title: Different prognostic impact of STK11 mutations in non-squamous non-small-cell lung cancer.
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 (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.
authors.affiliation: INSERM UMR-S1147, Paris Sorbonne Cité Université, Paris, France.|Department of Medical Oncology, Hôpital Européen Georges Pompidou (HEGP), Assistance Publique - Hôpitaux de Paris, Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Pécuchet
authors.affiliation: INSERM UMR-S1147, Paris Sorbonne Cité Université, Paris, France.|Department of Biochemistry, Pharmacogenetic and Molecular Oncology Unit, Hôpital Européen Georges Pompidou (HEGP), Assistance Publique - Hôpitaux de Paris, Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Laurent-Puig
authors.affiliation: Department of Pathology, Hôpital Cochin, Assistance Publique - Hôpitaux de Paris, Paris, France.|INSERM U1138, Paris Sorbonne Cité Université, Paris, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Mansuet-Lupo
authors.affiliation: INSERM UMR-S1147, Paris Sorbonne Cité Université, Paris, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Legras
authors.affiliation: Department of Thoracic Surgery, Hôpital Cochin, Assistance publique Hôpitaux de Paris, Paris, France.
authors.forename: Marco
authors.initials: M
authors.lastname: Alifano
authors.affiliation: INSERM UMR-S1147, Paris Sorbonne Cité Université, Paris, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Pallier
authors.affiliation: INSERM UMR-S1147, Paris Sorbonne Cité Université, Paris, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Didelot
authors.affiliation: Department of Pathology, Hôpital Européen Georges Pompidou (HEGP), Assistance Publique - Hôpitaux de Paris, Paris, France.
authors.forename: Laure
authors.initials: L
authors.lastname: Gibault
authors.affiliation: Department of Pathology, Hôpital Bichat, Assistance Publique - Hôpitaux de Paris, Paris, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Danel
authors.affiliation: Department of Pathology, Hôpital Cochin, Assistance Publique - Hôpitaux de Paris, Paris, France.
authors.forename: Pierre-Alexandre
authors.initials: PA
authors.lastname: Just
authors.affiliation: Department of Thoracic Surgery, Hôpital Européen Georges Pompidou (HEGP), Assistance Publique - Hôpitaux de Paris, Paris, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Riquet
authors.affiliation: Department of Thoracic Surgery, Hôpital Européen Georges Pompidou (HEGP), Assistance Publique - Hôpitaux de Paris, Paris, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Le Pimpec-Barthes
authors.affiliation: Department of Pathology, Hôpital Cochin, Assistance Publique - Hôpitaux de Paris, Paris, France.|INSERM U1138, Paris Sorbonne Cité Université, Paris, France.
authors.forename: Diane
authors.initials: D
authors.lastname: Damotte
authors.affiliation: INSERM UMR-S1147, Paris Sorbonne Cité Université, Paris, France.|Department of Medical Oncology, Hôpital Européen Georges Pompidou (HEGP), Assistance Publique - Hôpitaux de Paris, Paris, France.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Fabre
authors.affiliation: INSERM UMR-S1147, Paris Sorbonne Cité Université, Paris, France.|Department of Biochemistry, Pharmacogenetic and Molecular Oncology Unit, Hôpital Européen Georges Pompidou (HEGP), Assistance Publique - Hôpitaux de Paris, Paris, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Blons
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology; D005260:Female; D005838:Genotype; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D009154:Mutation; D011379:Prognosis; D020033:Protein Isoforms; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012189:Retrospective Studies
chemical_list: D020033:Protein Isoforms; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases
keywords: LKB1; STK11; isoforms; lung cancer; prognosis