Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Nov 1;8(11):1598-1606.
doi: 10.1001/jamaoncol.2022.4071.

Differences in Cancer Phenotypes Among Frequent CHEK2 Variants and Implications for Clinical Care-Checking CHEK2

Brittany L Bychkovsky  1   2   3 , Nihat B Agaoglu  1   4 , Carolyn Horton  5 , Jing Zhou  5 , Amal Yussuf  5 , Parichehr Hemyari  5 , Marcy E Richardson  5 , Colin Young  5 , Holly LaDuca  5 , Deborah L McGuinness  6 , Rochelle Scheib  1   2   3 , Judy E Garber  1   2   3 , Huma Q Rana  1   2   3
Affiliations

Differences in Cancer Phenotypes Among Frequent CHEK2 Variants and Implications for Clinical Care-Checking CHEK2

Brittany L Bychkovsky et al. JAMA Oncol. .

Abstract

Importance: Germline CHEK2 pathogenic variants (PVs) are frequently detected by multigene cancer panel testing (MGPT), but our understanding of PVs beyond c.1100del has been limited.

Objective: To compare cancer phenotypes of frequent CHEK2 PVs individually and collectively by variant type.

Design, setting, and participants: This retrospective cohort study was carried out in a single diagnostic testing laboratory from 2012 to 2019. Overall, 3783 participants with CHEK2 PVs identified via MGPT were included. Medical histories of cancer in participants with frequent PVs, negative MGPT (wild type), loss-of-function (LOF), and missense were compared.

Main outcomes and measures: Participants were stratified by CHEK2 PV type. Descriptive statistics were summarized including median (IQR) for continuous variables and proportions for categorical characteristics. Differences in age and proportions were assessed with Wilcoxon rank sum and Fisher exact tests, respectively. Frequencies, odds ratios (ORs), 95% confidence intervals were calculated, and P values were corrected for multiple comparisons where appropriate.

Results: Of the 3783 participants with CHEK2 PVs, 3473 (92%) were female and most reported White race. Breast cancer was less frequent in participants with p.I157T (OR, 0.66; 95% CI, 0.56-0.78; P<.001), p.S428F (OR, 0.59; 95% CI. 0.46-0.76; P<.001), and p.T476M (OR, 0.74; 95% CI, 0.56-0.98; P = .04) PVs compared with other PVs and an association with nonbreast cancers was not found. Following the exclusion of p.I157T, p.S428F, and p.T476M, participants with monoallelic CHEK2 PV had a younger age at first cancer diagnosis (P < .001) and were more likely to have breast (OR, 1.83; 95% CI, 1.66-2.02; P < .001), thyroid (OR, 1.63; 95% CI, 1.26-2.08; P < .001), and kidney cancer (OR, 2.57; 95% CI, 1.75-3.68; P < .001) than the wild-type cohort. Participants with a CHEK2 PV were less likely to have a diagnosis of colorectal cancer (OR, 0.62; 95% CI, 0.51-0.76; P < .001) compared with those in the wild-type cohort. There were no significant differences between frequent CHEK2 PVs and c.1100del and no differences between CHEK2 missense and LOF PVs.

Conclusions and relevance: CHEK2 PVs, with few exceptions (p.I157T, p.S428F, and p.T476M), were associated with similar cancer phenotypes irrespective of variant type. CHEK2 PVs were not associated with colorectal cancer, but were associated with breast, kidney, and thyroid cancers. Compared with other CHEK2 PVs, the frequent p.I157T, p.S428F, and p.T476M alleles have an attenuated association with breast cancer and were not associated with nonbreast cancers. These data may inform the genetic counseling and care of individuals with CHEK2 PVs.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Disclosures: Dr Horton reported personal fees from Ambry Genetics during the conduct of the study. Dr Yussuf reported personal fees from Ambry Genetics during the conduct of the study. Dr Richardson reported personal fees from Ambry Genetics as a full-time salaried employee during the conduct of the study. Dr Young reported being a salaried employee of Ambry Genetics. Dr LaDuca reported personal fees from Ambry Genetics for employment during the conduct of the study. Dr Garber reported genetic testing of specimens at Invitae Laboratories from a project outside the submitted work. Dr Rana reported nonfinancial support from Ambry Genetics for collaboration and research support outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Strengthening the Reporting of Observational Studies in Epidemiology Diagram
LOF indicates loss of function; MGPT, multigene cancer panel testing; PV, pathogenic or likely pathogenic variant.
Figure 2.
Figure 2.. Breast Cancer Prevalence by CHEK2 Variant
ap.I157F, p.S428F, and p.T476M were not included in other PVs. OR indicates odds ratio; PV, pathogenic or likely pathogenic variant.
Figure 3.
Figure 3.. Box Plot of Any Cancer and Breast Cancer by CHEK2 Pathogenic Variant Type and Age at Diagnosis
Only affected participants are included. For example, of the 21 participants with biallelic CHEK2 PVs, 20 were known to have cancer. PV indicates pathogenic or likely pathogenic variant; y, years. aStatistically significant findings.
See this image and copyright information in PMC

References

    1. Lukas C, Bartkova J, Latella L, et al. . DNA damage-activated kinase Chk2 is independent of proliferation or differentiation yet correlates with tissue biology. Cancer Res. 2001;61(13):4990-4993. - PubMed
    1. Hirao A, Kong YY, Matsuoka S, et al. . DNA damage-induced activation of p53 by the checkpoint kinase Chk2. Science. 2000;287(5459):1824-1827. doi:10.1126/science.287.5459.1824 - DOI - PubMed
    1. Bartek J, Falck J, Lukas J. CHK2 kinase—a busy messenger. Nat Rev Mol Cell Biol. 2001;2(12):877-886. doi:10.1038/35103059 - DOI - PubMed
    1. Cai Z, Chehab NH, Pavletich NP. Structure and activation mechanism of the CHK2 DNA damage checkpoint kinase. Mol Cell. 2009;35(6):818-829. doi:10.1016/j.molcel.2009.09.007 - DOI - PubMed
    1. Bell DW, Varley JM, Szydlo TE, et al. . Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome. Science. 1999;286(5449):2528-2531. doi:10.1126/science.286.5449.2528 - DOI - PubMed