Establishing a valid approach for estimating familial risk of cancer explained by common genetic variants

Abstract

We critically examined existing approaches for the estimation of the excess familial risk of cancer that can be attributed to identified common genetic risk variants and propose an alternative, more straightforward approach for calculating this proportion using well‐established epidemiological methodology. We applied the underlying equations of the traditional approaches and the new epidemiological approach for colorectal cancer (CRC) in a large population‐based case–control study in Germany with 4,447 cases and 3,480 controls, who were recruited from 2003 to 2016 and for whom interview, medical and genomic data were available. Having a family history of CRC (FH) was associated with a 1.77‐fold risk increase in our study population (95% CI 1.52–2.07). Traditional approaches yielded estimates of the FH‐associated risk explained by 97 common genetics variants from 9.6% to 23.1%, depending on various assumptions. Our alternative approach resulted in smaller and more consistent estimates of this proportion, ranging from 5.4% to 14.3%. Commonly employed methods may lead to strongly divergent and possibly exaggerated estimates of excess familial risk of cancer explained by associated known common genetic variants. Our results suggest that familial risk and risk associated with known common genetic variants might reflect two complementary major sources of risk.

Validation of Genetic Markers Associated with Survival in Colorectal Cancer Patients Treated with Oxaliplatin-Based Chemotherapy

“…DNA was extracted from blood samples (in 99.1% of participants) or buccal cells (in 0.9% of participants) using conventional methods. Details about genotyping and imputation for the DACHS population have been described in detail somewhere else ( 29 ). In short, genotyping was conducted using four different assays.…”

Colorectal Cancer Risk by Genetic Variants in Populations With and Without Colonoscopy History

“…Genotyping for the DACHS study population has been described in detail previously ( 18 ). In short, DNA was extracted from blood samples (in 99.1% of participants) or buccal cells (in 0.9% of participants).…”

Candidate Gene Discovery in Hereditary Colorectal Cancer and Polyposis Syndromes–Considerations for Future Studies

“…penetrant risk genes contributing to the heredity of CRC, it is estimated that common variants (minor allele frequency (MAF) in the general population >1%) may explain about ~12% of the relative risk for CRC [8][9][10][11].…”

“…At present, it is estimated that about 5–10% of all CRC and polyposis cases are explained by rare pathogenic variants in high-penetrant risk genes [ 2 , 6 , 7 , 8 ]. Next to identification of rare high-penetrant risk genes contributing to the heredity of CRC, it is estimated that common variants (minor allele frequency (MAF) in the general population >1%) may explain about ~12% of the relative risk for CRC [ 8 , 9 , 10 , 11 ].…”