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Retrospective and prospective validation of a 33-gene signature to predict recurrence of lung cancer after surgery.

ABSTRACT: We developed a 33-gene signature that is strongly correlated to the time to recurrence in non-small cell lung cancer (NSCLC). The signature was validated retrospectively in 5 cohorts of 972 NSCLC patients and in one prospective study of 111 NSCLC Stage IA patients. In all cohorts, and all stages of the disease, the signature identified a rare, aggressive tumor type that had a high proportion of recurrence after surgery and a median survival of 35 months (95% C.I.: 19-58). This tumor type forms a separate cluster in an analysis of the expression of the 33 genes in patient tumors. The signature is associated with cellular processes required by rapidly growing and spreading tumors: cell migration and invasion, vascularization, and response to hypoxia. The signature also identifies patients with good prognosis (median survival 114 months, (95% C.I.: 85-160), and intermediate prognosis (median survival 61 months (95% C. I.: 50-73). The signature is quite robust and works on tumor samples archived in RNAlater, Tissue-Tek, or formalin-fixed and paraffin embedded.

ORGANISM(S): Homo sapiens

PROVIDER: GSE77803 | GEO | 2016/02/11

SECONDARY ACCESSION(S): PRJNA311588

REPOSITORIES: GEO

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Project description:Importance: Severe alcoholic hepatitis (AH) is a highly lethal disease with a 3-month mortality up to 50%. Corticosteroids are the current standard of care although nearly 40% of the patients do not respond and accurate pre-treatment predictors of survival are lacking. Objective: To develop a prognostic score based on molecular and clinical variables before initiation of corticosteroids. Design, Setting, and Participants: Gene expression profiling of fixed liver biopsy obtained for diagnosis of severe AH assessed in 3 independent cohorts (1 prospective cohort for prognostic gene signature and integrative score derivation, and 2 retrospective cohorts for validation). Samples were obtained from 4 European and 1 US medical centers between July 2006 and February 2015. Exposures: Biopsy proven severe AH patients treated with corticosteroids. Main Outcome Measures: Identification of a gene signature combined with a validated clinical index to develop an integrative prognostic score of survival without death or liver transplantation in a derivation cohort (n=71). Prognostic performance of the score was validated in an independent multi-center validation cohort 1 (n=48). Finally, the score was implemented in an FDA-approved clinical diagnostic platform (NanoString) and tested in another independent validation cohort 2 (n=20). Results: A prognostic score, integrating a 123-gene signature and the model for end-stage liver disease (gs-MELD score), was defined in the derivation cohort, in which poor- and good-prognosis patients were discriminated with a cut-off value of 2.66 at 3 months (event-free survival rates of 32% vs. 76%, respectively, p<.001) and 6 months (26% vs. 65%, respectively, p<.001). In the validation cohort 1, the score similarly discriminated poor- and good-prognosis patients at 3 months (43%, [95% CI, 26%-70%] vs. 96% [95% CI, 89%-100%], respectively, p<.001, c-index of 0.83 [95% CI, 0.66-0.99]) and 6 months (34% [95% CI, 18%-61%] vs 84% [95% CI, 72%-100%], respectively, p<.001, c-index of 0.80 [95% CI, 0.66-0.94]), and outperformed other existing clinical indices. The NanoString-based gs-MELD score remained predictive of 3- (p=.03) and 6-month (p=.009) even-free survival in the validation cohort 2. Conclusion and Relevance: The gs-MELD score, incorporating clinically applicable gene signature test and the MELD score, enables pre-treatment survival prediction in severe AH patients.

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Retrospective and prospective validation of a 33-gene signature to predict recurrence of lung cancer after surgery.

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