Targeted next-generation sequencing reveals recurrence-associated genomic alterations in early-stage non-small cell lung cancer

Abstract

PurposeThe identification of genomic alterations related to recurrence in early-stage non-small cell lung cancer (NSCLC) patients may help better stratify high-risk individuals and guide treatment strategies. This study aimed to identify the molecular biomarkers of recurrence in early-stage NSCLC.ResultsOf the 42 tumors evaluable for genomic alterations, TP53 and EGFR were the most frequent alterations with population frequency 52.4% and 50.0%, respectively. Fusion genes were detected in four patients, which had lower mutational burden and relatively better genomic stability. EGFR mutation and fusion gene were mutually exclusive in this study. CDKN2A, FAS, SUFU and SMARCA4 genomic alterations were only observed in the relapsed patients. Increased copy number alteration index was observed in early relapsed patients. Among these genomic alterations, early-stage NSCLCs harboring CDKN2A, FAS, SUFU and SMARCA4 genomic alterations were found to be significantly associated with recurrence. Some of these new findings were validated using The Cancer Genome Atlas (TCGA) dataset.ConclusionsThe genomic alterations of CDKN2A, FAS, SUFU and SMARCA4 in early-stage NSCLC are found to be associated with recurrence, but confirmation in a larger independent cohort is required to define the clinical impact.Materials and MethodsPaired primary tumor and normal lung tissue samples were collected for targeted next-generation sequencing analysis. A panel targets exons for 440 genes was used to assess the mutational and copy number status of selected genes in three clinically relevant groups of stage I/II NSCLC patients: 1) Early relapse; 2) Late relapse; and 3) No relapse.

Multiomic Characterization of Stage I Lung Adenocarcinoma Reveals Distinct Genetic and Immunologic Features of Recurrent Disease

“…MUC16 is overexpressed in several cancers including ovarian, pancreatic, breast, and lung, and has been shown to be associated with cancer progression and poor prognosis 64 . SMARCA4, also frequently mutated in recurrent tumors in our study, has been previously shown to be associated with recurrence in lung adenocarcinoma 32,33 . SMARCA4 is a DNA-dependent ATPase which is involved in transcription regulation via the SWI/SNF chromatin remodeling complex 65 .…”

Targeted Next-Generation Sequencing Analysis for Recurrence in Early-Stage Lung Adenocarcinoma

“…The unknown genetic alterations, RNA editing factors mutations, transcription factor mutations, or epigenetic alterations, except known driver mutations, might cause recurrence in the tumors without alteration. 11 The number of mutations in the targeted NGS did not seem to be affected by clinical factors such as age or smoking history. However, previous whole gene or whole exon sequencing studies showed an association with the number of mutations and clinical factors.…”

“…However, 230 patients is not a small number for an NGS study focused only on early lung adenocarcinoma, compared with previous NGS studies. 11,27 The CTNNB1 and fusion genes were rare, and the recurrence rate of early lung cancer was low, so the number of patients with recurrencerelated specific genes was inevitably small. However, these genes showed strong correlations with recurrence.…”

“…9,10 However, only a few studies have attempted to describe recurrence-associated genomic alterations in early-stage NSCLC. 11,12 In this study, we hypothesized that specific genetic alterations might affect recurrence. To identify genetic risk factors for recurrence, we compared the molecular profiles of patient groups with and without recurrence and attempted to reveal what genetic alterations are related to recurrence of resected early lung adenocarcinoma through targeted NGS analysis.…”

Early immune pressure imposed by tissue resident memory T cells sculpts tumour evolution in non-small cell lung cancer

“…NS patients with lung cancer respond poorly to immune checkpoint inhibitors compared to ES 9 . It has been suggested that tumour cell intrinsic factors such as lower TMB (and presumably lower neoantigen load) and lower expression of PDL1 account for this reduced sensitivity 10,11,12 . Yet, even in a cohort selected for high expression of PDL1, NS LUAD patients had worse progression free survival and less durable responses to anti-PD(L)1 therapy than heavy smokers 13 .…”