Clinicopathological Characteristics and Mutations Driving Development of Early Lung Adenocarcinoma: Tumor Initiation and Progression.

Kentaro Inamura

doi:10.3390/ijms19041259

Abstract

Lung cancer is the leading cause of cancer-related deaths worldwide, with lung adenocarcinoma representing the most common lung cancer subtype. Among all lung adenocarcinomas, the most prevalent subset develops via tumorigenesis and progression from atypical adenomatous hyperplasia (AAH) to adenocarcinoma in situ (AIS), to minimally invasive adenocarcinoma (MIA), to overt invasive adenocarcinoma with a lepidic pattern. This stepwise development is supported by the clinicopathological and molecular characteristics of these tumors. In the 2015 World Health Organization classification, AAH and AIS are both defined as preinvasive lesions, whereas MIA is identified as an early invasive adenocarcinoma that is not expected to recur if removed completely. Recent studies have examined the molecular features of lung adenocarcinoma tumorigenesis and progression. EGFR-mutated adenocarcinoma frequently develops via the multistep progression. Oncogene-induced senescence appears to decrease the frequency of the multistep progression in KRAS- or BRAF-mutated adenocarcinoma, whose tumor evolution may be associated with epigenetic alterations and kinase-inactive mutations. This review summarizes the current knowledge of tumorigenesis and tumor progression in early lung adenocarcinoma, with special focus on its clinicopathological characteristics and their associations with driver mutations (EGFR, KRAS, and BRAF) as well as on its molecular pathogenesis and progression.

Highlights

Lung cancer is the leading cause of cancer-related deaths worldwide, with adenocarcinoma representing the most prevalent subtype
This review summarizes the state of knowledge of tumorigenesis and progression of early lung adenocarcinoma, with a special focus on its clinicopathological characteristics and their associations with driver mutations (EGFR, KRAS, and BRAF)
Most cases of lung adenocarcinoma are found at advanced stages; improved detection at curable stages is needed to decrease the number of disease-associated deaths

Summary

Introduction

Lung cancer is the leading cause of cancer-related deaths worldwide, with adenocarcinoma representing the most prevalent subtype. The recently updated World Health Organization (WHO) classification [1,2], which is based on the accumulated molecular features of cancer, has adopted this stepwise continuum of lung adenocarcinoma tumorigenesis and progression Considering that this process begins with AAH (the precursor of adenocarcinoma), the 2015 WHO classification divides adenocarcinoma into AIS (preinvasive lesion), MIA, and overt invasive adenocarcinoma, according to the extent of invasiveness [1]. AAH, AIS, and MIA are precursors of overt invasive adenocarcinoma with a lepidic pattern; a greater understanding of their development may elucidate the underlying mechanisms of tumor evolution in early lung adenocarcinoma. An analysis of these mechanisms will allow the development of more effective prevention and therapeutic strategies. This review presents the current knowledge of the processes of tumorigenesis and progression in early lung adenocarcinoma, with a focus on its clinicopathological characteristics and their associations with driver mutations (EGFR, KRAS, and BRAF)

Clinicopathological Characteristics

EGFR and KRAS

Driver Mutations in Lung Tumorigenesis

Findings

Conclusions and Future Directions