Methylation of O6-methylguanine-DNA methyltransferase (MGMT) promoter gene in triple-negative breast cancer patients.
Triple-negative breast cancers are characterized by the triple-negative (ER/PgR/Her2 negative) phenotype, are frequently associated with BRCA gene mutation, and are not candidate to currently available endocrine and HER2-targeted treatments. MGMT is involved in direct DNA repair exerted by cleavage of mutagenic alkyl adducts within DNA, and its epigenetic silencing confers susceptibility to DNA-damaging alkylating agents in glioblastomas and melanomas. MGMT methylation status has not been extensively investigated in breast cancer patients. The goal of our study was to evaluate the MGMT methylation status in TNBC patients, for most of which BRCA1 and BRCA2 mutational status was known. We evaluated MGMT methylation status by methylation-specific PCR (MSP) in formalin-fixed and paraffin-embedded tumor specimens from 92 TNBC patients. By using the GelDoc system (Biorad) software, the cases were further classified as follows: 0 (absence of methylated signal), 1 (prevalence of unmethylated signal, U/M ratio>1), 2 (prevalence of methylated signal, U/M ratio<1), and 3 (absence of unmethylated signal). MSP products were obtained in 89 (96.7%) of the cases. Overall, 15 (16.9%) cases were classified as 0, 33 (37.1%) cases as 1, 39 (43.8%) cases as 2, and 2 (2.2%) cases as 3. The 48 cases classified as 0 and 1 were considered as MGMT unmethylated, and the 41 cases classified as 2 and 3 as MGMT methylated. The prevalence of MGMT methylation in patients with BRCA1 mutated, wild-type, and unknown was 30.2% (13/43), 63.6% (14/22), and 58.3% (14/24), respectively. MGMT methylation was unrelated to the main clinical pathological characteristics, with the exception of a weak association with advanced age. In conclusion, our data suggest that in TNBC with wild-type BRCA1, the direct DNA repair system may be frequently (63.6%) silenced by MGMT methylation. The evaluation of the MGMT status could offer a new adjunct in predicting tumor response to alkylating drugs in TNBC patients.
Division of Pathology, European Institute of Oncology, Via Ripamonti 435, 20141, Milan, Italy.
Caterina
C
Fumagalli
Giancarlo
G
Pruneri
Paola
P
Possanzini
Michela
M
Manzotti
Monica
M
Barile
Irene
I
Feroce
Marco
M
Colleoni
Bernardo
B
Bonanni
Patrick
P
Maisonneuve
Paolo
P
Radice
Giuseppe
G
Viale
Massimo
M
Barberis
D000328:Adult; D000368:Aged; D019313:BRCA1 Protein / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics*; D004252:DNA Mutational Analysis; D045643:DNA Repair Enzymes / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D012189:Retrospective Studies; D025521:Tumor Suppressor Proteins / Q000235:genetics*
D019313:BRCA1 Protein; D015254:DNA Modification Methylases; D045643:DNA Repair Enzymes; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D025521:Tumor Suppressor Proteins; C492913:BRCA1 protein, human; C515491:MGMT protein, human; C508053:ERBB2 protein, human