Intra-tumor and Inter-tumor Heterogeneity in MET Exon 14 Skipping Mutations and Co-mutations in Pulmonary Pleomorphic Carcinomas

The efficacy of MET-TKI monotherapy for NSCLC with MET exon 14 skipping mutations is not satisfactory. Through the analysis of intratumor and intertumor heterogeneity in MET mutational status, we considered that the lower efficacies of MET-TKIs, compared with EGFR- or ALK-TKIs, were not due to heterogeneity in MET exon 14 skipping mutation status. While, we detected substantial intratumor and intertumor heterogeneity in co-occurring genetic alterations that may affect the efficacy of MET-TKIs. Background: MET exon 14 skipping mutation is a driver mutation in lung cancer and is highly enriched in pulmonary pleomorphic carcinomas (PPCs). Whether there is intratumor or intertumor heterogeneity in MET exon 14 skipping status or in co-occurring genetic alterations in lung cancers driven by MET exon 14 skipping is unknown. Methods: We analyzed tumor specimens obtained from 23 PPC patients (10 autopsied and 13 surgically resected). MET exon 14 skipping was detected by RT-PCR. For patients with MET exon 14 skipping mutation, further analyses were performed. Genomic DNA (gDNA) was extracted from various histological components for each patient who underwent surgical resection (to assess intratumor heterogeneity). In autopsied patients, gDNA and total RNA were extracted from all metastatic lesions (to assess intertumor heterogeneity). Results: MET exon 14 skipping mutation was detected in 4 patients (4/23, 17.4%): two surgically resected and two autopsied patients. We found no intratumor or intertumor heterogeneity in MET exon 14 skipping mutation status in these patients. We observed intratumor and intertumor heterogeneity in the copy number variations and/or mutational status of cancer-related genes; some of these differences may have an impact on MET tyrosine kinase inhibitor (TKI) efficacy. Conclusion: In our exploratory analysis of four cases, we observed that MET exon 14 skipping mutations are distributed homogeneously throughout histological components and between metastatic lesions. Our results also suggest that there is marked intertumor and intratumor heterogeneity in co-occurring genetic alterations, and therapeutic implications of such heterogeneity should be evaluated in future studies. (C) 2021 Elsevier Inc. All rights reserved.

Automated summary

The efficacy of MET-TKI monotherapy for NSCLC with MET exon 14 skipping mutations is unsatisfactory. Heterogeneity in co-occurring genetic alterations, rather than heterogeneity in MET exon 14 skipping mutation status, may affect the efficacy of MET-TKIs. Evaluating the therapeutic implications of intertumor and intratumor heterogeneity is important for future studies.