The nonsmokers’ and smokers’ pathways in lung adenocarcinoma: Histological progression and molecular bases

Abstract

There could be two carcinogenetic pathways for lung adenocarcinoma (LADC): the nonsmokers’ pathway and the smokers’ pathway. This review article describes the two pathways with special reference to potential relationships between histological subtypes, malignant grades, and driver mutations. The lung is composed of two different tissue units, the terminal respiratory unit (TRU) and the central airway compartment (CAC). In the nonsmokers’ pathway, LADCs develop from the TRU, and their histological appearances change from lepidic to micropapillary during the progression process. In the smokers’ pathway, LADCs develop from either the TRU or the CAC, and their histological appearances vary among cases in the middle of the progression process, but they are likely converged to acinar/solid at the end. On a molecular genetic level, the nonsmokers’ pathway is mostly driven by EGFR mutations, whereas in the smokers’ pathway, approximately one‐quarter of LADCs have KRAS mutations, but the other three‐quarters have no known driver mutations. p53 mutations are an important factor triggering the progression of both pathways, with unique molecular alterations associated with each, such as MUC21 expression and chromosome 12p13‐21 amplification in the nonsmokers’ pathway, and HNF4α expression and TTF1 mutations in the smokers’ pathway. However, investigation into the relationship between histological progression and genetic alterations is in its infancy. Tight cooperation between traditional histopathological examinations and recent molecular genetics can provide valuable insight to better understand the nature of LADCs.

Crosstalk between H1975 tumor cells and platelets to induce the proliferation, migration and tube formation of vascular endothelial cells

“…Lung adenocarcinoma is a type of lung cancer that easily metastasizes. Most patients with lung cancer who do not smoke suffer from lung adenocarcinoma with epidermal growth factor receptor (EGFR) mutations ( 3 ). In China, the proportion of women with lung cancer is increasing, while ~80% of Chinese women with lung cancer do not smoke ( 4 ).…”

Anoikis-related genes combined with single cell sequencing: Insights into model specification of lung adenocarcinoma and applicability for prognosis and therapy

“…Several treatment options are available including immunotherapy, targeted therapy, chemotherapy, radiotherapy, and surgical management (pneumonectomy and lung transplantation) ( Glanville and Wilson, 2018 ; Wang et al, 2022a ; Gross et al, 2022 ; Huo et al, 2022 ; Nguyen et al, 2022 ). However, LUAD is characterized by considerable heterogeneity in clinical features, pathological characteristics, and molecular alterations, as well as genomic instability ( Geng et al, 2021 ; Okudela et al, 2021 ). The prevalence of lung tumors in non-smokers has increased recently, despite the known association between smoking and lung cancer ( Jeon et al, 2018 ), underscoring the need to elucidate the underlying molecular mechanisms and develop effective therapies.…”

Ttc39c is a potential target for the treatment of lung cancer

“…Lung adenocarcinoma (LUAD) is the most common subtype of lung cancer, and its incidence rate is increasing every year [3,4]. This might be due to an increase in the number of smokers [5]. LUAD is more common among women (especially Asian women) than among men [6,7].…”