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Clin Transl Gastroenterol. 2019 Dec;10(12):e00106. doi: 10.14309/ctg.0000000000000106.

Head-to-Head Comparison of Family History of Colorectal Cancer and a Genetic Risk Score for Colorectal Cancer Risk Stratification.

Author information

1
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
2
German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
3
Medical Faculty Heidelberg, University of Heidelberg, Germany.
4
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
5
Department for General, Visceral and Transplantation Surgery, University Heidelberg, Germany.
6
Colon Cancer Genetics Group, Institute of Genetics and Molecular Medicine, University of Edinburgh and MRC Human Genetics Unit, Western General Hospital Colon Cancer Genetics Group, Edinburgh, Scotland, United Kingdom.
7
Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center of Tumour Diseases (NCT), Heidelberg, Germany.

Abstract

OBJECTIVES:

Family history (FH) is associated with increased risk of colorectal cancer (CRC). We aimed to examine the potential for CRC risk stratification by known common genetic variants beyond FH in a large population-based case-control study from Germany.

METHODS:

Four thousand four hundred forty-seven cases and 3,480 controls recruited in 2003-2016 were included for whom comprehensive interview, medical, and genomic data were available. Associations with CRC risk were estimated from multiple logistic regression models for FH and a genetic risk score (GRS) based on 90 previously identified risk variants.

RESULTS:

CRC in a first-degree relative was associated with a 1.71-fold (95% confidence interval 1.47-2.00) increase in CRC risk. A higher risk increase (odds ratio 2.06, 95% confidence interval 1.78-2.39) was estimated for the GRS when it was dichotomized at a cutoff yielding the same positivity rate as FH among controls. Furthermore, the GRS provides substantial additional risk stratification in both people with and especially without FH. Equal or even slightly higher risks were observed for participants without FH with a GRS in the upper 20% compared with participants with FH with a GRS below median. The observed patterns were confirmed in a replication study.

DISCUSSION:

In contrast to common perception, known genetic variants do not primarily reflect some minor share of the familial excess risk of CRC, but rather reflect a substantial share of risk independent of FH.

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