BRCA1: A Novel Prognostic Factor in Resected Non-Small-Cell Lung Cancer

Abstract

BackgroundAlthough early-stage non-small-cell lung cancer (NSCLC) is considered a potentially curable disease following complete resection, patients have a wide spectrum of survival according to stage (IB, II, IIIA). Within each stage, gene expression profiles can identify patients with a higher risk of recurrence. We hypothesized that altered mRNA expression in nine genes could help to predict disease outcome: excision repair cross-complementing 1 (ERCC1), myeloid zinc finger 1 (MZF1) and Twist1 (which regulate N-cadherin expression), ribonucleotide reductase subunit M1 (RRM1), thioredoxin-1 (TRX1), tyrosyl-DNA phosphodiesterase (Tdp1), nuclear factor of activated T cells (NFAT), BRCA1, and the human homolog of yeast budding uninhibited by benzimidazole (BubR1).Methodology and Principal FindingsWe performed real-time quantitative polymerase chain reaction (RT-QPCR) in frozen lung cancer tissue specimens from 126 chemonaive NSCLC patients who had undergone surgical resection and evaluated the association between gene expression levels and survival. For validation, we used paraffin-embedded specimens from 58 other NSCLC patients. A strong inter-gene correlation was observed between expression levels of all genes except NFAT. A Cox proportional hazards model indicated that along with disease stage, BRCA1 mRNA expression significantly correlated with overall survival (hazard ratio [HR], 1.98 [95% confidence interval (CI), 1.11-6]; P = 0.02). In the independent cohort of 58 patients, BRCA1 mRNA expression also significantly correlated with survival (HR, 2.4 [95%CI, 1.01-5.92]; P = 0.04).ConclusionsOverexpression of BRCA1 mRNA was strongly associated with poor survival in NSCLC patients, and the validation of this finding in an independent data set further strengthened this association. Since BRCA1 mRNA expression has previously been linked to differential sensitivity to cisplatin and antimicrotubule drugs, BRCA1 mRNA expression may provide additional information for customizing adjuvant antimicrotubule-based chemotherapy, especially in stage IB, where the role of adjuvant chemotherapy has not been clearly demonstrated.

In Situ Protein Expression of RRM1, ERCC1, and BRCA1 in Metastatic Breast Cancer Patients Treated with Gemcitabine-Based Chemotherapy

“…ERCC1 values had a 5-fold range, compared to near 100-fold range in NSCLC, with comparable median values in both diseases [14]. Consistent with what has been shown in NSCLC [12,[14][15][16][17][18], RRM1 and ERCC1 levels were significantly correlated. This finding suggests that the coexpression of both DNA repair proteins may be universal to epithelial malignancies.…”

“…In addition, we measured the levels of the excision repair cross-complementation group 1 (ERCC1) protein, given the statistically significant relationship between RRM1 and ERCC1 in NSCLC [12,[14][15][16][17][18]. We also investigated the expression of breast and ovarian cancer susceptibility gene 1 (BRCA1) in view of its emerging role as a marker of sensitivity to chemotherapy in breast cancer [19].…”

The DNA repair proteins BRCA1 and ERCC1 as predictive markers in sporadic ovarian cancer

“…[48][49][50] However, the finding was not confirmed in all studies. 13 Overall, the effect of ERCC1 as a biomarker of prognosis is not yet conclusive in lung cancer and there is comparatively little data available in OC. ERCC1 plays a rate-limiting role in incising DNA on the 5 0 side of a lesion, such as a platinum-induced DNA adduct, and cells without functional ERCC1 do not undergo DNA adduct repair.…”

High Expression of Bcl-2 Protein Predicts Favorable Outcome in Non-small Cell Lung Cancer: Evidence from a Systematic Review and Meta-analysis

“…EGFR) and markers of aggressive characteristics, such as angiogenesis (e.g. VEGF) (Mitsudomi et al, 2000;Mascaux et al, 2005;Bremnes et al, 2006;Rosell et al, 2007;Zheng et al, 2007;Coate et al, 2009;Pirker et al, 2012). Even though these prognostic markers are identified, their effects remain controversial in different cohorts and clinical utilities are rather limited.…”