Association of Mitotic Regulation Pathway Polymorphisms with Pancreatic Cancer Risk and Outcome

Couch, Fergus J.; Wang, Xianshu; Bamlet, William R.; Andrade, Mariza de; Petersen, Gloria M.; McWilliams, Robert R.

doi:10.1158/1055-9965.epi-09-0629

Cited by 23 publications

(30 citation statements)

References 27 publications

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“…These findings may not only be relevant in the context of beta cell apoptosis and diabetes. Loss of Trp53 and altered expression of mir-200 are commonly detected in tumorigenesis, and several direct miR-200 targets and executor proteins verified in this study have been linked to tumor formation 44,57,58 . Further analysis of their interaction will be informative in regard to endocrine tumor development (for example, insulinoma) and other physiological processes such as postpartum-associated islet remodeling.…”

Section: Discussionsupporting

confidence: 54%

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The microRNA-200 family regulates pancreatic beta cell survival in type 2 diabetes

Belgardt

Ahmed

Spranger

et al. 2015

Nat Med

248

249

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Pancreatic beta cell death is a hallmark of type 1 (T1D) and type 2 (T2D) diabetes, but the molecular mechanisms underlying this aspect of diabetic pathology are poorly understood. Here we report that expression of the microRNA (miR)-200 family is strongly induced in islets of diabetic mice and that beta cell-specific overexpression of miR-200 in mice is sufficient to induce beta cell apoptosis and lethal T2D. Conversely, mir-200 ablation in mice reduces beta cell apoptosis and ameliorates T2D. We show that miR-200 negatively regulates a conserved anti-apoptotic and stress-resistance network that includes the essential beta cell chaperone Dnajc3 (also known as p58IPK) and the caspase inhibitor Xiap. We also observed that mir-200 dosage positively controls activation of the tumor suppressor Trp53 and thereby creates a pro-apoptotic gene-expression signature found in islets of diabetic mice. Consequently, miR-200-induced T2D is suppressed by interfering with the signaling of Trp53 and Bax, a proapoptotic member of the B cell lymphoma 2 protein family. Our results reveal a crucial role for the miR-200 family in beta cell survival and the pathophysiology of diabetes.npg

show abstract

Section: Discussionsupporting

confidence: 54%

“…7a,b). Among them was Ypel2, a potential oncogene of unknown function, which has previously been associated with pancreatic and breast cancer 44 . Ypel2 harbors a conserved and functional miR-200c binding site in its 3′ UTR (Supplementary Fig.…”

Section: Mir-200 Regulates Anti-apoptotic Target Genesmentioning

confidence: 99%

The microRNA-200 family regulates pancreatic beta cell survival in type 2 diabetes

Belgardt

Ahmed

Spranger

et al. 2015

Nat Med

248

249

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“…A SNP in the 5’UTR region of TEX14 , rs302864, is associated with a significantly increased risk of pancreatic cancer for individuals with high body mass index (BMI>=30) (Couch et al, 2010). The rs302864 SNP, which is 64,936 bps upstream of the novel exonic variant we identified, has also been associated with breast cancer (Kelemen et al, 2009).…”

Section: Resultsmentioning

confidence: 99%

Population-scale analysis of human microsatellites reveals novel sources of exonic variation

McIver¹,

McCormick²,

Martin³

et al. 2013

Gene

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Using our microsatellite specific genotyping method, we analyzed tandem repeats, which are known to be highly variable with some recognized as biomarkers causative of disease, in over 500 individuals who were exon sequenced in a 1000 Genomes Project pilot study. We were able to genotype over 97% of the microsatellite loci in the targeted regions. A total of 25,115 variations were observed, including repeat length and single nucleotide polymorphisms, corresponding to an average of 45.6 variations per individual and a density of 1.1 variations per kilobase. Standard variant detection did not report 94.2% of the exonic repeat length variations in part because the alignment techniques are not ideal for repetitive regions. Additionally some standard variation detection tools rely on a database of known variations, making them less likely to call repeat length variations as only a small percent of these loci (~6,000) have been accurately characterized. A subset of the hundreds of non-synonymous variations we identified was experimentally validated, indicating an accuracy of 96.5% for our microsatellite-based genotyping method, with some novel variants identified in genes associated with cancer. We propose that microsatellite-based genotyping be used as a part of large scale sequencing studies to identify novel variants.

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“…Two of single nucleotide polymorphisms (SNPs), in APC (adenomatous polyposis coli gene) and NIN (ninein gene) genes, were statistically significant and associated with an increased and decreased risk, respectively. Other genes and their variants were significant taking into consideration BMI or smoking habit (for example MCPH1 gene polymorphism associated with increased risk former and ever smokers) 20. Jang et al .…”

Section: Nuclear Dna Changesmentioning

confidence: 99%

“…41. Interesting was also analysis of β-catenin signaling cascade, which is overexpressed in over 65% of pancreatic tumors, and possible participation of genetic variants in AXIN2 gene (axin2 gene) 20.…”

Section: Nuclear Dna Changesmentioning

confidence: 99%

An Overview of Genetic Changes and Risk of Pancreatic Ductal Adenocarcinoma

Sarnecka

Zagozda

Durlik³

2016

J. Cancer

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The pancreatic carcinoma is a leading cause of death in cancer carriers worldwide. The early diagnostic is difficult due to late stage during diagnosis, lack of characteristic symptoms and also multifactor basis. In cancer development take part both, environmental and genetic factors, alone or in conjunction with each other. The nonspecific biomarkers of cancers are a reason for the search for more accurate factors which allow for fast and personalized diagnostics. Some of cancers have identified molecular (metabolic, biochemical or genetic) markers but in most cases the only clue is patient`s interview and abnormal levels of organ functions markers.Possible genetic basis of cancer suggests to widen studies on connection between environmental factors with both, nuclear and mitochondrial, genes changes.

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Association of Mitotic Regulation Pathway Polymorphisms with Pancreatic Cancer Risk and Outcome

Cited by 23 publications

References 27 publications

The microRNA-200 family regulates pancreatic beta cell survival in type 2 diabetes

The microRNA-200 family regulates pancreatic beta cell survival in type 2 diabetes

Population-scale analysis of human microsatellites reveals novel sources of exonic variation

An Overview of Genetic Changes and Risk of Pancreatic Ductal Adenocarcinoma

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