Colorectal cancer-associated SNP rs17042479 is involved in the regulation of NAF1 promoter activity

A novel risk locus at 4q32.2, located between the Nuclear Assembly Factor 1 (NAF1) and Follistatin Like 5 (FSTL5) genes, was associated with increased risk of developing colorectal cancer (CRC), with SNP rs17042479 being the most associated. However, the link between CRC development and the risk loc...

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Published in:	PloS one Vol. 17; no. 9; p. e0274033
Main Authors:	Olsson, Josephine B, Gugerel, Marietta B, Jessen, Stine B, Jørgensen, Jannie, Gögenur, Ismail, Hansen, Camilla, Kirkeby, Lene T, Olsen, Jørgen, Pedersen, Ole B. V, Vestlev, Peter M, Dahlgaard, Katja, Troelsen, Jesper T
Format:	Journal Article
Language:	English
Published:	San Francisco Public Library of Science 06-09-2022 Public Library of Science (PLoS)
Subjects:	Analysis Biology and Life Sciences Biopsy Cancer Chromosome 4 Colorectal cancer Colorectal carcinoma Diagnosis Follistatin Gastrointestinal cancer Gene expression Genetic aspects Medicine and Health Sciences Mutation Phenotypes Proteins Research and analysis methods Risk analysis Single nucleotide polymorphisms Single-nucleotide polymorphism Tissues Tumors Denmark
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Summary:	A novel risk locus at 4q32.2, located between the Nuclear Assembly Factor 1 (NAF1) and Follistatin Like 5 (FSTL5) genes, was associated with increased risk of developing colorectal cancer (CRC), with SNP rs17042479 being the most associated. However, the link between CRC development and the risk locus at 4q32.2 is unknown. We investigated the promoter activity of NAF1 and FSTL5 and analyzed the risk locus at 4q32.2 as gene regulatory region. Our results showed that the activity of the FSTL5 promoter was low compared to the NAF1 promoter. Analyses of the NAF1 promoter in conjunction with the region containing the risk locus at 4q32.2 showed that the region functions as gene regulatory region with repressor activity on NAF1 promoter activity. The SNP rs17042479(G) increased the repressor effect of the region. CRC patients' biopsies were genotyped for SNP rs17042479(A/G), and NAF1 expression profiles were examined. We found an association between SNP rs17042479(G), cancer stage and tumor location. Additionally, patients with SNP rs17042479(G) showed lower NAF1 expression in comparison to patients with SNP rs17042479(A) in tumor tissue and the NAF1 expression in tumor tissue was lower compared to healthy tissue. The results in the study imply that reduced NAF1 expression in the tumor contribute to a more aggressive phenotype. Furthermore, this study suggests that the SNP rs17042479(G) change the expression of NAF1 and thereby increases the risk of developing CRC.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Competing Interests: The authors have declared that no competing interests exist.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0274033