BRCA1 promoter methylation status in 1031 primary breast cancers predicts favorable outcomes following chemotherapy
Menée à partir du pyroséquençage de l'ADN d'échantillons tumoraux prélevés sur 1 031 patientes atteintes d'un cancer primitif du sein, cette étude met en évidence une association entre le statut de méthylation du promoteur du gène BRCA1 et la survie des patientes après une chimiothérapie par cyclophosphamide, méthotrexate et fluorouracile
Background : BRCA1 is known to be inactivated in breast tumors by CpG promoter methylation. Tumor cells in patients carrying a germline mutation in BRCA1 are sensitive to cytotoxic drugs that cause DNA double strand breaks. However, very little is known on whether patients with BRCA1 promoter methylated tumors are similarly sensitive to cytotoxic drugs. In this study, we address this by making use of extensive follow-up data on patients treated with CMF (cyclophosphamide, methotrexate, fluorouracil) in Iceland between 1976 and 2007.
Methods : We analyzed BRCA1 promoter methylation by pyrosequencing DNA from tumor samples from 1031 patients with primary breast cancer. Of those, 965 were sporadic cases, 61 were BRCA2 and 5 were BRCA1 germline mutation carriers. All cases were examined with respect to clinicopathological parameters and breast cancer-specific survival in patients treated with cytotoxic drugs. Information on chemotherapy treatment in non-carriers was available for 26 BRCA1 methylated tumors and 857 unmethylated tumors.
Results : BRCA1 was promoter methylated in 29 sporadic tumors or in 3.0% of cases (29 of 965) whereas none of the tumors derived from BRCA germline mutation carriers were promoter methylated. Importantly, patients with BRCA1 promoter methylation receiving chemotherapeutic drug treatment show highly improved breast cancer specific survival compared with unmethylated controls (HR = 0.10, 95% CI 0.01-0.75; P = 0.02).
Conclusions : BRCA1 promoter methylation is predictive of improved disease outcome in patients receiving CMF drug treatment. Our results support the use of markers indicative of BRCAness in sporadic breast cancers to identify patients that are likely to benefit from the use of DNA damaging agents.
JNCI Cancer Spectrum , article en libre accès, 2018