Frequency of longitudinal changes in TP53 mutation status from gene sequencing of serial tumor biopsies from a large cohort of cancer patients.

Abstract

3124 Background: The p53 pathway is one of the most important in cancer biology, with mutation of the TP53 gene that encodes the p53 tumor suppressor protein observed in ≈50% of all cancers. We evaluated the frequency of changes in TP53 mutation status in a large cohort of serial tumor biopsies. Methods: From a database of >200,000 next-generation gene sequencing results we identified 16,592 samples arising from repeat biopsies from 7840 patients (pts), average 2.12 per pt, 1007 pts with ≥3, max 11; over an interval up to 234 months (mos), average 11.0 mos. TP53 mutations with known or unknown significance in successive biopsies and changes in assignment from TP53-Wild-Type (WT) to Mutant (Mut), or Mut to WT, were evaluated vs. cancer type and time between biopsies. Results: Table: N (%) of samples vs. change in TP53 status from previous biopsy vs. mos from initial biopsy in all samples (7840 initial + 8752 successive, 46% TP53-Mut) and the three most represented cancers: non-small cell lung cancer (NSCLC, 1189 initial + 1268 successive, 60% Mut), breast (947 initial + 993 successive, 55% Mut), multiple myeloma (MM, 578 initial + 981 successive, 18% Mut). Conclusions: Changes in TP53 status were rare (<10% of samples). Differences may occur in serial biopsy samples for pathophysiological reasons, e.g., a mutant clone becoming dominant and/or heterogeneity at different tumor biopsy sites, or analytical differences in biopsy tumor content or assay sensitivity between samples. In this analysis, WT-to-Mut changes were more frequent (5.9%) than Mut-to-WT changes (3.3%), suggesting a small selection pressure for TP53 alterations later in oncogenesis and indicating that these alterations are truncal. Mut-to-WT changes are not readily explained physiologically and may suggest these infrequent changes are mostly due to sampling or analytical variability, and genuine changes in TP53 mutation status are quite rare.[Table: see text]