- p53 and Rb alterations are confirmed as predisposing to SCLC transformation in EGFR- LUAD.
- Paired EGFR-LUAD/SCLC samples showed diverse clonal evolution patterns.
- TERT amplification is an acquired event during EGFR-LUAD to SCLC transformation.
Among the different mechanisms of acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) reported in EGFR-mutated lung adenocarcinoma (EGFR-LUAD) patients, histological transformation into small cell carcinoma (SCLC) occurs in 3–14% of resistant cases, regardless of the generation of EGFR-TKI. In recent studies, bi-allelic inactivation of TP53 and RB1 has been identified in a vast majority of transformed SCLCs. However, the molecular mechanisms driving this histologic transformation remain largely unknown, mainly due to the rarity of samples.
Patients and methods
Out of an initial cohort of 64 patients, tumor tissues of adequate quality and quantity for whole exome sequencing (WES) analysis were available for nine tumors for six patients: paired pre- and post-SCLC transformation samples for three Patients and post-SCLC transformation samples for three other patients.
Mutational analyses showed concurrent TP53
mutations and Rb pathway alterations in five of the six patients analyzed, confirming their suggested role as predisposing genetic alterations to SCLC transformation. In addition, TERT
amplification was detected in four of the six patients and found to be an event acquired during SCLC transformation. Clonal history evolution analyses from the paired LUAD/SCLC samples showed different evolution patterns. In two patients, a large proportion of mutations were present in the most recent common ancestor cell of the initial LUAD and the transformed SCLC clones, whereas in the third patient, few clonal mutations were common between the LUAD and SCLC samples and the ancestor clone that lead to SCLC was present at low frequency in the initial LUAD. Read more