Whole genome sequencing to identify predictive markers for the risk of drug-induced interstitial lung disease

Autoři: Chihiro Udagawa aff001;  Hidehito Horinouchi aff002;  Kouya Shiraishi aff003;  Takashi Kohno aff003;  Takuji Okusaka aff004;  Hideki Ueno aff004;  Kenji Tamura aff005;  Yuichiro Ohe aff002;  Hitoshi Zembutsu aff001
Působiště autorů: Division of Genetics, National Cancer Center Research Institute, Tokyo, Japan aff001;  Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan aff002;  Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan aff003;  Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan aff004;  Department of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo, Japan aff005;  Project for Development of Liquid Biopsy Diagnosis, Japanese Foundation for Cancer Research, Research Institute, Tokyo, Japan aff006
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article
doi: 10.1371/journal.pone.0223371


Drug-induced interstitial lung disease (DIILD) is a serious side effect of chemotherapy in cancer patients with an extremely high mortality rate. In this study, to identify genetic variants with greater risk of DIILD, we carried out whole genome sequencing (WGS) of germline DNA samples from 26 patients who developed DIILD, and conducted a case-control association study between these 26 cases and general Japanese population controls registered in the integrative Japanese Genome Variation Database (iJGVD) as a screening study. The associations of 42 single nucleotide variants (SNVs) showing P < 0.0001 were further validated using an independent cohort of 18 DIILD cases as a replication study. A further combined analysis of the screening and replication studies showed a possible association of two SNVs, rs35198919 in intron 1 of the chromosome 22 open reading frame 34 (C22orf34) and rs12625311 in intron 1 of the teashirt zinc finger homeobox 2 (TSHZ2), with DIILD (Pcombined = 1.87 × 10−5 and 5.16 × 10−5, respectively). Furthermore, in a subgroup analysis of epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitor (TKI)-induced interstitial lung disease (ILD), we observed seven candidate SNVs that were possibly associated with ILD (P < 0.00001). This is the first study to identify genetic markers for the risk of DIILD using WGS. Collectively, our novel findings indicate that these SNVs may be applicable for predicting the risk of DIILD in patients receiving chemotherapy.

Klíčová slova:

Cancer treatment – Genome analysis – Human genetics – Introns – Lung and intrathoracic tumors – Oxygen – Replication studies – Genetic screens


1. Bellamy EA, Husband JE, Blaquiere RM, Law MR. Bleomycin-related lung damage: CT evidence. Radiology. 1985;156(1):155–8. doi: 10.1148/radiology.156.1.2408293 2408293

2. Gurjal A, An T, Valdivieso M, Kalemkerian GP. Etoposide-induced pulmonary toxicity. Lung cancer (Amsterdam, Netherlands). 1999;26(2):109–12.

3. Yague XH, Soy E, Merino BQ, Puig J, Fabregat MB, Colomer R. Interstitial pneumonitis after oxaliplatin treatment in colorectal cancer. Clinical & translational oncology: official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico. 2005;7(11):515–7.

4. Sawada T, Inokuma S, Sato T, Otsuka T, Saeki Y, Takeuchi T, et al. Leflunomide-induced interstitial lung disease: prevalence and risk factors in Japanese patients with rheumatoid arthritis. Rheumatology (Oxford, England). 2009;48(9):1069–72.

5. Perez-Alvarez R, Perez-de-Lis M, Diaz-Lagares C, Pego-Reigosa JM, Retamozo S, Bove A, et al. Interstitial lung disease induced or exacerbated by TNF-targeted therapies: analysis of 122 cases. Seminars in arthritis and rheumatism. 2011;41(2):256–64. doi: 10.1016/j.semarthrit.2010.11.002 21277618

6. Koike T, Harigai M, Ishiguro N, Inokuma S, Takei S, Takeuchi T, et al. Safety and effectiveness of adalimumab in Japanese rheumatoid arthritis patients: postmarketing surveillance report of 7740 patients. Modern rheumatology. 2014;24(3):390–8. doi: 10.3109/14397595.2013.843760 24252049

7. Fernandez AB, Karas RH, Alsheikh-Ali AA, Thompson PD. Statins and interstitial lung disease: a systematic review of the literature and of food and drug administration adverse event reports. Chest. 2008;134(4):824–30. doi: 10.1378/chest.08-0943 18689579

8. Yamasaki K, Yatera K, Noguchi S, Oda K, Akata K, Nishida C, et al. Incidence and outcomes of bepridil-induced interstitial pneumonia. Respiratory medicine. 2013;107(12):2088–91. doi: 10.1016/j.rmed.2013.09.023 24140111

9. Kang IS, Kim KJ, Kim Y, Park SH. The diagnostic utility of chest computed tomography scoring for the assessment of amiodarone-induced pulmonary toxicity. The Korean journal of internal medicine. 2014;29(6):746–53. doi: 10.3904/kjim.2014.29.6.746 25378973

10. Skeoch S, Weatherley N, Swift AJ, Oldroyd A, Johns C, Hayton C, et al. Drug-Induced Interstitial Lung Disease: A Systematic Review. Journal of clinical medicine. 2018;7(10).

11. Furukawa H, Oka S, Shimada K, Tsuchiya N, Tohma S. Genetics of Interstitial Lung Disease: Vol de Nuit (Night Flight). Clinical medicine insights Circulatory, respiratory and pulmonary medicine. 2015;9(Suppl 1):1–7. doi: 10.4137/CCRPM.S23283 26056507

12. Schwaiblmair M, Behr W, Haeckel T, Markl B, Foerg W, Berghaus T. Drug induced interstitial lung disease. The open respiratory medicine journal. 2012;6:63–74. doi: 10.2174/1874306401206010063 22896776

13. Ripley B, Kelil T, Gill R. Deciphering drug-induced interstitial lung disease: A mechanistic approach2016. 9–18 p.

14. Ishikawa N, Hattori N, Yokoyama A, Tanaka S, Nishino R, Yoshioka K, et al. Usefulness of monitoring the circulating Krebs von den Lungen-6 levels to predict the clinical outcome of patients with advanced nonsmall cell lung cancer treated with epidermal growth factor receptor tyrosine kinase inhibitors. International journal of cancer. 2008;122(11):2612–20. doi: 10.1002/ijc.23411 18324627

15. Qin H, Xu XP, Zou J, Zhao XJ, Wu HW, Zha QF, et al. Krebs von den Lungen-6 associated with chest high-resolution CT score in evaluation severity of patients with interstitial lung disease. Pulmonology. 2018.

16. Nakamura K, Kato M, Shukuya T, Mori K, Sekimoto Y, Ihara H, et al. Surfactant protein-D predicts prognosis of interstitial lung disease induced by anticancer agents in advanced lung cancer: a case control study. BMC cancer. 2017;17(1):302. doi: 10.1186/s12885-017-3285-6 28464801

17. Ohnishi H, Yokoyama A, Kondo K, Hamada H, Abe M, Nishimura K, et al. Comparative study of KL-6, surfactant protein-A, surfactant protein-D, and monocyte chemoattractant protein-1 as serum markers for interstitial lung diseases. American journal of respiratory and critical care medicine. 2002;165(3):378–81. doi: 10.1164/ajrccm.165.3.2107134 11818324

18. Minami-Shimmyo Y, Ohe Y, Yamamoto S, Sumi M, Nokihara H, Horinouchi H, et al. Risk factors for treatment-related death associated with chemotherapy and thoracic radiotherapy for lung cancer. Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer. 2012;7(1):177–82.

19. Osawa M, Kudoh S, Sakai F, Endo M, Hamaguchi T, Ogino Y, et al. Clinical features and risk factors of panitumumab-induced interstitial lung disease: a postmarketing all-case surveillance study. International journal of clinical oncology. 2015;20(6):1063–71. doi: 10.1007/s10147-015-0834-3 25967287

20. Hamada T, Yasunaga H, Nakai Y, Isayama H, Matsui H, Fushimi K, et al. Interstitial lung disease associated with gemcitabine: A Japanese retrospective cohort study. Respirology (Carlton, Vic). 2016;21(2):338–43.

21. Tamura M, Saraya T, Fujiwara M, Hiraoka S, Yokoyama T, Yano K, et al. High-resolution computed tomography findings for patients with drug-induced pulmonary toxicity, with special reference to hypersensitivity pneumonitis-like patterns in gemcitabine-induced cases. The oncologist. 2013;18(4):454–9. doi: 10.1634/theoncologist.2012-0248 23404815

22. Johkoh T, Sakai F, Kusumoto M, Arakawa H, Harada R, Ueda M, et al. Association between baseline pulmonary status and interstitial lung disease in patients with non-small-cell lung cancer treated with erlotinib—a cohort study. Clinical lung cancer. 2014;15(6):448–54. doi: 10.1016/j.cllc.2014.06.003 25043209

23. Furukawa H, Oka S, Shimada K, Tsuchiya N, Tohma S. HLA-A*31:01 and methotrexate-induced interstitial lung disease in Japanese rheumatoid arthritis patients: a multidrug hypersensitivity marker? Annals of the rheumatic diseases. 2013;72(1):153–5. doi: 10.1136/annrheumdis-2012-201944 22887846

24. Nishimura M, Toyoda M, Takenaka K, Imamura Y, Chayahara N, Kiyota N, et al. The combination of HLA-B*15:01 and DRB1*15:01 is associated with gemcitabine plus erlotinib-induced interstitial lung disease in patients with advanced pancreatic cancer. Cancer chemotherapy and pharmacology. 2016;77(6):1165–70. doi: 10.1007/s00280-016-3026-6 27100735

25. Daly AK, Donaldson PT, Bhatnagar P, Shen Y, Pe'er I, Floratos A, et al. HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin. Nature genetics. 2009;41(7):816–9. doi: 10.1038/ng.379 19483685

26. Lucena MI, Molokhia M, Shen Y, Urban TJ, Aithal GP, Andrade RJ, et al. Susceptibility to amoxicillin-clavulanate-induced liver injury is influenced by multiple HLA class I and II alleles. Gastroenterology. 2011;141(1):338–47. doi: 10.1053/j.gastro.2011.04.001 21570397

27. Behr ER, Ritchie MD, Tanaka T, Kaab S, Crawford DC, Nicoletti P, et al. Genome wide analysis of drug-induced torsades de pointes: lack of common variants with large effect sizes. PloS one. 2013;8(11):e78511. doi: 10.1371/journal.pone.0078511 24223155

28. Nicoletti P, Aithal GP, Bjornsson ES, Andrade RJ, Sawle A, Arrese M, et al. Association of Liver Injury From Specific Drugs, or Groups of Drugs, With Polymorphisms in HLA and Other Genes in a Genome-Wide Association Study. Gastroenterology. 2017;152(5):1078–89. doi: 10.1053/j.gastro.2016.12.016 28043905

29. Martin M. Cutadapt removes adapter sequences from high-throughput sequencing reads. 2011. 2011;17(1):3.

30. Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics (Oxford, England). 2009;25(14):1754–60.

31. McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A, et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome research. 2010;20(9):1297–303. doi: 10.1101/gr.107524.110 20644199

32. Udagawa C, Nakamura H, Ohnishi H, Tamura K, Shimoi T, Yoshida M, et al. Whole exome sequencing to identify genetic markers for trastuzumab-induced cardiotoxicity. Cancer science. 2018;109(2):446–52. doi: 10.1111/cas.13471 29247589

33. Nagasaki M, Yasuda J, Katsuoka F, Nariai N, Kojima K, Kawai Y, et al. Rare variant discovery by deep whole-genome sequencing of 1,070 Japanese individuals. Nature communications. 2015;6:8018. doi: 10.1038/ncomms9018 26292667

34. Battle A, Brown CD, Engelhardt BE, Montgomery SB. Genetic effects on gene expression across human tissues. Nature. 2017;550(7675):204–13. doi: 10.1038/nature24277 29022597

35. Inaguma S, Riku M, Ito H, Tsunoda T, Ikeda H, Kasai K. GLI1 orchestrates CXCR4/CXCR7 signaling to enhance migration and metastasis of breast cancer cells. Oncotarget. 2015;6(32):33648–57. doi: 10.18632/oncotarget.5203 26413813

36. Riku M, Inaguma S, Ito H, Tsunoda T, Ikeda H, Kasai K. Down-regulation of the zinc-finger homeobox protein TSHZ2 releases GLI1 from the nuclear repressor complex to restore its transcriptional activity during mammary tumorigenesis. Oncotarget. 2016;7(5):5690–701. doi: 10.18632/oncotarget.6788 26744317

37. Ueta M. Cold medicine-related Stevens-Johnson syndrome/toxic epidermal necrolysis with severe ocular complications-phenotypes and genetic predispositions. Taiwan journal of ophthalmology. 2016;6(3):108–18. doi: 10.1016/j.tjo.2016.06.001 29018724

38. Kamata T, Sakamaki F, Fujita H, Urano T, Mori M, Yamaguchi K, et al. Toxic epidermal necrolysis with tracheobronchial and pulmonary complications. Internal medicine (Tokyo, Japan). 1994;33(4):252–5.

39. Lee T, Bae YJ, Park SK, Park HJ, Kim SH, Cho YS, et al. Severe pneumonia caused by combined infection with Pneumocystis jiroveci, parainfluenza virus type 3, cytomegalovirus, and Aspergillus fumigatus in a patient with Stevens-Johnson syndrome/toxic epidermal necrolysis. Acta dermato-venereologica. 2010;90(6):625–9. doi: 10.2340/00015555-0977 21057748

40. Cohen MH, Williams GA, Sridhara R, Chen G, McGuinn WD Jr., Morse D, et al. United States Food and Drug Administration Drug Approval summary: Gefitinib (ZD1839; Iressa) tablets. Clinical cancer research: an official journal of the American Association for Cancer Research. 2004;10(4):1212–8.

41. Gemma A, Kudoh S, Ando M, Ohe Y, Nakagawa K, Johkoh T, et al. Final safety and efficacy of erlotinib in the phase 4 POLARSTAR surveillance study of 10 708 Japanese patients with non-small-cell lung cancer. Cancer science. 2014;105(12):1584–90. doi: 10.1111/cas.12550 25287435

42. Zhang Y, Iwasaki H, Wang H, Kudo T, Kalka TB, Hennet T, et al. Cloning and characterization of a new human UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase, designated pp-GalNAc-T13, that is specifically expressed in neurons and synthesizes GalNAc alpha-serine/threonine antigen. The Journal of biological chemistry. 2003;278(1):573–84. doi: 10.1074/jbc.M203094200 12407114

43. Juge PA, Lee JS, Ebstein E, Furukawa H, Dobrinskikh E, Gazal S, et al. MUC5B Promoter Variant and Rheumatoid Arthritis with Interstitial Lung Disease. The New England journal of medicine. 2018;379(23):2209–19. doi: 10.1056/NEJMoa1801562 30345907

44. Seibold MA, Wise AL, Speer MC, Steele MP, Brown KK, Loyd JE, et al. A common MUC5B promoter polymorphism and pulmonary fibrosis. The New England journal of medicine. 2011;364(16):1503–12. doi: 10.1056/NEJMoa1013660 21506741

45. Selman M, Lin HM, Montano M, Jenkins AL, Estrada A, Lin Z, et al. Surfactant protein A and B genetic variants predispose to idiopathic pulmonary fibrosis. Human genetics. 2003;113(6):542–50. doi: 10.1007/s00439-003-1015-4 13680361

46. Wang Y, Kuan PJ, Xing C, Cronkhite JT, Torres F, Rosenblatt RL, et al. Genetic defects in surfactant protein A2 are associated with pulmonary fibrosis and lung cancer. American journal of human genetics. 2009;84(1):52–9. doi: 10.1016/j.ajhg.2008.11.010 19100526

47. Brehmer D, Greff Z, Godl K, Blencke S, Kurtenbach A, Weber M, et al. Cellular targets of gefitinib. Cancer research. 2005;65(2):379–82. 15695376

48. Tabara H, Naito Y, Ito A, Katsuma A, Sakurai MA, Ohno S, et al. Neonatal lethality in knockout mice expressing the kinase-dead form of the gefitinib target GAK is caused by pulmonary dysfunction. PloS one. 2011;6(10):e26034. doi: 10.1371/journal.pone.0026034 22022498

49. Ballester B, Milara J, Guijarro R, Morcillo E, Cortijo J. Role of MUC4 in idiopathic pulmonary fibrosis. European Respiratory Journal. 2018;52(suppl 62):PA4798.

Článek vyšel v časopise


2019 Číslo 10

Nejčtenější v tomto čísle

Tomuto tématu se dále věnují…


Zvyšte si kvalifikaci online z pohodlí domova

Léčba bolesti v ordinaci praktického lékaře
nový kurz
Autoři: MUDr. PhDr. Zdeňka Nováková, Ph.D.

Revmatoidní artritida: včas a k cíli
Autoři: MUDr. Heřman Mann

Jistoty a nástrahy antikoagulační léčby aneb kardiolog - neurolog - farmakolog - nefrolog - právník diskutují
Autoři: doc. MUDr. Štěpán Havránek, Ph.D., prof. MUDr. Roman Herzig, Ph.D., doc. MUDr. Karel Urbánek, Ph.D., prim. MUDr. Jan Vachek, MUDr. et Mgr. Jolana Těšínová, Ph.D.

Léčba akutní pooperační bolesti
Autoři: doc. MUDr. Jiří Málek, CSc.

Nové antipsychotikum kariprazin v léčbě schizofrenie
Autoři: prof. MUDr. Cyril Höschl, DrSc., FRCPsych.

Všechny kurzy
Kurzy Doporučená témata Časopisy
Zapomenuté heslo

Nemáte účet?  Registrujte se

Zapomenuté heslo

Zadejte e-mailovou adresu se kterou jste vytvářel(a) účet, budou Vám na ni zaslány informace k nastavení nového hesla.


Nemáte účet?  Registrujte se