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Review
. 2015 Oct;64(10):1623-36.
doi: 10.1136/gutjnl-2013-306705. Epub 2015 Jul 17.

Genetic architecture of colorectal cancer

Ulrike Peters  1 , Stephanie Bien  2 , Niha Zubair  2
Affiliations
Review

Genetic architecture of colorectal cancer

Ulrike Peters et al. Gut. 2015 Oct.

Abstract

Colorectal cancer (CRC) is a complex disease that develops as a consequence of both genetic and environmental risk factors. A small proportion (3-5%) of cases arise from hereditary syndromes predisposing to early onset CRC as a result of mutations in over a dozen well defined genes. In contrast, CRC is predominantly a late onset 'sporadic' disease, developing in individuals with no obvious hereditary syndrome. In recent years, genome wide association studies have discovered that over 40 genetic regions are associated with weak effects on sporadic CRC, and it has been estimated that increasingly large genome wide scans will identify many additional novel genetic regions. Subsequent experimental validations have identified the causally related variant(s) in a limited number of these genetic regions. Further biological insight could be obtained through ethnically diverse study populations, larger genetic sequencing studies and development of higher throughput functional experiments. Along with inherited variation, integration of the tumour genome may shed light on the carcinogenic processes in CRC. In addition to summarising the genetic architecture of CRC, this review discusses genetic factors that modify environmental predictors of CRC, as well as examples of how genetic insight has improved clinical surveillance, prevention and treatment strategies. In summary, substantial progress has been made in uncovering the genetic architecture of CRC, and continued research efforts are expected to identify additional genetic risk factors that further our biological understanding of this disease. Subsequently these new insights will lead to improved treatment and prevention of colorectal cancer.

Keywords: COLORECTAL CANCER.

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Conflict of interest statement

COMPETING INTERESTS

The authors have no competing interests to disclose.

Figures

Figure 1
Figure 1. Genetic architecture of known CRC genetic susceptibility loci
Allele frequency shown for the risk allele frequency of the ethnicity in which the locus was discovered; except for variants with a recessive effect (MUTYH), for which the frequency of the homozygote rare allele is shown. Supplemental Table 1 provides details on each genetic variant presented in this Figure 1.
Figure 2
Figure 2. Fine-mapping of GWAS findings. Association results (p-values) and correlation structure for all SNPs in the 8q24 risk locus
The top part of the Figure has physical position along the x axis, and the −log10 of the SNP-CRC association p-value on the y-axis. Each dot on the plot represents the p-value of the association for one SNP with risk of CRC. The most significant SNP (rs6983267) is marked as a purple diamond. The color scheme represents the pairwise correlation (r2) for the SNPs across the 8q24 region with the most significant SNP (rs6983267) based on the European descent participants from the 1000 Genomes Project data. Gray indicates that correlation was missing for this p-value because the variant had no r2 estimation due to low MAF or because the SNP is not in older versions of the 1000 Genomes data. The bottom half of the Figure shows the position of the genes across the region.
Figure 3
Figure 3. Most genetic variants are rare - Distribution of genetic variants by minor allele frequency (MAF)
Sources: Gorlov et al. Clin Genet 2011;[238] https://esp.gs.washingtonedu/drupal[239]
See this image and copyright information in PMC

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