Genome-wide association study using diversity outcross mice identified candidate genes of pancreatic cancer
Open accessAbstract
To understand the genetic causes of pancreatic cancer (PC), we conducted a genome-wide association study (GWAS) using the diversity outbred (DO) mice population to identify susceptibility genes underlying 7,12-dimethylbenzanthraene (DMBA) induced PC. The phenotype studied was the percent PC lesion area in the DO mice population. We genotyped 7851 SNP markers specifically designed for DO mice across the whole mouse genome. Four susceptibility genes with P values exceeding the genome-wide threshold for percent PC lesion area (P < 2.37 × 10-6) were identified, i.e., Epha4, Gpc5, Kcnj6, Arid1b. The most significant SNP of Gpc5 (UNC140360310) that is associated with PC lesion area in mice also significantly influences the Gpc5 expression, suggesting that this Gpc5 SNP exerts its role in PC through cis-regulating the gene expression of Gpc5. Together, our data supported that Gpc5 as a tumor suppressor gene involved in the etiology of PC.
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Zhao et al. showed that IL-17A mRNA and protein levels significantly increased after knock-down of RFX1 in CD4+ T cells, while a decrease was observed after overexpressing RFX1.
“They showed that the levels of IL-17A mRNA and protein signi cantly increased after knock-down of RFX1 in CD4 + T cells, while a decrease in IL-17A level was observed after overexpressing RFX1.”
From Identification of Genetic Variants Regulating the Abundance of Clinically Relevant Plasma Proteins using the Diversity Outbred Mouse Model (2021) · cites this paper as [27]
Section 3.3 reports an association between a genetic variant and Gpc5 expression in mice, not an RFX1 experiment in CD4+ T cells. Searches for RFX1, IL-17A, knock-down, and overexpression found no passage supporting the claimed changes in IL-17A mRNA or protein. The References section names a Zhao paper, but describes it as a study of GPC5 in lung adenocarcinoma, not the claimed experiment. (LLM, conf=0.76)
Experimental — accuracy not yet measuredRFX1 plays an important role in methylation and acetylation of the promoter region of IL17A.
“RFX1 also played an important role in methylation and acetylation of the promoter region of IL17A [27].”
From Identification of Genetic Variants Regulating the Abundance of Clinically Relevant Plasma Proteins using the Diversity Outbred Mouse Model (2021) · cites this paper as [27]
The Discussion and section 3.3 address pancreatic-cancer candidate genes and cis-regulation of Gpc5, not RFX1 or IL17A. Searches for RFX1, IL17A, and promoter methylation and acetylation found no passage in our copy addressing the claimed relationship. (LLM, conf=0.76)
Experimental — accuracy not yet measuredThe results from Zhao et al. provide functional evidence directly linking RFX1 and IL-17A.
“The results from Zhao et al. [27] provide functional evidence directly linking RFX1 and IL-17A.”
From Identification of Genetic Variants Regulating the Abundance of Clinically Relevant Plasma Proteins using the Diversity Outbred Mouse Model (2021) · cites this paper as [27]
The Results section (3.3, page unavailable) reports a link between Gpc5 expression and pancreatic lesion size in mice, not between RFX1 and IL-17A. Searches for “RFX1 IL-17A” and “RFX1 interleukin 17A” found no passage in our copy addressing the claimed functional link; its reference to a Zhao paper concerns GPC5 in lung adenocarcinoma. (LLM, conf=0.76)
Experimental — accuracy not yet measuredZhao et al. demonstrated that RFX1 directly affects IL-17A expression by binding one of its two binding sites upstream of the transcription start site of the IL17A gene.
“Furthermore, they demonstrated that RFX1 directly affects IL-17A expression by binding one of its two binding sites upstream of the transcription start site of the IL17A gene.”
From Identification of Genetic Variants Regulating the Abundance of Clinically Relevant Plasma Proteins using the Diversity Outbred Mouse Model (2021) · cites this paper as [27]
Section 3.3 reports cis-regulation of Gpc5 in mice, not regulation of IL-17A by RFX1. Searches for RFX1, IL17A and the claimed upstream binding sites found no passage addressing that mechanism; the Zhao work listed in the References concerns GPC5 in lung adenocarcinoma. (LLM, conf=0.76)
Experimental — accuracy not yet measured
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Cites
Smallwood, T. L., Gatti, D. M., Quizon, P., Weinstock, G. M., Jung, K.-C., Zhao, L., Hua, K., Pomp, D., & Bennett, B. J. (2014) · G3 Genes|Genomes|Genetics · doi:10.1534/g3.114.014704 · Cited by 54 · see citing works
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Research works printed but not linked: 1
- W. Zhang, R. Korstanje, J. Thaisz, F. Staedtler, N. Harttman, L. Xu, M. Feng, L. Yanas, H. Yang, W. Valdar, G.A. Churchill, K. Dipetrillo, Genome-wide associa- tion mapping of quantitative traits in outbred mice, G3 (Bethesda), Vol. 2 2012, pp. 167-174.
Cited by
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Philtjens, S., Acri, D. J., Kim, B., Kim, H., & Kim, J. (2021) · doi:10.21203/rs.3.rs-171899/v1 · Cited by 1 · see citing works
“Additionally, genetic modi ers that have been discovered via QTL mapping in the DO mouse population have uncovered genetic mechanisms that have been successfully translated to humans [24, 25].”
Background
- Authors
- Yang, C., Wang, Y., Xu, W., Liu, Z., Zhou, S., Zhang, M., & Cui, D.
- Affiliations
- China Medical University (CN)
- University of Shanghai for Science and Technology (CN)
- Sheng Jing Hospital (CN)
- Corresponding author
- Cui, Dongxu
- Venue
- Genomics
- Publisher
- Elsevier BV
- Published
- 2019-12
- Volume
- 111
- Issue
- 6
- Pages
- 1882-1888
- ISSN
- 0888-7543 (ISSN-L)
- OpenAlex
- W2906320785
- Cited by
- 9
- References
- 1
- Citations by year
- 2026: 1 · 2023: 5 · 2021: 1 · 2020: 1 · 2019: 1
- FWCI
- 0.28
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Genomics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- China Medical University
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- pancreatic cancer, susceptibility genes, Diversity Outbred mice, DMBA-induced carcinogenesis, GPC5, tumor suppressor, cis-regulation, EphA4, KCNJ6, ARID1B, cancer genetics
- MeSH terms
- Animals, Female, Male, Mice, Inbred Strains, Neoplasm Proteins, Pancreatic Neoplasms, Polymorphism, Single Nucleotide, Mice, Genes, Neoplasm, Genome-Wide Association Study
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