CHEK2*1100delC Heterozygosity in Women With Breast Cancer Associated With Early Death, Breast Cancer–Specific Death, and Increased Risk of a Second Breast Cancer

Abstract

A B S T R A C T PurposeWe tested the hypotheses that CHEK2*1100delC heterozygosity is associated with increased risk of early death, breast cancer-specific death, and risk of a second breast cancer in women with a first breast cancer. Patients and MethodsFrom 22 studies participating in the Breast Cancer Association Consortium, 25,571 white women with invasive breast cancer were genotyped for CHEK2*1100delC and observed for up to 20 years (median, 6.6 years). We examined risk of early death and breast cancer-specific death by estrogen receptor status and risk of a second breast cancer after a first breast cancer in prospective studies.Results CHEK2*1100delC heterozygosity was found in 459 patients (1.8%). In women with estrogen receptor-positive breast cancer, multifactorially adjusted hazard ratios for heterozygotes versus noncarriers were 1.43 (95% CI, 1.12 to 1.82; log-rank P ϭ .004) for early death and 1.63 (95% CI, 1.24 to 2.15; log-rank P Ͻ .001) for breast cancer-specific death. In all women, hazard ratio for a second breast cancer was 2.77 (95% CI, 2.00 to 3.83; log-rank P Ͻ .001) increasing to 3.52 (95% CI, 2.35 to 5.27; log-rank P Ͻ .001) in women with estrogen receptor-positive first breast cancer only. ConclusionAmong women with estrogen receptor-positive breast cancer, CHEK2*1100delC heterozygosity was associated with a 1.4-fold risk of early death, a 1.6-fold risk of breast cancer-specific death, and a 3.5-fold risk of a second breast cancer. This is one of the few examples of a genetic factor that influences long-term prognosis being documented in an extensive series of women with breast cancer.

Clinical and genetic characterization of hereditary breast cancer in a Chinese population

“…For example, women with inherited causative variant in the Fanconi anemia genes BRIP1 and PALB2 have a 20-50% lifetime risk of breast cancer [8,9]. Multiple studies have also demonstrated that genes such as ATM [10][11][12] and CHEK2 [13][14][15][16] are associated with increased breast cancer risk. In addition, inherited causative variants in TP53, PTEN, STK11, and CDH1 are associated with a moderate to very high-risk of developing breast cancer [17][18][19][20].…”

Association of CHEK2 polymorphisms with the efficacy of platinum-based chemotherapy for advanced non-small-cell lung cancer in Chinese never-smoking women

“…A DNA damage checkpoint can detect the DNA damage in the cell cycle and lead to cell cycle arrest to provide enough time to repair the damage (35). Many studies have reported that CHEK2 gene mutations could increase the risk of some cancers (20,22,27,(36)(37)(38). Many investigators have researched this area with special emphasis on CHEK2 1100delC.…”

“…DNA damage can cause CHEK2 phosphorylation (15), activated CHEK2 can lead to phosphorylation of the CDC25 family, BRCA1, p53, and other similar functional effectors in order to start the cell cycle checkpoint regulation (15)(16)(17). Results from previous studies have shown a relationship between the CHEK2 mutation and an increased risk for lung cancer (18,19), breast cancer (20,21), prostate cancer (22,23), colorectal cancer (24,25) and other cancers (26,27). In addition, there was a relationship between the decreased risk of endometrial cancer and the rs8135424 CHEK2 SNP (28).…”

Contralateral Prophylactic Mastectomy: Current Perspectives

“…Good candidates for CPM would be BRCA mutation carriers because of their high risk of CBC and possibly CHEK2 1100delC. 52,53 Other good candidates would be patients with family histories that are highly suspicious for a hereditary component, and those who have undergone mantle cell radiation. Patients who …”

“…[49][50][51] CBC risk for other gene mutation carriers who have breast cancer is not well studied with the exception of (CHEK2) 1100delC mutation carriers. 52,53 A SEER study showed that women ,50 years old with estrogen receptor (ER)-negative tumors had better breast cancer specific survival then older patients with ER positive tumors presumably because some of these patients could have been BRCA mutation carriers. 34 However, other studies have not shown survival benefit for ER-negative patients.…”