Risk for contralateral breast cancer among carriers of the CHEK2*1100delC mutation in the WECARE Study

Abstract

The protein encoded by the CHEK2 gene is involved in cellular repair of DNA damage. The truncating mutation, CHEK2*1100delC, seems to increase the risk for breast cancer. We investigated whether the CHEK2*1100delC mutation carrier status increases the risk for asynchronous contralateral breast cancer (CBC) and whether it interacts with radiation therapy (RT) or chemotherapy in regard to CBC risk. The germline mutation frequency was assessed in 708 women with CBC and 1395 women with unilateral breast cancer (UBC) in the Women's Environment, Cancer and Radiation Epidemiology (WECARE) Study whose first primary breast cancer was diagnosed before age 55 years and during 1985 -1999. Seven women with CBC (1.0%) and 10 women with UBC (0.7%) were CHEK2*1100delC variant carriers (rate ratio (RR) ¼ 1.8, 95% confidence interval (CI) ¼ 0.6 -5.4 for CBC vs UBC). Carriers who received RT for their first breast cancer, compared with non-carriers not treated with RT, had an RR of developing CBC of 2.6 (95% CI ¼ 0.8 -8.7). We found no significant associations between the CHEK2*1100delC mutation and CBC overall or among those treated with RT. However, the sampling variability was such that modest increases in risk could not be excluded. Nonetheless, because this is a rare mutation, it is unlikely to explain a major fraction of CBC in the population.

CHEK2*1100delC homozygosity in the Netherlands—prevalence and risk of breast and lung cancer

“…5,[13][14][15][16][17][18][19] For homozygous carriers, our observations indicate that (contralateral) breast cancer risk may be as high as to justify preventive mastectomy (or at least intensified screening), but longitudinal studies on more cases are needed to arrive at more accurate risk estimates.…”

“…One study has reported an increased contralateral breast cancer risk when heterozygous patients had received radiotherapy as part of the treatment for their first breast tumor; another reported a similar but not statistically significant tendency. 15,19 Genotyping of larger cohorts is needed to better understand the effect of different treatments on breast cancer patients carrying the 1100delC allele. In the future, this can lead to personalized treatment strategies for 1100delC heterozygous and homozygous patients.…”

“…3,[10][11][12][13] Breast cancer patients heterozygous for 1100delC also have an increased risk of developing contralateral breast cancer when compared with wild-type breast cancer patients. 5,[13][14][15][16][17][18][19][20] The contralateral breast cancer risk may be even higher when radiotherapy has been given to treat the first tumor. 15,19 It must be noted that in women who also carry a pathogenic BRCA1/2 mutation the 1100delC allele does not seem to modify breast cancer risk.…”

“…5,[13][14][15][16][17][18][19][20] The contralateral breast cancer risk may be even higher when radiotherapy has been given to treat the first tumor. 15,19 It must be noted that in women who also carry a pathogenic BRCA1/2 mutation the 1100delC allele does not seem to modify breast cancer risk. 3,14,21 An association of the 1100delC allele with increased colon cancer and prostate cancer risk has been described, while an association with melanoma could not be found.…”

Association of Common Genetic Variants With Contralateral Breast Cancer Risk in the WECARE Study

“…The risk is particularly high in women with rare high-penetrance sequence variants, such as mutations in BRCA1 or BRCA2, where the 10-year risk may approach 25% to 30% (4,5). Mutations in CHEK2 also increase the risk of CBC, albeit to a lesser degree (6,7), and rare pathogenic PALB2 mutations have also been shown to increase the risk of CBC (8,9). In some family studies and within subgroups of breast cancer patients, rare mutations in the ATM gene have also been shown to increase the risk of CBC (10,11).…”