Clinical Research Papers:
Different prognostic impact of STK11 mutations in non-squamous non-small-cell lung cancer
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Nicolas Pécuchet1,2, Pierre Laurent-Puig1,3, Audrey Mansuet-Lupo4,5, Antoine Legras1, Marco Alifano6, Karine Pallier1, Audrey Didelot1, Laure Gibault7, Claire Danel8, Pierre-Alexandre Just4, Marc Riquet9, Françoise Le Pimpec-Barthes9, Diane Damotte4,5,*, Elisabeth Fabre1,2,* and Hélène Blons1,3,*
1 INSERM UMR-S1147, Paris Sorbonne Cité Université, Paris, France
2 Department of Medical Oncology, Hôpital Européen Georges Pompidou (HEGP), Assistance Publique, Hôpitaux de Paris, Paris, France
3 Department of Biochemistry, Pharmacogenetic and Molecular Oncology Unit, Hôpital Européen Georges Pompidou (HEGP), Assistance Publique, Hôpitaux de Paris, Paris, France
4 Department of Pathology, Hôpital Cochin, Assistance Publique, Hôpitaux de Paris, Paris, France
5 INSERM U1138, Paris Sorbonne Cité Université, Paris, France
6 Department of Thoracic Surgery, Hôpital Cochin, Assistance publique Hôpitaux de Paris, Paris, France
7 Department of Pathology, Hôpital Européen Georges Pompidou (HEGP), Assistance Publique, Hôpitaux de Paris, Paris, France
8 Department of Pathology, Hôpital Bichat, Assistance Publique, Hôpitaux de Paris, Paris, France
9 Department of Thoracic Surgery, Hôpital Européen Georges Pompidou (HEGP), Assistance Publique, Hôpitaux de Paris, Paris, France
* These authors share senior authorship for this manuscript
Hélène Blons, email:
Keywords: lung cancer, STK11, LKB1, isoforms, prognosis
Received: July 20, 2015 Accepted: October 09, 2015 Published: November 25, 2015
STK11 is commonly mutated in lung cancer. In light of recent experimental data showing that specific STK11 mutants could acquire oncogenic activities due to the synthesis of a short STK11 isoform, we investigated whether this new classification of STK11 mutants could help refine its role as a prognostic marker. We conducted a retrospective high-throughput genotyping study in 567 resected non-squamous non-small-cell lung cancer (NSCLC) patients. STK11 exons 1 or 2 mutations (STK11ex1-2) with potential oncogenic activity were analyzed separately from exons 3 to 9 (STK11ex3-9). STK11ex1-2 and STK11ex3-9 mutations occurred in 5% and 14% of NSCLC. STK11 mutated patients were younger (P = .01) and smokers (P< .0001). STK11 mutations were significantly associated with KRAS and inversely with EGFR mutations. After a median follow-up of 7.2 years (95%CI 6.8-.4), patients with STK11ex1-2 mutation had a median OS of 24 months (95%CI 15-57) as compared to 69 months (95%CI 56-93) for wild-type (log-rank, P = .005) and to 91 months (95%CI 57-unreached) for STK11ex3-9 mutations (P = .003). In multivariate analysis, STK11ex1-2 mutations remained associated with a poor prognosis (P = .002). Results were validated in two public datasets. Western blots showed that STK11ex1-2 mutatedtumors expressed short STK11 isoforms. Finally using mRNAseq data from the TCGA cohort, we showed that a stroma-derived poor prognosis signature was enriched in STK11ex1-2 mutated tumors. All together our results show that STK11ex1-2 mutations delineate an aggressive subtype of lung cancer for which a targeted treatment through STK11 inhibition might offer new opportunities.
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