XPG mRNA Expression Levels Modulate Prognosis in Resected Non-small-cell Lung Cancer in Conjunction With BRCA1 and ERCC1 Expression

Roberta Bartolucci; Jia Wei; Jose Javier Sanchez; Laia Perez-Roca; Imane Chaib; Francesco Puma; Raffaele Farabi; Pedro Mendez; Fausto Roila; Tatsuro Okamoto; Miquel Taron; Rafael Rosell

Disclosures

Clin Lung Cancer. 2009;10(1):47-52. 

In This Article

Abstract and Introduction

Abstract

Background: Molecular markers can help identify patients with early-stage non-small-cell lung cancer (NSCLC) with a high risk of relapse. Excision repair cross-complementing 1 (ERCC1), Xeroderma pigmentosum group G (XPG), and breast cancer 1 (BRCA1) are involved in DNA damage repair, whereas ribonucleotide reductase M1 (RRM1) is implicated in DNA synthesis. Expression levels of these molecules might therefore have a prognostic role in lung cancer.
Patients and Methods: We examined ERCC1, RRM1, XPG, and BRCA1 mRNA levels by real-time quantitative polymerase chain reaction in 54 patients with stage IB-IIB resected NSCLC. A strong correlation was observed between the 4 genes.
Results: For patients with low BRCA1, regardless of XPG mRNA expression levels, disease-free survival (DFS) was not reached. For patients with intermediate/high BRCA1 and high XPG, DFS was 50.7 months. However, for patients with intermediate/high BRCA1 and low/intermediate XPG, DFS decreased to 16.3 months (P = .002). Similar differences were observed in overall survival, with median survival not reached for patients with low BRCA1, regardless of XPG levels, or for patients with intermediate/high BRCA1 and high XPG. Conversely, for patients with intermediate/high BRCA1 levels and low/intermediate XPG levels, median survival dropped to 25.5 months (P = .007).
Conclusion: BRCA1 and XPG were identified as independent prognostic factors for both median survival and DFS. High BRCA1 mRNA expression confers poor prognosis in early NSCLC, and the combination of high BRCA1 and low XPG expression still further increases the risk of shorter survival. These findings can help optimize the customization of adjuvant chemotherapy.

Introduction

Lung cancer is the most common cause of cancer-related death worldwide. Non-small-cell lung cancer (NSCLC) represents approximately 80% of lung cancer and has a 5-year survival rate of only 16%.[1] Patients with early-stage disease are treated primarily by surgical resection with curative intent. However, 30%-70% of these patients develop recurrence and die from their disease, indicating that a subgroup of these patients might benefit from adjuvant chemotherapy. A recent meta-analysis of adjuvant cisplatin-based chemotherapy in NSCLC from 5 trials with a total of 4584 patients found an absolute 5-year survival benefit for chemotherapy of 5.4%.[2] This poor outcome indicates the need to identify genetic markers that will help to improve survival in patients with completely resected stage IB-IIIA disease.

Currently, tumor stage remains the most accurate prognostic factor for survival in patients with NSCLC.[3] Only recently have molecular markers become integrated into decisions about the treatment of patients with lung cancer, largely based on mutations in the epidermal growth factor receptor and their predictive role in gefitinib or erlotinib response.[4]

Several microarray studies have identified gene signatures that could classify patients with significantly different prognoses.[5] However, because of the questionable reproducibility and requirement for fresh tissue, the use of microarrays in clinical practice is quite limited. Recently, we have reported models based on 3-[6] and 4-[7]gene expression signatures that can identify patients with early-resected NSCLC with a high risk of relapse.

A growing body of evidence shows that DNA repair genes can be both predictive and prognostic markers.[8,9] DNA repair can act as the 2 faces of Janus because overactive nucleotide excision repair (NER) and DNA replication systems might yield clinically relevant clues regarding both favorable prognosis and drug resistance. By preventing mutagenesis, DNA repair might not only prevent cancer but also retard molecular events related to progression in established tumors. ERCC1 (excision repair cross-complementing 1) and XPG (Xeroderma pigmentosum group G) are key genes in NER, which is a highly versatile pathway for DNA damage removal.[10] Breast cancer 1 (BRCA1) is implicated in NER, doublestrand break repair, and mismatch repair, indicating its crucial role in DNA repair.[11] Ribonucleotide reductase M1 (RRM1) is a key enzyme involved in DNA synthesis, catalyzing the biosynthesis of deoxyribonucleotides from the corresponding ribonucleotides, and involved in gemcitabine resistance.[12,13]

We used real-time quantitative polymerase chain reaction (PCR) to examine the mRNA expression levels of ERCC1, XPG, BRCA1, and RRM1 in formalin-fixed, paraffin-embedded tumor tissue from 54 patients with chemotherapy-naive NSCLC and correlated gene levels with clinical outcome.

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