-Culver, Natalia Antonenkova, Fiona Bruinsma, Elisa V Bandera, Yukie T Bean, Matthias W Beckmann, Maria Bisogna, Line Bjorge, Natalia Bogdanova, Louise A Brinton, Angela Brooks-Wilson, Clareann H Bunker, Ralf Butzow, Ian G Campbell, Karen Carty, Jenny Chang-Claude, Linda S Cook, Daniel W Cramer, Julie M Cunningham, Cezary Cybulski, Agnieszka Dansonka-Mieszkowska, Andreas du Bois, Evelyn Despierre, Weiva Sieh, Jennifer A Doherty, Thilo Dörk, Matthias Dürst, Douglas F Easton, Diana M Eccles, Robert P Edwards, Arif B Ekici, Peter A Fasching, Brooke L Fridley, Yu-Tang Gao, Aleksandra Gentry-Maharaj, Graham G Giles, Rosalind Glasspool, Marc T Goodman, Jacek Gronwald, Philipp Harter, Hanis N Hasmad, Alexander Hein, Florian Heitz, Michelle A T Hildebrandt, Peter Hillemanns, Claus K Hogdall, Estrid Hogdall, Satoyo Hosono, Edwin S Iversen, Anna Jakubowska, Allan Jensen, Bu-Tian Ji, Beth Y Karlan, Melissa Kellar, Lambertus A Kiemeney, Camilla Krakstad, Susanne K Kjaer, Jolanta Kupryjanczyk, Robert A Vierkant, Diether Lambrechts, Sandrina Lambrechts, Nhu D Le, Alice W Lee, Shashi Lele, Arto Leminen, Jenny Lester, Douglas A Levine, Dong Liang, Boon Kiong Lim, Jolanta Lissowska, Karen Lu, Jan Lubinski, Lene Lundvall, Leon F A G Massuger, Keitaro Matsuo, Valerie McGuire, John R McLaughlin, Ian McNeish, Usha Menon, Roger L Milne, Francesmary Modugno, Lotte Thomsen, Kirsten B Moysich, Roberta B Ness, Heli Nevanlinna, Ursula Eilber, Kunle Odunsi, Sara H Olson, Irene Orlow, Sandra Orsulic, Rachel Palmieri Weber, James Paul, Celeste L Pearce, Tanja Pejovic, Liisa M Pelttari, Malcolm C Pike, Elizabeth M Poole, Eva Schernhammer, Harvey A Risch, Barry Rosen, Mary Anne Rossing, Joseph H Rothstein, Anja Rudolph, Ingo B Runnebaum, Iwona K Rzepecka, Helga B Salvesen, Ira Schwaab, Xiao-Ou Shu, Yurii B Shvetsov, Nadeem Siddiqui, Honglin Song, Melissa C Southey, Beata Spiewankiewicz, Lara Sucheston-Campbell, Soo-Hwang Teo, Kathryn L Terry, Pamela J Thompson, Ingvild L Tangen, Shelley S Tworoger, Anne M van Altena, Ignace Vergote, Christine S Walsh, Shan Wang-Gohrke, Nicolas Wentzensen, Alice S Whittemore, Kristine G Wicklund, Lynne R Wilkens, Anna H Wu, Xifeng Wu, Yin-Ling Woo, Hannah Yang, Wei Zheng, Argyrios Ziogas, Ernest Amankwah, Andrew Berchuck, Joellen M Schildkraut, Linda E Kelemen, Susan J Ramus, Alvaro N A Monteiro, Ellen L Goode, Steven A Narod, Simon A Gayther, Paul D P Pharoah, Thomas A Sellers, Catherine M Phelan","doi":"10.23937/2378-3648/1410017","DOIUrl":"10.23937/2378-3648/1410017","url":null,"abstract":"<p><p>Disruption in circadian gene expression, whether due to genetic variation or environmental factors (e.g., light at night, shiftwork), is associated with increased incidence of breast, prostate, gastrointestinal and hematologic cancers and gliomas. Circadian genes are highly expressed in the ovaries where they regulate ovulation; circadian disruption is associated with several ovarian cancer risk factors (e.g., endometriosis). However, no studies have examined variation in germline circadian genes as predictors of ovarian cancer risk and invasiveness. The goal of the current study was to examine single nucleotide polymorphisms (SNPs) in circadian genes <i>BMAL1, CRY2, CSNK1E, NPAS2, PER3, REV1</i> and <i>TIMELESS</i> and downstream transcription factors <i>KLF10</i> and <i>SENP3</i> as predictors of risk of epithelial ovarian cancer (EOC) and histopathologic subtypes. The study included a test set of 3,761 EOC cases and 2,722 controls and a validation set of 44,308 samples including 18,174 (10,316 serous) cases and 26,134 controls from 43 studies participating in the Ovarian Cancer Association Consortium (OCAC). Analysis of genotype data from 36 genotyped SNPs and 4600 imputed SNPs indicated that the most significant association was rs117104877 in <i>BMAL1</i> (OR = 0.79, 95% CI = 0.68-0.90, p = 5.59 × 10<sup>-4</sup>]. Functional analysis revealed a significant down regulation of <i>BMAL1</i> expression following <i>cMYC</i> overexpression and increasing transformation in ovarian surface epithelial (OSE) cells as well as alternative splicing of <i>BMAL1</i> exons in ovarian and granulosa cells. These results suggest that variation in circadian genes, and specifically <i>BMAL1</i>, may be associated with risk of ovarian cancer, likely through disruption of hormonal pathways.</p>","PeriodicalId":91313,"journal":{"name":"Journal of genetics and genome research","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4722961/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68748536","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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