The Unique Genetic Mutation Characteristics Based on Large Panel Next-Generation Sequencing (NGS) Detection in Multiple Primary Lung Cancers (MPLC) Patients

Abstract

Background: With the wide application of multislice spiral computed tomography (CT), the frequency of detection of multiple lung cancer is increasing. This study aimed to analyze gene mutations characteristics in multiple primary lung cancers (MPLC) using large panel next-generation sequencing (NGS) assays.

Methods: Patients with MPLC surgically removed from the Affiliated Hospital of Guangdong Medical University from Jan 2020 to Dec 2021 enrolled the study. NGS sequencing of large panels of 425 tumor-associated genes was performed.

Results: The 425 panel sequencing of 114 nodules in 36 patients showed that epidermal growth factor receptor (EGFR) accounted for the largest proportion (55.3%), followed by Erb-B2 Receptor Tyrosine Kinase 2 (ERBB2) (9.6%), v-Raf murine sarcoma viral oncogene homolog B1 (BRAF), and Kirsten rat sarcoma viral oncogene (KRAS) (8.8%). Fusion target variation was rare (only 2, 1.8%). ERBB2 Y772_A775dup accounted for 73%, KRAS G12C for about 18%, and BRAF V600E for only 10%. AT-rich interaction domain 1A (ARID1A) mutations were significantly higher in invasive adenocarcinoma (IA) which contained solid/micro-papillary malignant components (p = 0.008). The tumor mutation burden (TMB) distribution was low, with a median TMB of 1.1 MUTS/Mb. There were no differences in the TMB distribution of different driver genes. In addition, 97.2% of MPLC patients (35/36) had driver gene mutations, and 47% had co-mutations, mainly in IA (45%) and invasive adenocarcinoma (MIA) (37%) nodule, with EGFR (39.4%), KRAS (9.1%), ERBB2 (6.1%), tumor protein 53 (TP53) (6.1%) predominately.

Conclusions: MPLC has a unique genetic mutation characteristic that differs from advanced patients and usually presents with low TMB. Comprehensive NGS helps to diagnose MPLC and guides the MPLC clinical treatment. ARID1A is significantly enriched in IA nodules containing micro-papillary/solid components, suggesting that these MPLC patients may have a poor prognosis.

Keywords: adenosquamous carcinoma of the lung; genomic diagnosis; multiple primary lung cancer (MPLC); mutational signature; next-generation sequencing (NGS).