Identification of Predictive Epigenetic Biomarkers of Lung Disease Severity in Cystic Fibrosis

NCT02976714 | Completed DMC

• 1 other identifier: RECHMPL16_0256
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 1

Brief Summary

The general aims of this project are (i) to identify predictive epigenetic biomarkers of lung disease severity in Cystic Fibrosis, (ii) to characterize a non-invasive cellular model, spontaneous sputum, for the analysis of these epigenetic biomarkers, (iii) to analyze the variations in DNA methylation for a same patient over time.

Conditions

Cystic Fibrosis

Keywords

Cystic Fibrosis; Lung disease; DNA methylation; Predictive biomarkers

Outcome Measures

Primary Outcomes (4)

• DNA methylation

  Spontaneous expectoration at baseline

  at time of inclusion

• DNA methylation

  Spontaneous expectoration at 6 months

  6 months

• DNA methylation

  Spontaneous expectoration at 12 months

  12 months

• DNA methylation

  Spontaneous expectoration at 18 months

  18 months

Study Arms (1)

CF patients

OTHER

CF patients carry a spontaneous sputum that is made in the context of bronchial drainage sessions conducted as part of usual care.

Other: spontaneous sputum

Interventions

spontaneous sputum OTHER

CF patients carry a spontaneous sputum that is made in the context of bronchial drainage sessions conducted as part of usual care (inclusion, 6 months, 12 months, 18 months). The collection of spontaneous sputum is carried out within the bronchial drainage sessions, which are routinely performed at each visit. The spontaneous sputum is collected in a sterile container. In order not to contaminate the sputum with buccal epithelial cells will be asked patients to rinse the mouth before expectorate.

CF patients

Eligibility Criteria

• Age: 12 Years - 30 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• free and informed consent obtained, and consent signed
• subject covered by a state insurance scheme
• women and men aged 12 to 30
• subject affected by cystic fibrosis, carrier of two severe mutations in trans (in the same allele) in the CFTR gene
• subject able to realize a spirometry before and during the study

You may not qualify if:

• subject placed under judicial protection, guardianship or supervision
• impossibility to give informed information to the subject
• subject who does not read fluently French
• pregnancy
• breastfeeding
• transplanted subject

Sponsors & Collaborators

• University Hospital, Montpellier: lead

Study Sites (1)

Uhmontpellier

Montpellier, 34295, France

Location

Related Publications (26)

• Audrezet MP, Munck A, Scotet V, Claustres M, Roussey M, Delmas D, Ferec C, Desgeorges M. Comprehensive CFTR gene analysis of the French cystic fibrosis screened newborn cohort: implications for diagnosis, genetic counseling, and mutation-specific therapy. Genet Med. 2015 Feb;17(2):108-16. doi: 10.1038/gim.2014.113. Epub 2014 Aug 14.

  PMID: 25122143 BACKGROUND

• Bergougnoux A, Rivals I, Liquori A, Raynal C, Varilh J, Magalhaes M, Perez MJ, Bigi N, Des Georges M, Chiron R, Squalli-Houssaini AS, Claustres M, De Sario A. A balance between activating and repressive histone modifications regulates cystic fibrosis transmembrane conductance regulator (CFTR) expression in vivo. Epigenetics. 2014 Jul;9(7):1007-17. doi: 10.4161/epi.28967. Epub 2014 Apr 29.

  PMID: 24782114 BACKGROUND

• Bergougnoux A, Claustres M, De Sario A. Nasal epithelial cells: a tool to study DNA methylation in airway diseases. Epigenomics. 2015;7(1):119-26. doi: 10.2217/epi.14.65.

  PMID: 25687471 BACKGROUND

• Besaratinia A, Maas LM, Brouwer EM, Kleinjans JC, Van Schooten FJ. Comparison between smoking-related DNA adduct analysis in induced sputum and peripheral blood lymphocytes. Carcinogenesis. 2000 Jul;21(7):1335-40. doi: 10.1093/carcin/21.7.1335.

  PMID: 10874011 BACKGROUND

• Brennan ML, Schrijver I. Cystic Fibrosis: A Review of Associated Phenotypes, Use of Molecular Diagnostic Approaches, Genetic Characteristics, Progress, and Dilemmas. J Mol Diagn. 2016 Jan;18(1):3-14. doi: 10.1016/j.jmoldx.2015.06.010. Epub 2015 Nov 26.

  PMID: 26631874 BACKGROUND

• Clarke LA, Sousa L, Barreto C, Amaral MD. Changes in transcriptome of native nasal epithelium expressing F508del-CFTR and intersecting data from comparable studies. Respir Res. 2013 Mar 28;14(1):38. doi: 10.1186/1465-9921-14-38.

  PMID: 23537407 BACKGROUND

• Collaco JM, Blackman SM, McGready J, Naughton KM, Cutting GR. Quantification of the relative contribution of environmental and genetic factors to variation in cystic fibrosis lung function. J Pediatr. 2010 Nov;157(5):802-7.e1-3. doi: 10.1016/j.jpeds.2010.05.018. Epub 2010 Jun 30.

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• Corvol H, Thompson KE, Tabary O, le Rouzic P, Guillot L. Translating the genetics of cystic fibrosis to personalized medicine. Transl Res. 2016 Feb;168:40-49. doi: 10.1016/j.trsl.2015.04.008. Epub 2015 Apr 15.

  PMID: 25940043 BACKGROUND

• Cutting GR. Modifier genes in Mendelian disorders: the example of cystic fibrosis. Ann N Y Acad Sci. 2010 Dec;1214:57-69. doi: 10.1111/j.1749-6632.2010.05879.x.

  PMID: 21175684 BACKGROUND

• Eckrich J, Zissler UM, Serve F, Leutz P, Smaczny C, Schmitt-Grohe S, Fussbroich D, Schubert R, Zielen S, Eickmeier O. Airway inflammation in mild cystic fibrosis. J Cyst Fibros. 2017 Jan;16(1):107-115. doi: 10.1016/j.jcf.2016.05.016. Epub 2016 Jun 11.

  PMID: 27296563 BACKGROUND

• Efthimiadis A, Spanevello A, Hamid Q, Kelly MM, Linden M, Louis R, Pizzichini MM, Pizzichini E, Ronchi C, Van Overvel F, Djukanovic R. Methods of sputum processing for cell counts, immunocytochemistry and in situ hybridisation. Eur Respir J Suppl. 2002 Sep;37:19s-23s. doi: 10.1183/09031936.02.00001902. No abstract available.

  PMID: 12361358 BACKGROUND

• Gu Y, Harley IT, Henderson LB, Aronow BJ, Vietor I, Huber LA, Harley JB, Kilpatrick JR, Langefeld CD, Williams AH, Jegga AG, Chen J, Wills-Karp M, Arshad SH, Ewart SL, Thio CL, Flick LM, Filippi MD, Grimes HL, Drumm ML, Cutting GR, Knowles MR, Karp CL. Identification of IFRD1 as a modifier gene for cystic fibrosis lung disease. Nature. 2009 Apr 23;458(7241):1039-42. doi: 10.1038/nature07811. Epub 2009 Feb 25.

  PMID: 19242412 BACKGROUND

• Guzman L, Depix MS, Salinas AM, Roldan R, Aguayo F, Silva A, Vinet R. Analysis of aberrant methylation on promoter sequences of tumor suppressor genes and total DNA in sputum samples: a promising tool for early detection of COPD and lung cancer in smokers. Diagn Pathol. 2012 Jul 20;7:87. doi: 10.1186/1746-1596-7-87.

  PMID: 22818553 BACKGROUND

• Hanrahan JW, Sampson HM, Thomas DY. Novel pharmacological strategies to treat cystic fibrosis. Trends Pharmacol Sci. 2013 Feb;34(2):119-25. doi: 10.1016/j.tips.2012.11.006.

  PMID: 23380248 BACKGROUND

• Magalhaes M, Rivals I, Claustres M, Varilh J, Thomasset M, Bergougnoux A, Mely L, Leroy S, Corvol H, Guillot L, Murris M, Beyne E, Caimmi D, Vachier I, Chiron R, De Sario A. DNA methylation at modifier genes of lung disease severity is altered in cystic fibrosis. Clin Epigenetics. 2017 Feb 14;9:19. doi: 10.1186/s13148-016-0300-8. eCollection 2017.

  PMID: 28289476 BACKGROUND

• Magalhaes M, Tost J, Pineau F, Rivals I, Busato F, Alary N, Mely L, Leroy S, Murris M, Caimmi D, Claustres M, Chiron R, De Sario A. Dynamic changes of DNA methylation and lung disease in cystic fibrosis: lessons from a monogenic disease. Epigenomics. 2018 Aug;10(8):1131-1145. doi: 10.2217/epi-2018-0005. Epub 2018 Jul 27.

  PMID: 30052057 BACKGROUND

• McCarthy C, Dimitrov BD, Meurling IJ, Gunaratnam C, McElvaney NG. The CF-ABLE score: a novel clinical prediction rule for prognosis in patients with cystic fibrosis. Chest. 2013 May;143(5):1358-1364. doi: 10.1378/chest.12-2022.

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• Ogilvie V, Passmore M, Hyndman L, Jones L, Stevenson B, Wilson A, Davidson H, Kitchen RR, Gray RD, Shah P, Alton EW, Davies JC, Porteous DJ, Boyd AC. Differential global gene expression in cystic fibrosis nasal and bronchial epithelium. Genomics. 2011 Nov;98(5):327-36. doi: 10.1016/j.ygeno.2011.06.008. Epub 2011 Jul 2.

  PMID: 21756994 BACKGROUND

• Oreo KM, Gibson PG, Simpson JL, Wood LG, McDonald VM, Baines KJ. Sputum ADAM8 expression is increased in severe asthma and COPD. Clin Exp Allergy. 2014 Mar;44(3):342-52. doi: 10.1111/cea.12223.

  PMID: 24147597 BACKGROUND

• Pineau F, Caimmi D, Magalhaes M, Fremy E, Mohamed A, Mely L, Leroy S, Murris M, Claustres M, Chiron R, De Sario A. Blood co-expression modules identify potential modifier genes of diabetes and lung function in cystic fibrosis. PLoS One. 2020 Apr 17;15(4):e0231285. doi: 10.1371/journal.pone.0231285. eCollection 2020.

  PMID: 32302349 BACKGROUND

• Schluchter MD, Konstan MW, Drumm ML, Yankaskas JR, Knowles MR. Classifying severity of cystic fibrosis lung disease using longitudinal pulmonary function data. Am J Respir Crit Care Med. 2006 Oct 1;174(7):780-6. doi: 10.1164/rccm.200512-1919OC. Epub 2006 Jul 20.

  PMID: 16858011 BACKGROUND

• Sood A, Petersen H, Blanchette CM, Meek P, Picchi MA, Belinsky SA, Tesfaigzi Y. Methylated Genes in Sputum Among Older Smokers With Asthma. Chest. 2012 Aug;142(2):425-431. doi: 10.1378/chest.11-2519.

  PMID: 22345380 BACKGROUND

• van Eijk KR, de Jong S, Boks MP, Langeveld T, Colas F, Veldink JH, de Kovel CG, Janson E, Strengman E, Langfelder P, Kahn RS, van den Berg LH, Horvath S, Ophoff RA. Genetic analysis of DNA methylation and gene expression levels in whole blood of healthy human subjects. BMC Genomics. 2012 Nov 17;13:636. doi: 10.1186/1471-2164-13-636.

  PMID: 23157493 BACKGROUND

• Wright JM, Merlo CA, Reynolds JB, Zeitlin PL, Garcia JG, Guggino WB, Boyle MP. Respiratory epithelial gene expression in patients with mild and severe cystic fibrosis lung disease. Am J Respir Cell Mol Biol. 2006 Sep;35(3):327-36. doi: 10.1165/rcmb.2005-0359OC. Epub 2006 Apr 13.

  PMID: 16614352 BACKGROUND

• Pineau F, Caimmi D, Taviaux S, Reveil M, Brosseau L, Rivals I, Drevait M, Vachier I, Claustres M, Chiron R, De Sario A. DNA Methylation at ATP11A cg11702988 Is a Biomarker of Lung Disease Severity in Cystic Fibrosis: A Longitudinal Study. Genes (Basel). 2021 Mar 19;12(3):441. doi: 10.3390/genes12030441.

  PMID: 33808877 RESULT

• Tost J, Caimmi D, Pastore M, Reynes C, Busato F, Pineau F, Claustres M, Vachier I, Chiron R, De Sario A. DNA methylation predicts lung function and pulmonary exacerbation in sputum samples from patients with cystic fibrosis. Clin Epigenetics. 2025 Dec 5;18(1):10. doi: 10.1186/s13148-025-02032-6.

  PMID: 41351062 RESULT

MeSH Terms

Conditions

Cystic Fibrosis; Lung Diseases

Condition Hierarchy (Ancestors)

Pancreatic Diseases; Digestive System Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Infant, Newborn, Diseases

Study Officials

• Davide CAIMMI

  University Hospital, Montpellier

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 8, 2016
• First Posted: November 29, 2016
• Study Start: December 12, 2016
• Primary Completion: July 13, 2021
• Study Completion: July 13, 2021
• Last Updated: April 2, 2026

Record last verified: 2026-03

Locations

FR (1)