10P - Characterization of chromosomal region 18q in NSCLC KRAS mutant tumors

Date 15 April 2016
Event European Lung Cancer Conference 2016 (ELCC) 2016
Session Poster lunch
Topics Lung and other Thoracic Tumours
Pathology/Molecular Biology
Translational Research
Presenter Sergi Clavé
Citation Journal of Thoracic Oncology (2016) 11 (supplement 4): S57-S166. S1556-0864(16)X0004-4
Authors S. Clavé1, L. Pijuan1, D. Casadevall2, G. Piquer1, F. Rojo3, E. Carcereny4, Á. Taus2, E. Arriola5, B. Bellosillo1, M. Salido1
  • 1Pathology Department, Hospital del Mar, 08003 - Barcelona/ES
  • 2Oncology Department, Hospital del Mar, 08003 - Barcelona/ES
  • 3Pathology Department, Fundación Jimenez Díaz, 28040 - Madrid/ES
  • 4Oncology Department, Institut Català d'Oncologia-Hospital Germans Trias i Pujol, 08916 - Badalona/ES
  • 5Cancer Sciences Unit, Southampton General Hospital, SO16 6YD - Southampton/GB

Abstract

Background

KRAS mutations are the most prevalent known alterations in NSCLC. Coexistence with other mutations and copy number alterations (CNAs) might have a role in tumorigenesis and responsiveness to targeted treatments. The aim of our study was to detect additional genomic alterations with a potential prognostic and predictive value in this subset of patients.

Methods

DNA samples from 21 advanced NSCLC patients (15 KRAS mutated and 6 KRAS wt) with a median age of 59 years, 73% males, 73% ever smokers and all with adenocarcinoma (ADC) histology were selected. CNAs were assessed using SNP arrays (Oncoscan FFPE Express 2.0, Affymetrix) and mutational status was determined by targeted resequencing (Ion AmpliSeq Panel, Thermo Fisher Scientific). To confirm SNP array alterations, FISH and IHC for NEDD4L gene were studied in a validation cohort of 73 surgical molecularly unselected ADC patients (12/63 were KRAS mutated).

Results

Regarding mutational analysis, TP53 substitutions were the most frequent events (8/21 cases) without differences according KRAS status. SNP array analysis revealed that loss of 18q12.1-q23 was restricted exclusively to KRAS mutated tumors (n = 7/15). Genes contained in this region were reviewed, and NEDD4L status was studied in a validation cohort. FISH detected loss of NEDD4L in 19/73 cases (3 KRAS mutated) and 19/61 assessable cases had low expression of NEDD4L protein by IHC (3 KRAS mutated). No correlation between FISH and IHC was observed. Patients with low NEDD4L protein expression had shorter overall survival (84.6 month; 95% CI, 8.7 to 160.6) than patients with normal or higher expression of NEDD4L (median OS not reached) (p = 0.042).

Conclusions

The combined use of SNP-array and targeted resequencing panels allows a reliable genomic characterization, even using archived FFPE samples. Although loss of 18q12.1-q23 was restricted to KRAS mutated tumors, no association between KRAS mutation and NEDD4L deletion/low expression was confirmed in the validation cohort. As this region contains relevant genes (NEDD4L, SMAD4) affecting TGF-signaling pathway further characterization of these alteration in a larger series of advanced NSCLC KRAS mutant tumors is warranted.

Clinical trial identification

Legal entity responsible for the study

Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona, Spain

Funding

Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona, Spain

Disclosure

All authors have declared no conflicts of interest.