Significant accumulation of <em>KRAS</em> mutations in bronchiolar metaplasia‑associated honeycomb lesions of interstitial pneumonia

Kataoka,Toshiaki; Okudela,Koji; Matsumura,Mai; Baba,Tomohisa; Kitamura,Hideya; Arai,Hiromasa; Suzuki,Takeshisa; Koike,Chihiro; Mutsui,Hideaki; Sekiya,Motoki; Sugiyama,Misaki; Takemura,Tamiko; Iwasawa,Tae; Ogura,Takashi; Ohashi,Kenichi

doi:10.3892/ol.2022.13346

Significant accumulation of KRAS mutations in bronchiolar metaplasia‑associated honeycomb lesions of interstitial pneumonia

Authors:
- Toshiaki Kataoka
- Koji Okudela
- Mai Matsumura
- Tomohisa Baba
- Hideya Kitamura
- Hiromasa Arai
- Takeshisa Suzuki
- Chihiro Koike
- Hideaki Mutsui
- Motoki Sekiya
- Misaki Sugiyama
- Tamiko Takemura
- Tae Iwasawa
- Takashi Ogura
- Kenichi Ohashi
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Affiliations: Department of Pathology, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236‑0004, Japan, Division of Respirology, Kanagawa Prefectural Cardiovascular and Respiratory Center Hospital, Yokohama, Kanagawa 236‑0051, Japan, Division of Surgery, Kanagawa Prefectural Cardiovascular and Respiratory Center Hospital, Yokohama, Kanagawa 236‑0051, Japan, Division of Pathology, Kanagawa Prefectural Cardiovascular and Respiratory Center Hospital, Yokohama, Kanagawa 236‑0051, Japan, Division of Radiology, Kanagawa Prefectural Cardiovascular and Respiratory Center Hospital, Yokohama, Kanagawa 236‑0051, Japan
Published online on: May 26, 2022 https://doi.org/10.3892/ol.2022.13346
Article Number: 225
Copyright: © Kataoka et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Interstitial pneumonia (IP) is a major risk factor for lung adenocarcinoma (LADC). IP‑related LADC predominantly develops in the bronchiolar metaplasia lining in honeycomb lesions. Kirsten rat sarcoma virus (KRAS) is the most common oncogene mutated in IP‑related LADC. The present study examined the metaplastic epithelia in honeycomb lesions for KRAS mutations using digital droplet polymerase chain reaction (ddPCR), a sensitive method used to detect infrequent mutations. Significantly higher KRAS mutation variant allele frequencies (VAFs) were detected in the metaplastic lung epithelia from 13 patients with IP compared with those in 46 non‑lesioned lung samples from patients without IP (G12V, P=0.0004, G12C, P=0.0181, and G12A, P=0.0234; Mann Whitney U test). Multivariate analyses revealed that higher KRAS G12V (logistic regression model; P=0.0133, odds ratio=7.11) and G12C (P=0.0191, odds ratio=5.81) VAFs in patients with IP were independent of confounding variables, such as smoking and age. In patients with IP, metaplastic epithelia exhibited significantly higher KRAS G12V and G12C VAFs compared with the non‑lesioned counterparts (paired t‑test; G12V, P=0.0158, G12C, P=0.0465). These results suggested that IP could increase KRAS mutations and supported the hypothesis that bronchiolar metaplasia could be a precursor for IP‑related LADC.

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