Population-Based Estimates of the Age-Specific Cumulative Risk of Breast Cancer for Pathogenic Variants in CHEK2: Findings from the Australian Breast Cancer Family Registry.

Tú Nguyen-Dumont,Jason A Steen,Melissa C Southey,James G Dowty,Anne-Laure Renault,Ingrid M Winship,John L Hopper,Maryam Mahmoodi,Fleur Hammet,Amanda Rewse,Derrick Theys,Helen Tsimiklis,Roger L Milne,Graham G Giles

doi:10.3390/cancers13061378

Abstract

Simple SummaryIt is well established that women who carry pathogenic CHEK2 variants have about a 3-fold increased risk of developing breast cancer. CHEK2 is now commonly included in genetic tests for breast cancer predisposition and increasingly used to inform the clinical management of women who are identified to carry pathogenic variants. Important information for counselling these women includes knowing how breast cancer risk, due to having a pathogenic variant in CHEK2, changes over a woman’s lifetime. This information is currently not well established. By conducting a population-based case-control-family study of pathogenic CHEK2 variants we aimed to provide this information and estimated the penetrance (age-specific cumulative risk) of breast cancer to be 18% (95% CI 11–30%) to age 60 years and 33% (95% CI 21–48%) to age 80 years. These findings provide new and important information for the clinical management of breast cancer risk for women carrying pathogenic variants in CHEK2.Case-control studies of breast cancer have consistently shown that pathogenic variants in CHEK2 are associated with about a 3-fold increased risk of breast cancer. Information about the recurrent protein-truncating variant CHEK2 c.1100delC dominates this estimate. There have been no formal estimates of age-specific cumulative risk of breast cancer for all CHEK2 pathogenic (including likely pathogenic) variants combined. We conducted a population-based case-control-family study of pathogenic CHEK2 variants (26 families, 1071 relatives) and estimated the age-specific cumulative risk of breast cancer using segregation analysis. The estimated hazard ratio for carriers of pathogenic CHEK2 variants (combined) was 4.9 (95% CI 2.5–9.5) relative to non-carriers. The HR for carriers of the CHEK2 c.1100delC variant was estimated to be 3.5 (95% CI 1.02–11.6) and the HR for carriers of all other CHEK2 variants combined was estimated to be 5.7 (95% CI 2.5–12.9). The age-specific cumulative risk of breast cancer was estimated to be 18% (95% CI 11–30%) and 33% (95% CI 21–48%) to age 60 and 80 years, respectively. These findings provide important information for the clinical management of breast cancer risk for women carrying pathogenic variants in CHEK2.

Highlights

Cell-cycle checkpoint kinase 2 (CHEK2) is an established breast cancer predisposition gene whose protein plays an important role in cell-cycle checkpoint regulation and DNA damage repair [1,2]
Pathogenic CHEK2 Variants Identified in the Australian Breast Cancer Family Registry
In gene panel sequencing for breast cancer predisposition, CHEK2 is consistently found to have a high number of pathogenic variants, usually only surpassed by the number of pathogenic variants identified in BRCA1 and BRCA2 in most settings not involving selection by breast cancer subtype [21,22]

Summary

Introduction

Cell-cycle checkpoint kinase 2 (CHEK2) is an established breast cancer predisposition gene whose protein plays an important role in cell-cycle checkpoint regulation and DNA damage repair [1,2]. CHEK2 c.1100delC is the most common protein-truncating variant in European populations and has been the focus of work that has estimated the magnitude of breast cancer risk associated with CHEK2 pathogenic variants [3,4,5,6]. A meta-analysis of breast cancer risk associated with CHEK2 c.1100delC estimated an odds ratio (OR) of 2.7 (95% CI, 2.1–3.4) for unselected breast cancer cases and OR 4.8 (95% CI, 3.3–7.2) for women with a family history of breast cancer [6]. Schmidt et al used the resources of the Breast Cancer Association Consortium (BCAC) including 44,777 women with breast cancer and 42,997 unaffected women from 33 studies and estimated the odds ratio (OR) for invasive breast cancer as 2.30 (95% Confidence Interval, 1.90–2.69) which was predominantly a risk for estrogen receptor (ER) positive disease OR 2.55 (95% CI, 2.10–3.10) [14]. The estimated cumulative risks for the development of ER-positive disease for carriers of CHEK2 c.1100delC was 20% to age 80 years [14]

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