Genomic Alteration Spectrum of Non-Small Cell Lung Cancer Patients in East-China Characterized by Tumor Tissue DNA and Cell-Free DNA

Abstract

Introduction From an oncologic perspective, genetic detection is becoming a frontline clinical test, used to identify actionable alterations for targeted therapy, monitor molecular clonal tumor evolution, indicate disease progression and prognosis, and predict medication efficacy and resistance. From analysis of both tumor tissue and cell-free DNA from a large cohort of non-small cell lung cancer patients in East-China, we characterized the full spectrum of genomic alterations. Methods The study comprised 3000 unpaired samples including 1351 tumor tissue DNA (tDNA) and 1649 cell-free circulating tumor DNA (cfDNA) samples, from which 67 cancer-related genes were sequenced and the genetic alteration profiles were depicted. Integrative molecular analyses identified the frequently mutated genes, uncovered co-occurring somatic alterations, described the distribution of hotspot variants, analyzed the frequency of variant alleles, and notably distinguished actionable, novel variants. Results The most commonly affected genes were EGFR, TP53, KRAS, CDKN2A, and PIK3CA in both tDNA and cfDNA samples. EGFR and CTNNB1, PIK3CA and PTEN, ERBB2 and SMO were found to have frequent co-occurring alterations in tDNA samples, while EGFR and SMO, KRAS and PDGFRA, PIK3CA and KDR were in cfDNA samples. A large number of primary druggable variants were identified in tDNA samples, while numerous drug-resistance variants, rare actionable variants, and non-EGFR actionable variants were detected in cfDNA samples. Novel variants were enriched in KDR, KIT, TP53, ABL1, FGFR1 in tDNA samples while the majority of novel variants were distributed in PDGFRA, EGFR, KIT, ROS1, BRCA2 in cfDNA samples. Variant allele frequency in tDNA samples was significantly (P < 0.001) higher than that in cfDNA samples. Conclusion The results revealed considerable differences in the alteration characteristics between the two kinds of specimens. To date, this study represents the largest real-world investigation of its kind, derived from the largest number of patients in East-China. It reinforced and expanded the mechanism of molecular analysis of neoplastic genetic profiles.

Advanced non-small-cell lung cancer: how to manage EGFR and HER2 exon 20 insertion mutation-positive disease

“…Of these alterations, approximately 90% are represented by exon 19 deletions and exon 21 L858R point mutation, so-called ‘common’ EGFR mutations. 3 , 4 The remaining 10% of ‘uncommon’ alterations mainly constitute mutations involving exons 18–21 and exon 20 insertions. 3 , 4 On the contrary, HER2 mutations have a significantly lower prevalence in patients with NSCLC than EGFR mutations but most occur in exon 20 as codon 776 insertions or duplications of YVMA amino acids.…”

“… 3 , 4 The remaining 10% of ‘uncommon’ alterations mainly constitute mutations involving exons 18–21 and exon 20 insertions. 3 , 4 On the contrary, HER2 mutations have a significantly lower prevalence in patients with NSCLC than EGFR mutations but most occur in exon 20 as codon 776 insertions or duplications of YVMA amino acids. 4 , 5 Herein, we provide a practical but comprehensive review of the literature regarding the clinical management of patients with NSCLC harbouring EGFR and HER2 exon 20 insertions.…”