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Excision repair cross-complementing 1 (ERCC1) level of expression can be a prognostic and predictive biomarker for benefit of cisplatin-based chemotherapy in non–small-cell lung cancer (NSCLC). The role ofERCC1genetic variations has never been reported. A retrospective review of 235 patients with NSCLC showed thatERCC1gene amplification (GA) assessed using fluorescence in situ hybridization (FISH) portended a worse outcome of untreated patients.Excision repair cross complementing 1 gene expression level has potential as a prognostic and predictive marker of the efficacy of chemotherapy in NSCLC. The effect of ERCC1 gene copy number (CN) variation (CNV) on ERCC1 expression and the clinical outcome of patients with NSCLC are not known.Copy number variation of the 19q13.3 region carrying the ERCC1 gene, classified as gene amplification (GA) or high polysomy (HP), was evaluated on 235 formalin-fixed and paraffin-embedded tumors from resected NSCLC patient samples and 16 NSCLC cell lines using FISH. We analyzed the potential correlations between FISH status and ERCC1 expression, patient's outcome, and cisplatin sensitivity in the cohort or cell lines.An increase of 19q13.3 gene CN was detected in 60 cases (25.5%) including 27 cases with GA and 33 cases with HP. A nonsignificant trend for higher ERCC1 expression in HP patients compared with GA and patients with low CNV was found (P = .06). In patients not treated with chemotherapy, FISH negative status cases had longer disease-free survival (DFS) compared with patients with 19q13-ERCC1 GA (P = .02). A 3-fold increase in IC50 of cisplatin in cell lines with high 19q13-ERCC1 CN compared with cells without CNV was shown.ERCC1 CN increase assessed using FISH did not determine ERCC1 expression status but yields potential prognostic information on DFS in untreated patients with NSCLC. The clinical relevance of an association of 19q13-ERCC1 FISH status and chemosensitivity or prognosis in patients needs further investigation and validation.