title: Combined effects of asbestos and cigarette smoke on the development of lung adenocarcinoma: different carcinogens may cause different genomic changes.
abstract: The carcinogens in cigarette smoke are distinct from asbestos. However, an understanding of their differential effects on lung adenocarcinoma development remains elusive. We investigated loss of heterozygosity (LOH) and the p53 mutation in 132 lung adenocarcinomas, for which asbestos body burden (AB; in numbers per gram of dry lung) was measured using adjacent normal lung. All cases were classified into 9 groups based on a matrix of cumulative smoking (CS in pack‑years; CS=0, 0<CS<25, ≥25 CS) and AB (AB=0, 0<AB<1,000, ≥1,000 AB). AB=0 indicates a lower level than the detection limit of ~100. LOH frequency increased only slightly with the elevation of CS in the AB=0 groups. In the AB>0 groups, LOH frequency increased as AB and/or CS was elevated and was significantly higher in the ≥1,000 AB, ≥25 CS group (p=0.032). p53 mutation frequency was the lowest in the AB=0, CS=0 group, increased as AB and/or CS rose, and was significantly higher in the ≥1,000 AB, ≥25 CS group (p=0.039). p53 mutations characteristic of smoking were frequently observed in the CS>0 groups contrary to non-specific mutations in the CS=0, AB>0 groups. Combined effects of asbestos and smoking were suggested by LOH and p53 analyses. Sole exposure to asbestos did not increase LOH frequency but increased non‑specific p53 mutations. These findings indicate that the major carcinogenic mechanism of asbestos may be tumor promotion, acting in an additive or synergistic manner, contributing to the genotoxic effect of smoking. Since this study was based on a general cancer center's experience, the limited sample size did not permit the consideration that the result was conclusive. Further investigation with a large sample size is needed to establish the mechanism of asbestos-induced lung carcinogenesis.
authors.affiliation: Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research (JFCR), Koto-ku, Tokyo 135‑8550, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Inamura
authors.affiliation: Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research (JFCR), Koto-ku, Tokyo 135‑8550, Japan.
authors.forename: Hironori
authors.initials: H
authors.lastname: Ninomiya
authors.affiliation: Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research (JFCR), Koto-ku, Tokyo 135‑8550, Japan.
authors.forename: Kimie
authors.initials: K
authors.lastname: Nomura
authors.affiliation: Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research (JFCR), Koto-ku, Tokyo 135‑8550, Japan.
authors.forename: Eiju
authors.initials: E
authors.lastname: Tsuchiya
authors.affiliation: Department of Thoracic Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa 228‑8555, Japan.
authors.forename: Yukitoshi
authors.initials: Y
authors.lastname: Satoh
authors.affiliation: Department of Thoracic Surgery, The Cancer Institute Hospital, JFCR, Koto-ku, Tokyo 135‑8550, Japan.
authors.forename: Sakae
authors.initials: S
authors.lastname: Okumura
authors.affiliation: Department of Thoracic Surgery, The Cancer Institute Hospital, JFCR, Koto-ku, Tokyo 135‑8550, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Nakagawa
authors.affiliation: Department of Preventive Medicine, St. Marianna University School of Medicine, Miyamae-ku, Kawasaki, Kanagawa 216-8511, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Takata
authors.affiliation: Faculty of Economics, Toyo University, Bunkyo-ku, Tokyo 12-8608, Japan.
authors.forename: Norihiko
authors.initials: N
authors.lastname: Kohyama
authors.affiliation: Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research (JFCR), Koto-ku, Tokyo 135‑8550, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Ishikawa
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology*; D000077192:Adenocarcinoma of Lung; D000328:Adult; D000368:Aged; D001194:Asbestos / Q000633:toxicity*; D003043:Cocarcinogenesis / Q000235:genetics; D005260:Female; D006801:Humans; D019656:Loss of Heterozygosity; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D016273:Occupational Exposure; D012907:Smoking / Q000009:adverse effects*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D016159:Tumor Suppressor Protein p53; D001194:Asbestos