A predictor based on the somatic genomic changes of the BRCA1/BRCA2 breast cancer tumors identifies the non-BRCA1/BRCA2 tumors with BRCA1 promoter hypermethylation.
The genetic changes underlying in the development and progression of familial breast cancer are poorly understood. To identify a somatic genetic signature of tumor progression for each familial group, BRCA1, BRCA2, and non-BRCA1/BRCA2 (BRCAX) tumors, by high-resolution comparative genomic hybridization, we have analyzed 77 tumors previously characterized for BRCA1 and BRCA2 germ line mutations. Based on a combination of the somatic genetic changes observed at the six most different chromosomal regions and the status of the estrogen receptor, we developed using random forests a molecular classifier, which assigns to a given tumor a probability to belong either to the BRCA1 or to the BRCA2 class. Because 76.5% (26 of 34) of the BRCAX cases were classified with our predictor to the BRCA1 class with a probability of >50%, we analyzed the BRCA1 promoter region for aberrant methylation in all the BRCAX cases. We found that 15 of the 34 BRCAX analyzed tumors had hypermethylation of the BRCA1 gene. When we considered the predictor, we observed that all the cases with this epigenetic event were assigned to the BRCA1 class with a probability of >50%. Interestingly, 84.6% of the cases (11 of 13) assigned to the BRCA1 class with a probability >80% had an aberrant methylation of the BRCA1 promoter. This fact suggests that somatic BRCA1 inactivation could modify the profile of tumor progression in most of the BRCAX cases.
Alvarez
Sara
S
Human Genetics Department, Molecular Pathology Programme, Spanish National Cancer Centre, c/o Melchor Fernandez Almagro, 28029 Madrid, Spain. salvarez@cnio.es
Diaz-Uriarte
Ramon
R
Osorio
Ana
A
Barroso
Alicia
A
Melchor
Lorenzo
L
Paz
Maria Fe
MF
Honrado
Emiliano
E
Rodríguez
Raquel
R
Urioste
Miguel
M
Valle
Laura
L
Díez
Orland
O
Cigudosa
Juan Cruz
JC
Dopazo
Joaquin
J
Esteller
Manel
M
Benitez
Javier
J
D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics; D002887:Chromosomes, Human, Pair 18 / Q000235:genetics; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D019175:DNA Methylation; D005260:Female; D015894:Genome, Human; D006801:Humans; D008297:Male; D009154:Mutation; D009693:Nucleic Acid Hybridization / Q000379:methods; D011401:Promoter Regions, Genetic / Q000235:genetics*
D019313:BRCA1 Protein; D024682:BRCA2 Protein