Federico Rotolo1,2,3, Chang-Qi Zhu4, Elisabeth Brambilla5, Stephen L Graziano6, Ken Olaussen7, Thierry Le-Chevalier8, Jean-Pierre Pignon1,2,3, Robert Kratzke9, Jean-Charles Soria7,8, Frances A Shepherd4,10, Lesley Seymour11, Stefan Michiels1,2,3, Ming-Sound Tsao4,12. 1. Gustave Roussy, Université Paris-Saclay, Service de Biostatistique et d'Epidémiologie, Villejuif, France. 2. Université Paris-Saclay, Univ. Paris-Sud, UVSQ, CESP, INSERM, Villejuif, France. 3. Ligue Nationale Contre le Cancer Meta-Analysis Platform, Gustave Roussy, Villejuif, France. 4. University Health Network, Princess Margaret Cancer Centre, Toronto, ON, Canada. 5. Department of Pathology, Institut Albert Bonniot, Hopital Albert Michallon, Grenoble, France. 6. Medical Oncology, SUNY Upstate Medical University, Syracuse, NY, USA. 7. INSERM U981, Université Paris-Sud, Université Paris-Saclay and Gustave Roussy Cancer Campus, Villejuif, France. 8. Department of Medical Oncology, Gustave Roussy Cancer Campus, Villejuif, France. 9. Department of Medical Oncology, University of Minnesota, Minneapolis, MN, USA. 10. Department of Medicine, Division of Medical Oncology, University of Toronto, Toronto, ON, Canada. 11. Canadian Cancer Trials Group and Queen's University, Kingston, ON, Canada. 12. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
Abstract
BACKGROUND: Adjuvant chemotherapy (ACT) provides modest benefit in resected non-small cell lung cancer (NSCLC) patients. Genome-wide studies have identified gene copy number aberrations (CNA), but their prognostic implication is unknown. METHODS: DNA from 1,013 FFPE tumor samples from three pivotal multicenter randomized trials (ACT vs. control) in the LACE-Bio consortium (median follow-up: 5.2 years) was successfully extracted, profiled using a molecular inversion probe SNP assay, normalized relative to a pool of normal tissues and segmented. Minimally recurrent regions were identified. P values were adjusted to control the false discovery rate (Q values). RESULTS: A total of 976 samples successfully profiled, 414 (42%) adenocarcinoma (ADC), 430 (44%) squamous cell carcinoma (SCC) and 132 (14%) other NSCLC; 710 (73%) males. We identified 431 recurrent regions, with on average 51 gains and 43 losses; 253 regions (59%) were ≤3 Mb. Most frequent gains (up to 48%) were on chr1, 3q, 5p, 6p, 8q, 22q; most frequent losses (up to 40%) on chr3p, 8p, 9p. CNA frequency of 195 regions was significantly different (Q≤0.05) between ADC and SCC. Fourteen regions (7p11-12, 9p21, 18q12, and 19p11-13) were associated with disease-free survival (DFS) (univariate P≤0.005, Q<0.142), with poorer DFS for losses of regions including CDKN2A/B [hazard ratio (HR) for 2-fold lower CN: 1.5 (95% CI: 1.2-1.9), P<0.001, Q=0.020] and STK11 [HR =2.4 (1.3-4.3), P=0.005, Q=0.15]. Chromosomal instability was associated with poorer DFS (HR =1.5, P=0.015), OS (HR =1.2, P=0.189) and lung-cancer specific survival (HR =1.7, P=0.003). CONCLUSIONS: These large-scale genome-wide analyses of gene CNA provide new candidate prognostic markers for stage I-III NSCLC.
BACKGROUND: Adjuvant chemotherapy (ACT) provides modest benefit in resected non-small cell lung cancer (NSCLC) patients. Genome-wide studies have identified gene copy number aberrations (CNA), but their prognostic implication is unknown. METHODS: DNA from 1,013 FFPE tumor samples from three pivotal multicenter randomized trials (ACT vs. control) in the LACE-Bio consortium (median follow-up: 5.2 years) was successfully extracted, profiled using a molecular inversion probe SNP assay, normalized relative to a pool of normal tissues and segmented. Minimally recurrent regions were identified. P values were adjusted to control the false discovery rate (Q values). RESULTS: A total of 976 samples successfully profiled, 414 (42%) adenocarcinoma (ADC), 430 (44%) squamous cell carcinoma (SCC) and 132 (14%) other NSCLC; 710 (73%) males. We identified 431 recurrent regions, with on average 51 gains and 43 losses; 253 regions (59%) were ≤3 Mb. Most frequent gains (up to 48%) were on chr1, 3q, 5p, 6p, 8q, 22q; most frequent losses (up to 40%) on chr3p, 8p, 9p. CNA frequency of 195 regions was significantly different (Q≤0.05) between ADC and SCC. Fourteen regions (7p11-12, 9p21, 18q12, and 19p11-13) were associated with disease-free survival (DFS) (univariate P≤0.005, Q<0.142), with poorer DFS for losses of regions including CDKN2A/B [hazard ratio (HR) for 2-fold lower CN: 1.5 (95% CI: 1.2-1.9), P<0.001, Q=0.020] and STK11 [HR =2.4 (1.3-4.3), P=0.005, Q=0.15]. Chromosomal instability was associated with poorer DFS (HR =1.5, P=0.015), OS (HR =1.2, P=0.189) and lung-cancer specific survival (HR =1.7, P=0.003). CONCLUSIONS: These large-scale genome-wide analyses of gene CNA provide new candidate prognostic markers for stage I-III NSCLC.
Entities:
Keywords:
Copy number aberrations (CNA); biomarkers; non-small cell lung cancer (NSCLC); phase III; platinum-based chemotherapy
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