Abstract
PurposeCompared to breast cancer risk genes such as BRCA2, ATM, PALB2, and NBN, no defined phenotype is currently associated with biallelic pathogenic variants (PVs) in CHEK2. This study compared the prevalence of breast and other cancers in women with monoallelic and biallelic CHEK2 PVs.MethodsCHEK2 PV carriers were identified through commercial hereditary cancer panel testing (09/2013–07/2019). We compared cancer histories of 6473 monoallelic carriers to 31 biallelic carriers. Breast cancer risks were estimated using multivariate logistic regression and are reported as odds ratios (OR) with 95% confidence intervals (CI).ResultsBreast cancer frequency was higher among biallelic CHEK2 PV carriers (80.6%, 25/31) than monoallelic carriers (41.2%, 2668/6473; p < 0.0001). Biallelic carriers were more likely to be diagnosed at or before age 50 (61.3%, 19/31) and to have a second breast cancer diagnosis (22.6%, 7/31) compared to monoallelic carriers (23.9%, 1548/6473; p < 0.0001 and 8.1%, 523/6473; p = 0.0107, respectively). Proportionally more biallelic carriers also had any cancer diagnosis and > 1 primary diagnosis. Compared to women with no PVs, biallelic PV carriers had a higher risk of developing ductal invasive breast cancer (OR 8.69, 95% CI 3.69–20.47) and ductal carcinoma in situ (OR 4.98, 95% CI 2.00–12.35) than monoallelic carriers (OR 2.02, 95% CI 1.90–2.15 and OR 1.82, 95% CI 1.66–2.00, respectively).ConclusionsThese data suggest that biallelic CHEK2 PV carriers have a higher risk for breast cancer, are more likely to be diagnosed younger, and to have multiple primary breast cancers compared to monoallelic carriers. Biallelic carriers also appear to have a higher risk of cancer overall. Therefore, more aggressive management may be appropriate for women with biallelic PVs in CHEK2 compared with current recommendations for monoallelic carriers.
Highlights
CHEK2 is considered a moderate risk breast cancer gene, with estimates of the relative risk for women carrying a single pathogenic variant (PV) ranging from 2.0 to 4.8 for a first breast cancer
Of those 42 biallelic CHEK2 PV carriers, phase was confirmed to be in trans for 31 cases, 16 of which were homozygous for CHEK2 c.1100del
A Confirmed in trans b Only includes patients with a cancer diagnosis (28 biallelic PV carriers, 3239 monoallelic PV carriers) c Only includes patients with a breast cancer diagnosis (25 biallelic PV carriers, 2668 monoallelic PV carriers) d Other includes Native American, Pacific Islander, and all other ancestries e Rows are not exclusive; patients could have a personal history of multiple cancers were diagnosed with breast and other cancers at younger ages than monoallelic carriers
Summary
CHEK2 is considered a moderate risk breast cancer gene, with estimates of the relative risk for women carrying a single pathogenic variant (PV) ranging from 2.0 to 4.8 for a first breast cancer. The risk for a second primary breast cancer following an initial diagnosis is estimated to be increased 2.8- to 3.5-fold over individuals with breast cancer without pathogenic variants (PVs) in breast cancer risk genes [1–4]. An increased risk of colorectal cancer has been reported for CHEK2 PV carriers, the evidence for this association is not well established [5–7]. Despite known and possible cancer associations for CHEK2 PV carriers, phenotypic differences between monoallelic and biallelic carriers are not yet understood. Biallelic carriers of PVs in other, dominant breast cancer susceptibility genes such as BRCA2, ATM, PALB2, and NBN are known to have more severe cancer phenotypes than monoallelic carriers [11–13]. Similar patterns for CHEK2 PV carriers have yet to be adequately established
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