Multiregional sequence revealed SMARCA4 R1192C mutant clones acquired EGFR C797S mutation in the metastatic site of an EGFR-mutated NSCLC patient

Lung Cancer. 2020 Oct;148:28-32. doi: 10.1016/j.lungcan.2020.07.035. Epub 2020 Aug 3.


Objectives: Intratumor heterogeneity (ITH) is reportedly involved in the clinical course and in the response to treatment, although the detailed mechanism underlying this effect remains unclear. In this study, we investigated the effect of epithelial growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment on ITH with an EGFR-mutated lung cancer patient using the multiregional sequence (MRS) analysis of surgical specimens both before and after EGFR-TKI treatment.

Materials and methods: We performed the MRS analysis of primary lung and resistant metastatic lesions, respectively through targeted sequencing, covering whole exons of 53 significantly mutated, lung cancer-associated genes. Through the comparison of primary lung and metastatic lesion mutation profiles, along with PyClone analysis of sequence data, we revealed the trajectory of resistant clones from a primary to metastatic site.

Results: MRS revealed high ITH at the primary lung lesion and low ITH at the metastatic site, suggesting that the EGFR-TKI treatment followed an attenuated progression pattern. Tumor cell clones harboring EGFR G719S, L861R, SMARCA4 R1192C and KMT2D Q1139R mutations in the primary lesion metastasized and acquired the EGFR-TKI-resistant EGFR C797S mutation.

Conclusion: MRS revealed attenuated progression pattern and clonal evolution. In the case of high ITH with attenuated progression pattern, as observed in the present case, local treatment may be effective when oligometastasis emerged.

Keywords: EGFR-TKI resistance; Intratumor heterogeneity; Multiregional sequencing; SMARCA4.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Clone Cells
  • DNA Helicases
  • Drug Resistance, Neoplasm / genetics
  • ErbB Receptors* / genetics
  • Humans
  • Lung Neoplasms* / drug therapy
  • Lung Neoplasms* / genetics
  • Mutation
  • Nuclear Proteins
  • Protein Kinase Inhibitors / therapeutic use
  • Transcription Factors


  • Nuclear Proteins
  • Protein Kinase Inhibitors
  • Transcription Factors
  • EGFR protein, human
  • ErbB Receptors
  • SMARCA4 protein, human
  • DNA Helicases