Genome-wide copy number analyses of samples from LACE-Bio project identify novel prognostic and predictive markers in early stage non-small cell lung cancer

Federico Rotolo, Chang-Qi Zhu, Elisabeth Brambilla, Stephen L. Graziano, Ken Olaussen, Thierry Le-Chevalier, Jean-Pierre Pignon, Robert Kratzke, Jean-Charles Soria, Frances A. Shepherd, Lesley Seymour, Stefan Michiels, Ming-Sound Tsao, on behalf of the LACE-Bio Consortium


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.