Functional analyses of a low-penetrance risk variant rs6702619/1p21.2 associating with colorectal cancer  in Polish population

Malgorzata Statkiewicz; Natalia Maryan; Maria Kulecka; Urszula Kuklinska; Jerzy Ostrowski; Michal Mikula

doi:10.18388/abp.2019_2775

Functional analyses of a low-penetrance risk variant rs6702619/1p21.2 associating with colorectal cancer in Polish population

Malgorzata Statkiewicz Department of Genetics, Maria Sklodowska-Curie Institute and Oncology Center; Warsaw, Poland https://orcid.org/0000-0003-2170-1909
Natalia Maryan Department of Gastroenterology, Hepatology and Clinical Oncology, Medical Center for Postgraduate Education; Warsaw, Poland
Maria Kulecka Department of Gastroenterology, Hepatology and Clinical Oncology, Medical Center for Postgraduate Education; Warsaw, Poland https://orcid.org/0000-0002-9830-8892
Urszula Kuklinska Department of Genetics, Maria Sklodowska-Curie Institute and Oncology Center; Warsaw, Poland https://orcid.org/0000-0002-5752-3887
Jerzy Ostrowski 1Department of Genetics, Maria Sklodowska-Curie Institute and Oncology Center; Warsaw, Poland; 2Department of Gastroenterology, Hepatology and Clinical Oncology, Medical Center for Postgraduate Education; Warsaw, Poland https://orcid.org/0000-0003-1363-3766
Michal Mikula Department of Genetics, Maria Sklodowska-Curie Institute and Oncology Center; Warsaw, Poland https://orcid.org/0000-0003-3447-7328

DOI: https://doi.org/10.18388/abp.2019_2775

Abstract

Several studies employed the genome-wide association (GWA) analysis of single-nucleotide polymorphisms (SNPs) to identify susceptibility regions in colorectal cancer (CRC). However, the functional studies exploring the role of associating SNPs with cancer biology are limited. Herein, using chromatin immunoprecipitation assay (ChIP), reporter assay and chromosome conformation capture sequencing (3C-Seq) augmented with publically available genomic and epigenomic databases we aimed to define the function of rs6702619/1p21.2 region associated with CRC in the Polish population. Using ChIP we confirmed that rs6702619 region is occupied by a CTCF, a master regulator of long-range genomic interactions, and is decorated with enhancer-like histone modifications. The enhancer blocking assay revealed that rs6702619 region acts as an insulator with activity dependent on the SNP genotype. Finally, a 3C-Seq survey indicated more than a hundred loci in the rs6702619 locus interactome, including GNAS gene that is frequently amplified in CRC. Taken together, we showed that the CRC-associated rs6702619 region has in vitro and in vivo properties of an insulator that demonstrates long-range physical interactions with CRC-relevant loci.

Published

2019-09-17

Issue

Vol. 66 No. 3 (2019)

Section

Articles

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