Inclusion of a Genetic Risk Score into a Validated Risk Prediction Model for Colorectal Cancer in Japanese Men Improves Performance

Abstract

We previously developed and validated a risk prediction model for colorectal cancer in Japanese men using modifiable risk factors. To further improve risk prediction, we evaluated the degree of improvement obtained by adding a genetic risk score (GRS) using genome-wide association study (GWAS)-identified risk variants to our validated model. We examined the association between 36 risk variants identified by GWAS and colorectal cancer risk using a weighted Cox proportional hazards model in a nested case-control study within the Japan Public Health Center-based Prospective Study. GRS was constructed using six variants associated with risk in this study of the 36 tested. We assessed three models: a nongenetic model that included the same variables used in our previously validated model; a genetic model that used GRS; and an inclusive model, which included both. The c-statistic, integrated discrimination improvement (IDI), and net reclassification improvement (NRI) were calculated by the 5-fold cross-validation method. We estimated 10-year absolute risks for developing colorectal cancer. A statistically significant association was observed between the weighted GRS and colorectal cancer risk. The mean c-statistic for the inclusive model (0.66) was slightly greater than that for the nongenetic model (0.60). Similarly, the mean IDI and NRI showed improvement when comparing the nongenetic and inclusive models. These models for colorectal cancer were well calibrated. The addition of GRS using GWAS-identified risk variants to our validated model for Japanese men improved the prediction of colorectal cancer risk..

Performance of individual and joint risk stratification by an environmental risk score and a genetic risk score in a colorectal cancer screening setting

“…[18][19][20][21] Recent studies have demonstrated that combination of environmental and genetic factors may substantially improve prediction of CRC risk. [22][23][24][25] However, to the best of our knowledge, no previous study has combined information from environmental risk scores (ERS) and genetic risk scores (GRS) for predicting the presence of CRC and its precursors, the targets for CRC screening, in a true screening setting.…”

The effects of genetic variants related to insulin metabolism pathways and the interactions with lifestyles on colorectal cancer risk

“…Approximately 90% of new cases and deaths occur in people of age 50 and older 1 . About 35% of the susceptibility to CRC is attributed to genetic factors, while the remaining 65% is attributed to non-modifiable and modifiable environmental factors such as age (particularly, 40 to 69 years), obesity, high fat diet, smoking, alcohol, and Type II diabetes (T2DM) [2][3][4][5] . The effect of the obesity-related lifestyle factors on CRC risk may be mediated by insulin-like growth factor-I (IGF-I)/insulin pathway.…”

The Japan Public Health Center-based Prospective Study for the Next Generation (JPHC-NEXT): Study Design and Participants

“…However, lifestyle and life-environment factors among the Japanese population have undergone drastic changes during these decades, 3 and many molecular epidemiological studies have reported associations between genetic and environmental factors and diseases [4][5][6] and identified biomarkers that may be useful in predicting disease risk in individuals. 7,8 The addition of such biomarker information to environmental factors will be helpful in establishing personalized healthcare.…”