High risk of breast cancer in women with biallelic pathogenic variants in CHEK2

Abstract

Purpose Compared 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. Methods CHEK2 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). Results Breast 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). Conclusions These 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.

CHEK2 Pathogenic Variants in Greek Breast Cancer Patients: Evidence for Strong Associations with Estrogen Receptor Positivity, Overuse of Risk-Reducing Procedures and Population Founder Effects

“…We also observed an association with ductal carcinoma diagnosis, which has been also demonstrated by other researchers [ 20 ], along with an increased rate, i.e., 19.2%, of contralateral breast cancer diagnoses. This is in concordance with other reports, where rates have been reported to range between 9.4–21% [ 26 , 27 , 28 ]. Furthermore, in our series, hormone therapy and/or mastectomy at primary diagnoses seem to have a positive effect on survival of CHEK2 carriers.…”

CHEK2 Germline Variants in Cancer Predisposition: Stalemate Rather than Checkmate

“…The same is true also for somatic mutations in these two kinases. Individuals carrying bi-allelic CHEK2 mutations have a normal phenotype; however, they carry an increased cancer risk in comparison with heterozygotes and noncarriers [ 103 , 104 ]. However, the cell-type specific demand for CHK2 activation in human tissues is largely unknown.…”

“…The most frequent ones were c.1100delC and p.I157T homozygotes, of whom 66% and 60% were diagnosed with BC, respectively. Rainville summarized data from 31 biallelic mutation carriers identified among 6473 monoallelic CHEK2 mutation carriers tested by Myriad Genetics, of whom 16/31 were c.1100delC mutation carriers [ 104 ]. Compared with monoallelic carriers, biallelic carriers developed breast cancer more frequently (81% vs. 41%; p < 0.0001) and more likely before the age of 50 (61% vs. 24%; p < 0.0001), they developed secondary breast cancer with a higher frequency (23% vs. 8%; p = 0.01), and finally they had a higher risk of developing any primary cancer and multiple primary cancer.…”

“…Compared with monoallelic carriers, biallelic carriers developed breast cancer more frequently (81% vs. 41%; p < 0.0001) and more likely before the age of 50 (61% vs. 24%; p < 0.0001), they developed secondary breast cancer with a higher frequency (23% vs. 8%; p = 0.01), and finally they had a higher risk of developing any primary cancer and multiple primary cancer. The ORs for the development of ductal carcinoma in situ (DCIS) and ductal carcinoma were high (OR 8.7, 95% CI 3.7–20.5 and OR 5.0, 95% CI 2.0–12.4, respectively) [ 104 ]. Case reports of homozygous carriers, which included other CHEK2 mutations, have been published episodically [ 103 , 198 , 199 ], and they indicate an increased risk of the development of variable primary cancers with an early age at onset.…”

Germline Pathogenic Variants in the Ataxia Telangiectasia Mutated (ATM) Gene are Associated with High and Moderate Risks for Multiple Cancers

“…These calculations have been described in detail previously [7,31]. Briefly, age-specific incidence rates were estimated as products of ORs and general population incidences; ORs for PVs were calculated as specified above and were combined with age-specific SEER incidence rates from 2009 to 2013 in 5-year intervals to estimate absolute cancer risks [7,32,33].…”