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

Acta Biochim Pol. 2019 Sep 17;66(3):329-336. doi: 10.18388/abp.2019_2775.


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.

MeSH terms

  • Binding Sites
  • CCCTC-Binding Factor / chemistry
  • CCCTC-Binding Factor / genetics
  • Carcinogenesis / genetics
  • Chromogranins / genetics
  • Chromosomes, Human, Pair 1 / genetics
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / pathology
  • Epigenesis, Genetic
  • GTP-Binding Protein alpha Subunits, Gs / genetics
  • Genetic Loci
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • HCT116 Cells
  • HeLa Cells
  • Humans
  • Penetrance*
  • Poland
  • Polymorphism, Single Nucleotide / genetics*
  • Population / genetics*
  • Promoter Regions, Genetic
  • Risk


  • CCCTC-Binding Factor
  • CTCF protein, human
  • Chromogranins
  • GNAS protein, human
  • GTP-Binding Protein alpha Subunits, Gs