Predictive advantage of a cell type classification for pulmonary adenocarcinoma coupled with data for p53, K‐ras and EGFR alterations

Abstract

We analyzed relationships between histological subtypes of pulmonary adenocarcinomas and three gene alterations (p53, K-ras, and epidermal growth factor receptor gene), or thyroid transcription factor-1 (TTF-1) expression, and also studied prognoses by the subtypes, with or without combined multiple gene mutation status. Our purpose was to clearly determine pathogenesis, along with the best predictive value for biology and therapy-related traits. A total of 223 consecutively resected pulmonary adenocarcinomas were sub-classified using either the World Health Organization (WHO) or our five-cell type (FCT) classification system (hobnail, columnar ⁄ cuboidal, mixed, polygonal ⁄ oval, and goblet cell types). DNAs extracted from frozen samples of the adenocarcinomas were examined for gene alterations, and TTF-1 expressions were determined using immunohistochemistry. Next, relationships among the various data and clinicopathological factors were analyzed. The most striking result was: while almost 70% of adenocarcinomas were sub-classified as a mixed subtype by WHO, the FCT classified many of them as other cell subtypes. The FCT closely reflected differences in etiological factors, cellular lineages, and frequencies of gene mutations; and whether the data from combined gene mutations were used or not, differences among the cell types in postoperative survivals appeared. In contrast, subtypes of WHO did not show any association with the gene alteration or prognosis, and the FCT more suitably indicated sensitivity to gefitinib therapy than did WHO. The FCT combined with multiple gene mutation status appears to be useful in indicating pathogenesis and predicting the biological nature of pulmonary adenocarcinomas, and it could facilitate development of new therapies for each subtype.

KEAP1 gene mutations and NRF2 activation are common in pulmonary papillary adenocarcinoma

“…For example, mutations of the RB gene are common in small cell cancers but rare in non small lung cell cancers (NSCLC), whereas mutations (or methylation) of P16 are characteristic in the non-small cell cancers [1]. Among NSCLCs, coding mutations of the KRAS and EGFR genes are relatively restricted to adenocarcinoma [2], with EGFR mutations being particular prevalent in adenocarcinoma tumors with the bronchioalveolar histological pattern of growth [3]. Thus, genomic data for lung cancer cannot be generalized across various histological types of the disease.…”

EGFR mutational status of primary Lung Adenocarcinoma in an Indian cohort based on 2015 WHO classification of lung tumors

“…Although the polygonal cell type was the commonest, the cuboidal cell type was significantly associated with EGFR mutations. A similar study by Okada et al [23] proposed the five-cell type classification and found the hobnail cell type to be significantly associated with EGFR mutations (p<0.001), followed by mixed, columnar/ cuboidal, polygonal and goblet cells. The study also found a higher percentage of smokers to be significantly associated with the cuboidal/ columnar and polygonal cell type, similar to findings in this study where the polygonal cell type was associated with smokers.…”