J Mol Diagn. 2018 May 19. pii: S1525-1578(17)30521-4. doi: 10.1016/j.jmoldx.2018.04.002. [Epub ahead of print]
Validity of targeted next-generation sequencing in routine care for identifying clinically relevant molecular profiles in non-small-cell lung cancer: results of a 2-year experience on 1,343 samples.
Legras A1, Barritault M2, Tallet A2, Fabre E3, Guyard A2, Rance B4, Digan W4, Pecuchet N3, Giroux-Leprieur E5, Julie C6, Jouveshomme S7, Duchatelle V8, Giraudet V2, Gibault L9, Cazier A10, Pastre J11, Pimpec-Barthes FL12, Laurent-Puig P13, Blons H14.
Theranostic assays are based on single gene testing but the ability of next-generation sequencing (NGS) to interrogate numerous geneticalterations will progressively replace single gene assays. Although NGS was evaluated to screen for theranostic mutations, its usefulness in clinical practice on large series of samples remains to be demonstrated. NGS performance was assessed following guidelines. TaqMan probes and NGS were compared for their ability to detect EGFR and KRAS mutations and NGS mutation profiles were analyzed on a large series of NSCLC (n=1,343). The R2 correlation between expected and measured allelic ratio, using commercial samples, was >0.96. Mutation detection threshold was 2% for 10ng of DNA input. Kappa-scores for TaqMan versus NGS were 0.99 [0.97-1.00]95%CI for EGFR and 0.98 [0.97-1.00]95%CI for KRAS after exclusion of rare EGFR (n=40) and KRAS (n=60) mutations. NGS identified 693 and 292 mutations in validated and potential oncogenic drivers, respectively. Significant associations were found between EGFR and PI3KCA or CTNNB1 and between KRAS and STK11. Potential oncogenic driver mutations or gene amplifications were more frequent in validated oncogenic driver non-mutated samples. This work is a proof of concept that targeted NGS is accessible in routine including large screening at reasonable cost. Clinical data should be collected and implemented in specific databases to make molecular data meaningful for direct patients' benefit.
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