DNA repair gene patterns as prognostic and predictive factors in molecular breast cancer subtypes.
DNA repair pathways can enable tumor cells to survive DNA damage induced by chemotherapy and thus provide prognostic and/or predictive value. We evaluated Affymetrix gene expression profiles for 145 DNA repair genes in untreated breast cancer (BC) patients (n = 684) and BC patients treated with regimens containing neoadjuvant taxane/anthracycline (n = 294) or anthracycline (n = 210). We independently assessed estrogen receptor (ER)-positive/HER2-negative, HER2-positive, and ER-negative/HER2-negative subgroups for differential expression, bimodal distribution, and the prognostic and predictive value of DNA repair gene expression. Twenty-two genes were consistently overexpressed in ER-negative tumors, and five genes were overexpressed in ER-positive tumors, but no differences in expression were associated with HER2 status. In ER-positive/HER2-negative tumors, the expression of nine genes (BUB1, FANCI, MNAT1, PARP2, PCNA, POLQ, RPA3, TOP2A, and UBE2V2) was associated with poor prognosis, and the expression of one gene (ATM) was associated with good prognosis. Furthermore, the prognostic value of specific genes did not correlate with proliferation. A few genes were associated with chemotherapy response in BC subtypes and treatment-specific manner. In ER-negative/HER2-negative tumors, the MSH2, MSH6, and FAN1 (previously MTMR15) genes were associated with pathological complete response and residual invasive cancer in taxane/anthracycline-treated patients. Conversely, PMS2 expression was associated with residual invasive cancer in treatments using anthracycline as a single agent. In HER2-positive tumors, TOP2A was associated with patient response to anthracyclines but not to taxane/anthracycline regimens. In genes expressed in a bimodal fashion, RECQL4 was significantly associated with clinical outcome. In vitro studies showed that defects in RECQL4 impair homologous recombination, sensitizing BC cells to DNA-damaging agents.
Translational Research Unit, Department of Oncology, Istituto Toscano Tumori, Prato, Italy;
Libero
L
Santarpia
Takayuki
T
Iwamoto
Angelo
A
Di Leo
Naoki
N
Hayashi
Giulia
G
Bottai
Martha
M
Stampfer
Fabrice
F
André
Nicholas C
NC
Turner
W Fraser
WF
Symmans
Gabriel N
GN
Hortobágyi
Lajos
L
Pusztai
Giampaolo
G
Bianchini
D000328:Adult; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D004260:DNA Repair / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D059765:Homologous Recombination / Q000235:genetics; D006801:Humans; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000145:classification / Q000235:genetics*; D011379:Prognosis; D053484:RecQ Helicases / Q000096:biosynthesis / Q000235:genetics*; D059467:Transcriptome
D009363:Neoplasm Proteins; C506731:RECQL4 protein, human; D053484:RecQ Helicases
Breast cancer subtypes; DNA damaging agents; DNA repair pathways; Neoadjuvant therapies; Predictive factors