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Colorectal cancer risk stratification enhanced by combining family history and genetic risk scores


Key clinical point: Jointly using family history and genetic risk scores enhances their independent considerations for CRC risk stratifications.

Major finding: CRC in the highest decile compared with lowest decile was associated with 3.0-fold and 6.1-fold increased risks when considering genetic risk scores independently and jointly with family history, respectively.

Study details: Ongoing population-based study involving 22 hospitals in Germany with 2,363 CRC cases compared to 2,198 controls.

Disclosures: The authors reported that they had no conflicts of interest.

Source: Weigl K et al. Clin Epidemiol. 2018;10:143-52.



Stratification of colorectal cancer (CRC) risk was enhanced by joint consideration of the independent family history and genetic risk score predictors, according to an ongoing population-based, case-control study of patients recruited during 2003-2010.

Courtesy Wikimedia Commons/Nephron/Creative Commons License

The research was conducted using data from DACHS (Colorectal Cancer: Chances for Prevention Through Screening), an ongoing population-based, case-control study in Germany, reported Korbinian Weigl, PhD, and his colleagues in the journal Clinical Epidemiology (doi: 10.2147/CLEP.S145636). They included 2,363 eligible CRC patients who were identified by 22 participating hospitals and frequency matched with respect to sex, age, and residential location to 2,198 randomly selected controls that had genome-wide association studies data. The population consisted of 40% women, and the median ages for cases and controls were 69 and 70 years, respectively.

Genetic risk score was calculated by genotyping 53 single-nucleotide polymorphisms reported in published literature to be associated with higher CRC risk for individuals of European descent. Seven genetic risk score groups – very low, low, low-medium, medium, medium-high, high, and very high – were established according to categories generated on the basis of weighted risk allele distribution among controls. Family history referred to CRC in first-degree and second-degree relatives. Selected potential confounders included age, sex, body mass index, education, hormone replacement therapy in women, smoking, and colonoscopy history. Odds ratios with 95% confidence intervals were estimated by multiple logistic regression models that included adjustment for potential confounders. Statistical calculations examined individual and joint family history and genetic risk score associations with risk for CRC and the effect of potential confounding factors.

At least one colonoscopy was performed on over half the individuals in the control group, while a significantly lower number (P less than .0001) were performed on case individuals (22.1%). Family history of CRC in first-degree relatives was reported by 316 case participants (13.4%) and 214 controls (9.7%; P less than .0001). The calculated genetic risk score ranged from 20 to 48, with a substantially higher proportion of cases in the higher deciles.

Investigators compared the risk for CRC in the top decile with that in the lowest and found an increased risk of 2.9-fold (OR, 2.94) based on genetic risk analysis adjusted for sex and age and an increased risk of 3.0-fold (OR, 3.0) when all other covariates except family history were included. Comparing results against analysis with the 27 single-nucleotide polymorphisms that had been used in previous studies indicated a sizable improvement in genetic risk stratification as a result of increasing the number of single-nucleotide polymorphisms (P value for increase in c statistic = .003) included in the analysis.

Risk associated with having a family history of CRC in a first-degree relative was 1.5-fold (OR, 1.47) higher in an age- and sex-adjusted analysis. Risk prediction increased to an OR of 1.86 when calculations were adjusted with covariates, especially with previous colonoscopies. Using genetic risk scoring as a calculation adjustment only slightly changed the result (OR, 1.83). A similar trend, but with lower-magnitude associations, was observed with family history of CRC in second-degree relatives.

A dose-response association between the number of risk alleles and CRC risk determined by a logistic regression model revealed a curvilinear relationship between genetic risk score and CRC risk. At higher genetic risk score levels, the increase in CRC risk was particularly strong. The dose-response association indicated an independent relationship between family history and CRC such that individuals with first-degree relatives with CRC will reach the same risk level with a lower genetic risk score as those with a higher genetic risk score but no first-degree relatives with CRC.

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