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

on behalf of the LACE-Bio Consortium

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5 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)416-427
Number of pages12
JournalTranslational Lung Cancer Research
Volume7
Issue number3
DOIs
StatePublished - Jun 1 2018

Bibliographical note

Funding Information:
The authors would like to acknowledge Ni Liu (Princess Margaret Cancer Centre), Nicolas Lemaitre (Institut Albert Bonniot) and Shakeel Virk (Canadian Cancer Trials Group) for technical assistance. Grants from the US NCI R01 grant, Ligue Nationale Contre le Cancer (France), le Programme National d’Excellence Spécialisé cancer du poumon de l’Institut National du Cancer (INCa) (France), Canadian Cancer Society, the Gustave Roussy Foundation, the Princess Margaret Cancer Foundation and the European contract EU-FP7 Curelung.

Publisher Copyright:
© Translational lung cancer research.

Keywords

  • Biomarkers
  • Copy number aberrations (CNA)
  • Non-small cell lung cancer (NSCLC)
  • Phase III
  • Platinum-based chemotherapy

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