By Laura Cowen

Researchers have identified three new colorectal cancer (CRC) risk loci, including one on the X-chromosome, bringing the total number of independent loci associated with the disease to 20.

The loci identified on the X-chromosome represents "the first evidence for the role of X-chromosome variation in predisposition to a non-sex specific cancer," say Malcolm Dunlop (University of Edinburgh, UK) and colleagues in Nature Genetics.

"This may help explain why bowel cancer is slightly more common in men. Ultimately, it could also help us target screening to those who are more at risk of the disease," said study co-author Richard Houlston (Institute of Cancer Research, Sutton, UK) in a press statement.

The researchers performed a meta-analysis of five genome-wide association studies, comprising 8682 CRC cases and 9649 controls, to identify common variants influencing CRC risk that may not have been identified in the individual studies due to limited statistical power.

They then conducted a replication analysis in case-control sets totaling 21,096 CRC cases and 19,555 controls.

They identified three single nucleotide polymorphisms (SNPs) showing evidence of association with CRC at genome-wide significance.

The first, rs3824999 maps to chromosome 11q13 within intron 9 of the POLD3 gene (encoding polymerase DNA-directed δ3). The POLD3 protein is a component of the DNA polymerase-δ complex involved in suppression of homologous recombination and DNA mismatch and base-excision repair. These are major processes shown to be defective in Mendelian CRC susceptibility disorders, the researchers note.

The second SNP, rs1321311, maps to chromosome 6p21 within a region of linkage disequilibrium (LD) that encompasses the CDKN1A gene (encoding cyclin-dependent kinase inhibitor 1A, also known as p21). The p21 protein mediates p53-dependent G1 growth arrests, acts as a controller of a number of tumor-suppressor pathways, and blocks DNA synthesis.

The third SNP the researchers discovered was rs5934683, which maps to chromosome Xp22.2 within a 43 kb region of LD within the distal promoter region of SHROOM2 (encoding shroom family member 2). The rs5934683 genotype accounted for 55% of the variation in expression of this gene.

Dunlop et al explain that SHROOM2 is known to have broad roles in cell morphogenesis during endothelial and epithelial tissue development. Mutations in this gene have previously been linked to cancer.

Furthermore, SHROOM2 regulates melanosome biogenesis and localization in the retinal pigment epithelium, and the team notes that abnormal retinal pigmentation has previously been shown to be an extracolonic feature of nonfamilial adenomatous polyposis CRC.

Dunlop and co-authors conclude that their study "provides further insight into the genetic architecture of inherited susceptibility to CRC."

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