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A. Stenzinger

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    Poster Display session (Friday) (ID 65)

    • Event: ELCC 2018
    • Type: Poster Display session
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 4/13/2018, 12:30 - 13:00, Hall 1
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      22P - Clonal and subclonal occurrence of oncogenic mutations in lung adenocarcinoma (ID 642)

      12:30 - 13:00  |  Author(s): A. Stenzinger

      • Abstract

      Increasing evidence emerges that oncogenic mutations in cancer occur at both clonal and subclonal levels. Targeted drug treatment programs based on clinical mutation testing do not consider the clonal or subclonal frequencies of oncogenic mutations but the pure presence. Our aim was to study the clonal and subclonal frequencies of (oncogenic) mutations in lung adenocarcinoma (LUAD).

      Fresh frozen and formalin-fixed paraffin embedded tumor and normal tissues of 50 LUAD patients were investigated by WES. Computational analysis for accurate estimation of purity, ploidy and absolute copy numbers followed by assessment of the cancer cell fractions (CCF, ratio of the observed and the expected allelic fraction of a mutation) for each detected mutation in the individual adenocarcinoma was performed. Statistical distribution of CCFs was performed to assign mutations to distinct clonal and subclonal clusters. Clonal and subclonal mutational status was verified by digital droplet PCR of selected cases. Tumor mutational burden was calculated as exonic non-synonymous mutations per case. Mutational signatures were determined.

      In the study cohort, 14 (28%) tumor samples were composed of clonal mutations and 36 (72%) of clonal and subclonal mutations. Of the 36 cases with subclonal clusters, 22 (61%) showed 1 subclonal cluster, 11 (31%) revealed 2 subclonal clusters and 3 (8%) 3 subclonal clusters. Among the subclonal mutations, we found known oncogenic mutations: KRAS c.34G > T (p.G12C), KRAS c.35G > T (G12V), KRAS c.182_183delinsTC (p.Q61L). The average number of tumor exonic non-synonymous mutations per case was 155 (median 103, ranging from 27 to 1593). The average exonic non-synonymous mutation rate was 5 per million base pairs. We found mutational signatures that are correlated with tobacco smoking, age, AID/APOBEC.

      We detected clonal and subclonal mutations in the majority of LUAD. We found oncogenic mutations in KRAS and EGFR. Our findings indicate the importance of the determination of clonal and subclonal status of oncogenic mutations and could also be meaningful for the estimation of tumor mutational burden as potential clinical marker.

      Clinical trial identification:

      Legal entity responsible for the study:

      Swiss Cancer League

      R. Thomas: Ownership interests (including patents) for AstraZeneca, Bayer, Novartis, and Roche; consultant/advisory board member for AstraZeneca, Bayer, Boehringer-Ingelheim, Clovis, Daiichi-Sankyo, Johnson & Johnson, Lilly, Merck, MSD, New Oncology, Puma, Roche, and Sanofi-Aventis. All other authors have declared no conflicts of interest.