Deleterious pulmonary surfactant system gene mutations in lung adenocarcinomas associated with usual interstitial pneumonia

Takayuki Honda, Hiroyuki Sakashita, Kyohei Masai, Hirohiko Totsuka, Noriko Motoi, Masashi Kobayashi, Takumi Akashi, Sachiyo Mimaki, Katsuya Tsuchihara, Suenori Chiku, Kouya Shiraishi, Yoko Shimada, Ayaka Otsuka, Yae Kanai, Kenichi Okubo, Shun Ichi Watanabe, Koji Tsuta, Naohiko Inase, Takashi Kohno

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
JournalJCO Precision Oncology
Volume2
DOIs
Publication statusPublished - 2018 Jan 1

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Pulmonary Surfactants
Idiopathic Pulmonary Fibrosis
Mutation
Genes
Carcinogenesis
Smoking
Adenocarcinoma of lung
Exome
Neoplasms
Lung
Oncogenes
Mutagenesis
Nucleotides
Logistic Models
Regression Analysis

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Deleterious pulmonary surfactant system gene mutations in lung adenocarcinomas associated with usual interstitial pneumonia. / Honda, Takayuki; Sakashita, Hiroyuki; Masai, Kyohei; Totsuka, Hirohiko; Motoi, Noriko; Kobayashi, Masashi; Akashi, Takumi; Mimaki, Sachiyo; Tsuchihara, Katsuya; Chiku, Suenori; Shiraishi, Kouya; Shimada, Yoko; Otsuka, Ayaka; Kanai, Yae; Okubo, Kenichi; Watanabe, Shun Ichi; Tsuta, Koji; Inase, Naohiko; Kohno, Takashi.

In: JCO Precision Oncology, Vol. 2, 01.01.2018.

Research output: Contribution to journalArticle

Honda, T, Sakashita, H, Masai, K, Totsuka, H, Motoi, N, Kobayashi, M, Akashi, T, Mimaki, S, Tsuchihara, K, Chiku, S, Shiraishi, K, Shimada, Y, Otsuka, A, Kanai, Y, Okubo, K, Watanabe, SI, Tsuta, K, Inase, N & Kohno, T 2018, 'Deleterious pulmonary surfactant system gene mutations in lung adenocarcinomas associated with usual interstitial pneumonia', JCO Precision Oncology, vol. 2. https://doi.org/10.1200/PO.17.00301
Honda, Takayuki ; Sakashita, Hiroyuki ; Masai, Kyohei ; Totsuka, Hirohiko ; Motoi, Noriko ; Kobayashi, Masashi ; Akashi, Takumi ; Mimaki, Sachiyo ; Tsuchihara, Katsuya ; Chiku, Suenori ; Shiraishi, Kouya ; Shimada, Yoko ; Otsuka, Ayaka ; Kanai, Yae ; Okubo, Kenichi ; Watanabe, Shun Ichi ; Tsuta, Koji ; Inase, Naohiko ; Kohno, Takashi. / Deleterious pulmonary surfactant system gene mutations in lung adenocarcinomas associated with usual interstitial pneumonia. In: JCO Precision Oncology. 2018 ; Vol. 2.
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abstract = "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.",
author = "Takayuki Honda and Hiroyuki Sakashita and Kyohei Masai and Hirohiko Totsuka and Noriko Motoi and Masashi Kobayashi and Takumi Akashi and Sachiyo Mimaki and Katsuya Tsuchihara and Suenori Chiku and Kouya Shiraishi and Yoko Shimada and Ayaka Otsuka and Yae Kanai and Kenichi Okubo and Watanabe, {Shun Ichi} and Koji Tsuta and Naohiko Inase and Takashi Kohno",
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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

PY - 2018/1/1

Y1 - 2018/1/1

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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