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BRCA1 alterations with additional defects in DNA damage response genes may confer chemoresistance to BRCA‐like breast cancers treated with neoadjuvant chemotherapy
Author(s) -
Takada Mamoru,
Nagai Shigenori,
Haruta Masayuki,
Sugino Ryuichi P.,
Tozuka Katsunori,
Takei Hiroyuki,
Ohkubo Fumie,
Inoue Kenichi,
Kurosumi Masafumi,
Miyazaki Masaru,
SatoOtsubo Aiko,
Sato Yusuke,
Ogawa Seishi,
Kaneko Yasuhiko
Publication year - 2017
Publication title -
genes, chromosomes and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.754
H-Index - 119
eISSN - 1098-2264
pISSN - 1045-2257
DOI - 10.1002/gcc.22445
Subject(s) - cancer research , breast cancer , palb2 , anthracycline , fanca , ercc1 , dna damage , biology , cancer , phenotype , dna repair , brca mutation , chemotherapy , medicine , oncology , mutation , germline mutation , gene , genetics , dna , fanconi anemia , nucleotide excision repair
The BRCA‐like phenotype is a feature that some sporadic breast cancers share with those occurring in BRCA1 or BRCA2 mutation carriers. As tumors with the phenotype have defects in the DNA damage response pathway, which may increase sensitivity to drugs such as DNA cross‐linking agents and PARP inhibitors, a method to identify this phenotype is important. The prediction of chemoresistance, which frequently develops in these tumors, is also crucial for improving therapy. We examined genomic aberrations and BRCA1 promoter methylation in tumors of 73 breast cancer (20 HR−/HER2− and 53 HR+/HER2−) patients, who received neoadjuvant chemotherapy with anthracycline, cyclophosphamide, and taxane, using SNP array CGH and quantitative PCR. The methylation and/or loss or uniparental disomy (UPD) of BRCA1 ( BRCA1 alterations) and the loss or UPD of BRCA2 ( BRCA2 alterations) were detected in 27 (37%) and 21 (29%), respectively, of the 73 tumors. Tumors with BRCA1 or BRCA2 alterations were associated with a higher number of genomic aberrations ( P < 0.001 and P < 0.001) and higher percentage of TP53 alterations ( P < 0.001 and P < 0.001) than those without. Overall survival (OS) rates were similar between patients with or without BRCA1 or BRCA2 alterations. However, when 27 patients with BRCA1 ‐altered tumors were classified into those with or without the loss or UPD of PALB2 , PAGR1 , RAD51B , FANCM , MLL4 , or ERCC1/2 in tumors, patients with additional defects in DNA damage response genes had worse OS ( P = 0.037, 0.045, 0.038, 0.044, 0.041, or 0.019) than those without. These defects may confer chemoresistance and predict poor outcomes in patients with BRCA1 ‐altered breast cancer.