1312 - Aberrant ALK1 mRNA expression patterns are associated with poor prognosis in non-small cell lung cancer (NSCLC) patients. A Hellenic Cooperative Onc...

Date 28 September 2012
Event ESMO Congress 2012
Session Publication Only
Topics Non-Small-Cell Lung Cancer, Metastatic
Pathology/Molecular Biology
Presenter Vassiliki Kotoula
Authors V. Kotoula1, M. Bobos2, S. Lakis2, K. Papadopoulou2, S. Levva2, D. Repana2, V. Karavasilis2, E. Samantas3, P. Kosmidis2, G. Fountzilas4
  • 1Department Of Pathology, Hellenic Cooperative Oncology Group (HECOG), Athens/GR
  • 2Data Office, Hellenic Cooperative Oncology Group (HECOG), Athens/GR
  • 3Hellenic Cooperative Oncology Group (HECOG), Athens/GR
  • 4Medical Oncology Clinic, Hellenic Cooperative Oncology Group (HECOG), Athens/GR

Abstract

Background–aim

ALK1 (ALK) translocation is a rare event in NSCLC, which more often seem to harbor aberrant ALK gene copies. Herein, we investigated the still undefined impact of ALK gene copies and of ALK mRNA expression on NSCLC patient outcome.

Methods

The presence and relative quantity of two ALK exon spanning transcript targets located before (ALK-5') and after (ALK-3') the translocation breakpoints of this gene were assessed with qRT-PCR in 198 NSCLC RNA samples from paraffin tissues upon stringent intra- and inter-run assay performance validation. ALK mRNA expression was compared with ALK gene status assessed with FISH. Patients had been treated in the adjuvant and/or 1st line setting. None of them received crizotinib.

Results

Four patterns of ALK mRNA expression emerged: tumors negative for both transcripts (85/198, 42.9%) or positive for both (56/198, 28.3%), which were considered as close to normal (ALK-N); and, ALK-5' positive only (34/198, 17.2%) or ALK-3' positive only (23/198, 11.6%), which were termed as aberrant (ALK-A). ALK translocation was observed in 9/124 cases (7.3%). ALK copies >2.2 were noticed in 40 cases (32.3%) with >6 copies in 26 cases (21%) and overall complex gene gain patterns. ALK mRNA was unrelated to ALK translocation, but ALK-3' was associated with increased ALK gene copies (p = 0.017). ALK-A was more common in stage IIIB-IV tumors, while ALK mRNA and gene copy gains were not associated with gender, smoking and histology. ALK gene status was not associated with patient outcome. In comparison to patients with tumors expressing ALK-N, those with ALK-A had a significantly shorter overall survival (OS, median 29.3 vs. 13.1 months, CI95% 19.1-39.6 vs. 5.4-20.9, p = 0.0007). The same unfavorable impact of ALK-N vs. ALK-A was observed on stage IIIB-IV patient OS (median 17.5 vs. 11 months, CI95% 9.1-26.0 vs. 6.6-15.3, p = 0.0050).

Conclusions

ALK gene status and mRNA expression seem to suffer a complex pathology in NSCLC. When expressed, ALK mRNA may be fragmented, possibly due to currently unknown genomic alterations. Aberrant ALK mRNA expression appears to have an unfavorable prognostic impact on NSCLC patient outcome; its role on NSCLC biology merits further evaluation.

Disclosure

All authors have declared no conflicts of interest.