Ability of known susceptibility SNPs to predict colorectal cancer risk for persons with and without a family history

Abstract

Before SNP-based risk can be incorporated in colorectal cancer (CRC) screening, the ability of these SNPs to estimate CRC risk for persons with and without a family history of CRC, and the screening implications need to be determined. We estimated the association with CRC of a 45 SNP-based risk using 1181 cases and 999 controls, and its correlation with CRC risk predicted from detailed family history. We estimated the predicted change in the distribution across predefined risk categories, and implications for recommended screening commencement age, from adding SNP-based risk to family history. The inter-quintile risk ratio for colorectal cancer risk of the SNP-based risk was 3.28 (95% CI 2.54-4.22). SNP-based and family history-based risks were not correlated (r = 0.02). For persons with no first-degree relatives with CRC, screening could commence 4 years earlier for women (5 years for men) in the highest quintile of SNP-based risk. For persons with two first-degree relatives with CRC, screening could commence 16 years earlier for men and women in the highest quintile, and 7 years earlier for the lowest quintile. This 45 SNP panel in conjunction with family history, can identify people who could benefit from earlier screening. Risk reclassification by 45 SNPs could inform targeted screening for CRC prevention, particularly in clinical genetics settings when mutations in high-risk genes cannot be identified. Yet to be determined is cost-effectiveness, resources requirements, community, patient and clinician acceptance, and feasibility with potentially ethical, legal and insurance implications.

Keywords: Colorectal cancer; Family history; Prediction model; Risk prediction; Single nucleotide polymorphism.

Figure 1.

The distribution of lifetime risk of colorectal cancer (CRC) i.e., cumulative risk to age 80 years for the US population, by three categories of SNP-based risk and three categories of family history (. Risks are shown for those in the lowest quintile of SNP-based risk (left column), those at average risk (centre column), and those in the highest quintile of SNP-based risk (right column) by for those with no first-degree relative with CRC (top row), those with one first-degree relative with CRC (middle row), and those with two or more first-degree relatives with CRC (bottom row).

Figure 2.

Cumulative risk of colorectal cancer (CRC) for the US population by three categories of SNP-based risk (lowest quintile, average, highest quintile) and two categories of family history (no first-degree relatives with CRC labelled “No family history” and two first-degree relatives with CRC).