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Genetic modifiers of CHEK2*1100delC-associated breast cancer risk.

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Greco, Dario 
Aittomäki, Kristiina 

Abstract

PURPOSE: CHEK21100delC is a founder variant in European populations that confers a two- to threefold increased risk of breast cancer (BC). Epidemiologic and family studies have suggested that the risk associated with CHEK21100delC is modified by other genetic factors in a multiplicative fashion. We have investigated this empirically using data from the Breast Cancer Association Consortium (BCAC). METHODS: Using genotype data from 39,139 (624 1100delC carriers) BC patients and 40,063 (224) healthy controls from 32 BCAC studies, we analyzed the combined risk effects of CHEK21100delC and 77 common variants in terms of a polygenic risk score (PRS) and pairwise interaction. RESULTS: The PRS conferred odds ratios (OR) of 1.59 (95% CI: 1.21-2.09) per standard deviation for BC for CHEK21100delC carriers and 1.58 (1.55-1.62) for noncarriers. No evidence of deviation from the multiplicative model was found. The OR for the highest quintile of the PRS was 2.03 (0.86-4.78) for CHEK21100delC carriers, placing them in the high risk category according to UK NICE guidelines. The OR for the lowest quintile was 0.52 (0.16-1.74), indicating a lifetime risk close to the population average. CONCLUSION: Our results confirm the multiplicative nature of risk effects conferred by CHEK21100delC and the common susceptibility variants. Furthermore, the PRS could identify carriers at a high lifetime risk for clinical actions.Genet Med advance online publication 06 October 2016.

Description

Keywords

Breast Neoplasms, Checkpoint Kinase 2, Female, Genes, Modifier, Genetic Predisposition to Disease, Humans, Odds Ratio, Penetrance, Sequence Deletion

Journal Title

Genet Med

Conference Name

Journal ISSN

1098-3600
1530-0366

Volume Title

19

Publisher

Elsevier BV
Sponsorship
Cancer Research Uk (None)
National Cancer Institute (R01CA128978)
Cancer Research Uk (None)
National Cancer Institute (U19CA148537)
National Cancer Institute (U19CA148065)
European Commission (223175)
Cancer Research UK (12014)
Cancer Research UK (10118)
Cancer Research Uk (None)
UK funders include Cancer Research UK, Breakthrough Breast Cancer and NIHR. See article for full list of funders.