Different prognostic impact ofSTK11mutations in non-squamous non-small-cell lung cancer

// Nicolas Pécuchet 1,2 , Pierre Laurent-Puig 1,3 , Audrey Mansuet-Lupo 4,5 , Antoine Legras 1 , Marco Alifano 6 , Karine Pallier 1 , Audrey Didelot 1 , Laure Gibault 7 , Claire Danel 8 , Pierre-Alexandre Just 4 , Marc Riquet 9 , Françoise Le Pimpec-Barthes 9 , Diane Damotte 4,5,* , Elisabeth Fabre 1,2,* and Hélène Blons 1,3,* 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 Correspondence: Hélène Blons, email: // Keywords : lung cancer, STK11, LKB1, isoforms, prognosis Received : July 20, 2015 Accepted : October 09, 2015 Published : November 25, 2015 Abstract 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 (STK11 ex1-2 ) with potential oncogenic activity were analyzed separately from exons 3 to 9 (STK11 ex3-9 ). STK11 ex1-2 and STK11 ex3-9 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 STK11 ex1-2 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 STK11 ex3-9 mutations ( P = .003 ). In multivariate analysis, STK11 ex1-2 mutations remained associated with a poor prognosis ( P = .002 ). Results were validated in two public datasets. Western blots showed that STK11 ex1-2 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 STK11 ex1-2 mutated tumors. All together our results show that STK11 ex1-2 mutations delineate an aggressive subtype of lung cancer for which a targeted treatment through STK11 inhibition might offer new opportunities.