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Some lung cancers escape a targeted pill by changing into a different kind of cancer. Reading whole genomes from the same patients over time showed the change was set up from the beginning, in tumours that had already lost two particular genes.
Twenty-one patients with advanced EGFR-mutant lung adenocarcinoma that transformed into resistant small-cell lung cancer were investigated, with whole-genome sequencing of nine tumours from four patients at various time points to reconstruct clonal evolutionary history. The resistant adenocarcinomas and small-cell cancers shared a common clonal origin and followed branched evolutionary trajectories, with the small-cell ancestors diverging before the first treatment. Complete inactivation of both RB1 and TP53 was present from the early adenocarcinoma stage. Immunohistochemistry in early-stage tissue from 75 patients treated with EGFR inhibitors found inactivation of both Rb and p53 in 82% of the transformed group against 3% of the non-transformed group, odds ratio 131. Among 65 patients in a predefined cohort, an adenocarcinoma with both proteins inactivated carried a 43-fold higher risk of transformation. APOBEC-induced hypermutation was frequent in the branches leading to transformation.
It made transformation predictable from the first biopsy, using two stains that most pathology laboratories can already run, which is the practical way to know which patients need close watching and early rebiopsy.
Shares Histologic transformation, RB1, Mutagenesis & mutational signatures, Mutational signature.
Shares Histologic transformation, RB1, Lineage plasticity & neuroendocrine transformation, Resistance routes: how a blocked pathway comes back.
Shares Histologic transformation, RB1, Lineage plasticity & neuroendocrine transformation, Resistance routes: how a blocked pathway comes back.
Shares Mutagenesis & mutational signatures, Mutational signature, Whole-exome & whole-genome sequencing, TP53.
Shares Histologic transformation, Lineage plasticity & neuroendocrine transformation, Resistance routes: how a blocked pathway comes back, Drug resistance (primary and acquired).
Shares Mutagenesis & mutational signatures, Mutational signature, Clonal evolution & minimal residual disease, Whole-exome & whole-genome sequencing.
Shares Mutagenesis & mutational signatures, Mutational signature, Clonal evolution & minimal residual disease, Whole-exome & whole-genome sequencing.
Shares Resistance routes: how a blocked pathway comes back, Clonal evolution & minimal residual disease, Drug resistance (primary and acquired), EGFR.