Author of

• 11344

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  MO10 - Molecular Pathology II (ID 127)

  • Event: WCLC 2013
  • Type: Mini Oral Abstract Session
  • Track: Pathology
  • Presentations: 1
  • Moderators:W.A. Franklin, A. Mahar
  • Coordinates: 10/28/2013, 16:15 - 17:45, Bayside 104, Level 1

  • 11350

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    MO10.06 - Intertumour heterogeneity revealed by integrative analysis of targeted somatic mutation profiling and whole genome copy-number alterations in non-squamous non-small cell lung carcinomas (ID 3386)

    16:45 - 16:50  |  Author(s): M. Alifano
    • Abstract
    • Presentation
    • Slides

    Background
    Molecular subtypes of NSCLC are delineated through single driver alterations, although this likely underestimates the extent of inter-tumor heterogeneity. The goal of this study was to evaluate the potential impact of co-occuring mutations and copy number alterations in a series of tumours from both East-Asian (EA) and Western-Europe (WE) origins.

    Methods
    230 non-squamous non-small cell lung carcinomas (NSCLC) were analysed using the MassARRAY LungCarta™ panel (Sequenom) which examines 214 mutations in 26 oncogenes and tumour suppressor genes. Results were integrated with copy number alterations evaluated using Affymetrix Genome-Wide Human SNP 6.0 arrays and clinical variables.

    Results
    Out of the 230 tumours tested, 185 mutations were observed, with 138 tumours (60%) with at least one mutation – 97 tumours (42.2%) with a single mutation in a single gene, 36 tumours (15.7%) with two mutations (either in the same gene or two different genes), four tumours (2.2%) with three mutations and one with four mutations. The most frequent mutations were EGFR (38.5% EA;10.1% WE), KRAS (10.9% EA;31.6% WE), P53 (8.8% EA;15.1% WE), MET (14.3% EA;2.2% WE), STK11 (9.9% EA;2.8% WE) and PIK3CA (2.2% EA;4.3% WE). Co-occurring mutations were found in up to 30% of tumors, although the likelihood differed for each gene: KRAS (16/54, 31%), EGFR (18/49, 37%), MET (6/16, 38%), P53 (13/29, 45%), STK11 (8/13, 62%) and PIK3CA (5/8; 62%). Among the eight tumors harbouring PIK3CA mutations, five cases had a co-mutation (four cases with EGFR, one case with KRAS). In EGFR mutant cancers, co-occuring mutations include p53 (10%), PIK3CA (8%), STK11 (6%) and MET (4%). Significant relationships were also detected between EGFR mutation and CNAs on chromosomes 1p, 7p, and 13q. There were also significant relationships between KRAS mutation and CNAs on chromosomes 1q and 3q. For stage I, we found a worse prognosis for patients with at least one mutation. PIK3CA was significantly correlated with poor prognosis. Consistent with recent pooled analysis, KRAS alone is not prognostic but when CNAs and mutation status are combined, patients having both KRAS mutation and the highest related CNA (3q22.3 copy loss) showed a significant poorer prognosis.

    Conclusion
    This study highlights the wide diversity of mutation profiles within molecularly-defined NSCLCs, revealing co-mutations and associations with numerical chromosomal abnormalities that are clinically relevant. This diversity should be taken into account when designing stratified treatment approaches and underscores the need for customized assays that broadly screen for “actionable” mutations and copy-number alterations.

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