TY - JOUR
T1 - Deleterious pulmonary surfactant system gene mutations in lung adenocarcinomas associated with usual interstitial pneumonia
AU - Honda, Takayuki
AU - Sakashita, Hiroyuki
AU - Masai, Kyohei
AU - Totsuka, Hirohiko
AU - Motoi, Noriko
AU - Kobayashi, Masashi
AU - Akashi, Takumi
AU - Mimaki, Sachiyo
AU - Tsuchihara, Katsuya
AU - Chiku, Suenori
AU - Shiraishi, Kouya
AU - Shimada, Yoko
AU - Otsuka, Ayaka
AU - Kanai, Yae
AU - Okubo, Kenichi
AU - Watanabe, Shun Ichi
AU - Tsuta, Koji
AU - Inase, Naohiko
AU - Kohno, Takashi
N1 - Publisher Copyright:
© 2019 American Society of Clinical Oncology.
PY - 2018
Y1 - 2018
N2 - Purpose Usual interstitial pneumonia (UIP) is a risk factor for lung carcinogenesis. This study was performed to characterize mutagenesis and mutational target genes underlying lung carcinogenesis in patients with UIP. Patients and Methods A cohort of 691 Japanese patients with lung adenocarcinoma (LADC), of whom 54 had UIP and 637 did not, was studied for driver oncogene aberrations. Whole-exome analysis was performed for 296 cases, including 51 with UIP, to deduce mutagenic processes and identify commonly affected genes. Logistic regression analysis was used to detect associations of gene aberrations with clinicopathological factors. Results The EGFR mutation was markedly less prevalent in patients with LADC with UIP than in those without (1.9% [one of 54] v. 49.9% [318 of 637]; P <.001), even in heavy smokers (25.3% [38 of 150] of patients with > 40 pack-years; P <.001). Mutational signature analysis indicated that UIP-positive LADCs develop through accumulation of single-nucleotide and indel mutations caused by smoking. Pulmonary surfactant system genes (PSSGs) NKX2-1/TTF1, SFTPA1, SFTPA2, SFTPB, and SFTPC were identified as targets for mutations (preferentially indels), and mutations were specifically associated with shorter overall survival of patients with UIP-positive LADC, independent of pathologic stage (hazard ratio, 4.9; 95% CI, 1.7 to 14.4; P =.0037). Conclusion LADCs with UIP develop through mutational events caused by smoking, independently of EGFR mutation. PSSGs were identified as a mutational target and as a novel prognostic factor in UIP-positive LADC. PSSG deficiency might increase the malignancy of tumor cells by increasing the tumor-promoting effects of UIP.
AB - Purpose Usual interstitial pneumonia (UIP) is a risk factor for lung carcinogenesis. This study was performed to characterize mutagenesis and mutational target genes underlying lung carcinogenesis in patients with UIP. Patients and Methods A cohort of 691 Japanese patients with lung adenocarcinoma (LADC), of whom 54 had UIP and 637 did not, was studied for driver oncogene aberrations. Whole-exome analysis was performed for 296 cases, including 51 with UIP, to deduce mutagenic processes and identify commonly affected genes. Logistic regression analysis was used to detect associations of gene aberrations with clinicopathological factors. Results The EGFR mutation was markedly less prevalent in patients with LADC with UIP than in those without (1.9% [one of 54] v. 49.9% [318 of 637]; P <.001), even in heavy smokers (25.3% [38 of 150] of patients with > 40 pack-years; P <.001). Mutational signature analysis indicated that UIP-positive LADCs develop through accumulation of single-nucleotide and indel mutations caused by smoking. Pulmonary surfactant system genes (PSSGs) NKX2-1/TTF1, SFTPA1, SFTPA2, SFTPB, and SFTPC were identified as targets for mutations (preferentially indels), and mutations were specifically associated with shorter overall survival of patients with UIP-positive LADC, independent of pathologic stage (hazard ratio, 4.9; 95% CI, 1.7 to 14.4; P =.0037). Conclusion LADCs with UIP develop through mutational events caused by smoking, independently of EGFR mutation. PSSGs were identified as a mutational target and as a novel prognostic factor in UIP-positive LADC. PSSG deficiency might increase the malignancy of tumor cells by increasing the tumor-promoting effects of UIP.
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U2 - 10.1200/PO.17.00301
DO - 10.1200/PO.17.00301
M3 - Article
AN - SCOPUS:85063925522
VL - 2
SP - 1
EP - 24
JO - JCO Precision Oncology
JF - JCO Precision Oncology
SN - 2473-4284
ER -