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.
Highlights
Molecular classification of non-small cell lung cancer (NSCLC) has a direct impact on treatment decisions
Mutations occurring in tumor suppressor genes, such as TP53, have been shown to gain oncogenic functions [17]
Non-disruptive TP53 mutations with potential gain of function have been associated with poor outcomes in multiple tumor types such as squamous cell carcinomas of the head and neck [18], chronic lymphocytic leukemia [19] and metastatic lung cancer [20]
Summary
Molecular classification of non-small cell lung cancer (NSCLC) has a direct impact on treatment decisions. A short STK11 isoform lacking the 124 N-terminal amino acids has recently been described as an oncogene [12] This ΔN isoform is produced from internal translation using an alternative ATG initiation codon located in exon 3 in the context of a mutation occurring in exon 1 or 2 and lacks the nuclear localization signal and part of the kinase domain. Cytoplasmic STK11 was shown to interact with ERα/SRC/PI3K to stimulate the AKT pathway and was linked to a shorter survival [13]. These findings suggest that STK11 may have tumor suppressor or oncogene functions. This dual mechanism may explain the absence of a clear association between STK11 alterations and prognosis in lung cancer [14]
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