Genomic Landscape Features of Minimally Invasive Adenocarcinoma and Invasive Lung Adenocarcinoma

Abstract

Background The widespread implementation of computed tomography has significantly increased the detection of small pulmonary nodules, including atypical adenomatous hyperplasia, minimally invasive adenocarcinoma (MIA), and invasive adenocarcinoma (IAC). Few studies have focused on the genomic differences between MIA and IAC.

Methods We retrospectively analyzed patients with lung adenocarcinoma (LUAD) who underwent surgery from January 2020 to December 2023. Patients were categorized into MIA and IAC groups. The mutation status of common driver genes was assessed using next-generation sequencing.

Results A total of 422 LUAD patients were included in the study, comprising 119 MIA cases and 303 IAC cases. MIA patients were younger and predominantly female compared with IAC patients. EGFR mutations were detected in 251 patients (59.5%), with the frequency of EGFR mutations increasing from 37.0% in MIA to 68.3% in IAC (p < 0.001). TP53 mutations were found in 108 patients (25.6%), with 7 patients (5.9%) in MIA and 101 patients (33.3%) in IAC (p < 0.001). ERBB2 mutations were identified in 23 MIA patients (19.3%) and 20 IAC patients (6.6%) (p < 0.001). Additionally, CDKN2A mutations were detected in 23 IAC patients (7.6%), while no mutations in this gene were found in the MIA group. Moreover, ALK and RET gene fusions were identified in 11 patients, respectively.

Conclusion ERBB2 mutations and RET fusions are early genomic events in LUAD, while TP53 and CDKN2A mutations and ALK fusions occur later. Genomic intratumor heterogeneity likely arises early, before invasive characteristics develop.

Keywords

lung cancer / minimally invasive adenocarcinoma / invasive adenocarcinoma / mutations

References

[1] Li Y, Yan B, He S. Advances and challenges in the treatment of lung cancer. Biomed Pharmacother 2023; 169: 115891

[2] She J, Yang P, Hong Q, Bai C. Lung cancer in China: challenges and interventions. Chest 2013; 143(04) 1117-1126

[3] Su H, Dai C, Xie H, et al. Risk factors of recurrence in patients with clinical stage IA adenocarcinoma presented as ground-glass nodule. Clin Lung Cancer 2018; 19(05) e609-e617

[4] Travis WD, Brambilla E, Noguchi M, et al. Diagnosis of lung adenocarcinoma in resected specimens: implications of the 2011 International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification. Arch Pathol Lab Med 2013; 137(05) 685-705

[5] Zhang Y, Deng C, Fu F, et al. Excellent prognosis of patients with invasive lung adenocarcinomas during surgery misdiagnosed as atypical adenomatous hyperplasia, adenocarcinoma in situ, or minimally invasive adenocarcinoma by frozen section. Chest 2021; 159(03) 1265-1272

[6] Zhao W, Wang H, Xie J, Tian B. A clinicopathological study of small lung adenocarcinoma 1 cm or less in size: emphasis on histological subtypes associated with lymph node metastasis and recurrence. Int J Surg Pathol 2018; 26(01) 4-11

[7] Krysan K, Tran LM, Grimes BS, et al. The immune contexture associates with the genomic landscape in lung adenomatous premalignancy. Cancer Res 2019; 79(19) 5022-5033

[8] Qian J, Zhao S, Zou Y, et al. Genomic underpinnings of tumor behavior in in situ and early lung adenocarcinoma. Am J Respir Crit Care Med 2020; 201(06) 697-706

[9] Zhu J, Wang W, Xiong Y, et al. Evolution of lung adenocarcinoma from preneoplasia to invasive adenocarcinoma. Cancer Med 2023; 12(05) 5545-5557

[10] Vallabhaneni E, Kareff SA, Barnett RM, et al. Characterization of incidental pathogenic germline findings detected via ctDNA among patients with non-small cell lung cancer in a predominantly Hispanic/Latinx population. Cancers (Basel) 2024; 16(06) 1150

[11] Imielinski M, Berger AH, Hammerman PS, et al. Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing. Cell 2012; 150(06) 1107-1120

[12] Hu X, Fujimoto J, Ying L, et al. Multi-region exome sequencing reveals genomic evolution from preneoplasia to lung adenocarcinoma. Nat Commun 2019; 10(01) 2978

[13] Li Y, Li X, Li H, et al. Genomic characterisation of pulmonary subsolid nodules: mutational landscape and radiological features. Eur Respir J 2020; 55(02) 1901409

[14] Zhang C, Zhang J, Xu FP, et al. Genomic landscape and immune microenvironment features of preinvasive and early invasive lung adenocarcinoma. J Thorac Oncol 2019; 14(11) 1912-1923

[15] Li M, Li C, Ke L, Zhan M, Cheng M. Significance of the epidermal growth factor receptor mutation status and differences among molecular subgroups in surgically resected lung microinvasive adenocarcinoma. Oncol Lett 2018; 16(06) 7057-7067

[16] D'Angelo SP, Janjigian YY, Ahye N, et al. Distinct clinical course of EGFR-mutant resected lung cancers: results of testing of 1118 surgical specimens and effects of adjuvant gefitinib and erlotinib. J Thorac Oncol 2012; 7(12) 1815-1822

[17] Yoshizawa A, Motoi N, Riely GJ, et al. Impact of proposed IASLC/ATS/ERS classification of lung adenocarcinoma: prognostic subgroups and implications for further revision of staging based on analysis of 514 stage I cases. Mod Pathol 2011; 24(05) 653-664

[18] Lai Y, Zhang Z, Li J, et al. EGFR mutations in surgically resected fresh specimens from 697 consecutive Chinese patients with non-small cell lung cancer and their relationships with clinical features. Int J Mol Sci 2013; 14(12) 24549-24559

[19] Kobayashi Y, Mitsudomi T, Sakao Y, Yatabe Y. Genetic features of pulmonary adenocarcinoma presenting with ground-glass nodules: the differences between nodules with and without growth. Ann Oncol 2015; 26(01) 156-161

[20] Stachler MD, Taylor-Weiner A, Peng S, et al. Paired exome analysis of Barrett's esophagus and adenocarcinoma. Nat Genet 2015; 47(09) 1047-1055

[21] Teixeira VH, Pipinikas CP, Pennycuick A, et al. Deciphering the genomic, epigenomic, and transcriptomic landscapes of pre-invasive lung cancer lesions. Nat Med 2019; 25(03) 517-525

[22] Chen H, Carrot-Zhang J, Zhao Y, et al. Genomic and immune profiling of pre-invasive lung adenocarcinoma. Nat Commun 2019; 10(01) 5472

[23] Goh AM, Coffill CR, Lane DP. The role of mutant p53 in human cancer. J Pathol 2011; 223(02) 116-126

[24] Sinha S, Barbosa K, Cheng K, et al. A systematic genome-wide mapping of oncogenic mutation selection during CRISPR-Cas9 genome editing. Nat Commun 2021; 12(01) 6512

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