Abstract
Genes involved in DNA repair and replication have been recently investigated as predictive markers of response to chemotherapy in non-small cell lung cancer (NSCLC). However, few data on the expression of these genes in tumor compared with corresponding normal lung are available. The aim of this study was to evaluate differential mRNA levels of 22 DNA repair genes of five different DNA repair pathways: direct, base excision, nucleotide excision (NER), double-strand break (DSBR), and postreplicative repair. In addition, six genes involved in DNA replication (REP) and three telomere maintenance genes were investigated. Total RNAs extracted from fresh-frozen tumors and corresponding normal tissues of 50 consecutive chemo-naïve resected NSCLC patients were analyzed. Transcript levels were quantified by real-time PCR. A significant overexpression was detected in 20 of 30 (67%) genes, mostly belonging to DSBR pathways, whereas others (XPA, XPC, and UBE2N; 10%) were significantly underexpressed. For 7 of 30 (23%) genes, mostly belonging to NER pathway, no significant difference between paired tumor and normal samples was observed. Transcript overexpression of DSBR and REP genes was significantly higher in poorly differentiated carcinomas and DSBR levels were higher in men compared with women. The transcriptional overexpression of four genes (XRCC5, TOP3B, TYMS, and UNG) showed significant correlation with a shorter patients' outcome at the univariate, whereas only stage of disease appeared as an independent factor affecting prognosis, as assessed by multivariate analysis. In conclusion, genes belonging to DNA repair/replication pathways are overexpressed in NSCLC and are associated with a more aggressive phenotype.
Highlights
The high incidence of genomic instability in lung cancers is wellestablished and in some cases it has been associated with poor prognosis [1,2,3]
Many of the cytotoxic agents used in the systemic treatment of non–small cell lung cancer (NSCLC) are interfering with DNA activity and the possibility of individualizing DNA repair profiles is becoming a central issue in the search for improved chemotherapy results
Most of the molecular markers currently used to predict the responsiveness to chemotherapeutic treatment are genes involved in DNA damage response such as p53 [7], BRCA1 [8], ERCC1 [9], MLH1 and MSH2 [10], Rad51 [11], ERCC2, XRCC1, XPA [12], XPC, or involved in DNA replication such as RRM1 [13] and TYMS [14]
Summary
The high incidence of genomic instability in lung cancers is wellestablished and in some cases it has been associated with poor prognosis [1,2,3]. No exhaustive data on the differential expression of these DNA repair/ DNA replication genes in lung tumor versus corresponding normal tissue are currently available. The aim of the present study was to evaluate, in 50 tumor and paired normal lung tissues, the differential transcript expression of the following 22 human DNA repair genes belonging to five DNA repair pathways: MGMT in direct repair; OGG1, UNG, and XRCC1 in base excision repair (BER); XPA, XPC, ERCC1, ERCC2, ERCC4, ERCC5, ERCC6, and XAB2 in nucleotide excision repair (NER); XRCC2, XRCC3, XRCC4, XRCC5, BRCA1, BRCA2, and UBE2V2 in double-strand break repair (DSBR); and UBE2A, UBE2B, and UBE2N in postreplicative repair (PRR). Nine genes involved in DNA replication (REP; TYMS, RRM2B, RRM2, RRM1, TOP3A, and TOP3B) and in telomere maintenance (TERT, TERF1, and TERF2) were investigated (see Supplementary Data Table S1)
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