DNA hypermethylation analysis in sputum of asymptomatic subjects at risk for lung cancer participating in the NELSON trial: Argument for maximum screening interval of 2years

A. Jasmijn Hubers; Danielle A. M. Heideman; Sylvia Duin; Birgit I. Witte; Harry J. de Koning; Hendricus Groen; Clemens F. M. Prinsen; Anne S. Bolijn; Mandy Wouters; Susanne E. van der Meer; Renske D. M. Steenbergen; Peter J. F. Snijders; Anne Uyterlinde; Hans Berkhof; Egbert F. Smit; Erik Thunnissen

doi:10.1136/jclinpath-2016-203734

DNA hypermethylation analysis in sputum of asymptomatic subjects at risk for lung cancer participating in the NELSON trial: Argument for maximum screening interval of 2years

A. Jasmijn Hubers, Danielle A. M. Heideman, Sylvia Duin, Birgit I. Witte, Harry J. de Koning, Hendricus Groen, Clemens F. M. Prinsen, Anne S. Bolijn, Mandy Wouters, Susanne E. van der Meer, Renske D. M. Steenbergen, Peter J. F. Snijders, Anne Uyterlinde, Hans Berkhof, Egbert F. Smit, Erik Thunnissen^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

Aims Lung cancer is the major contributor to cancer mortality due to metastasised disease at time of presentation. The current study investigated DNA hypermethylation of biomarkers RASSF1A, APC, cytoglobin, 3OST2, FAM19A4, PHACTR3 and PRDM14 in sputum of asymptomatic high-risk individuals from the NELSON lung cancer low-dose spiral CT screening trial to detect lung cancer at preclinical stage.

Methods Subjects were selected with (i) lung cancer in follow-up (cases; n=65), (ii) minor cytological aberrations (controls; n=120) and (iii) a random selection of subjects without cytological aberrations (controls; n=99). Median follow-up time for controls was 80months. Cut-off values were based on high specificity to assess diagnostic value of the biomarkers.

ResultsRASSF1A may denote presence of invasive cancer because of its high specificity (93% (95% CI 89% to 96%); sensitivity 17% (95% CI 4% to 31%), with best performance in a screening interval of 2 years. The panel of RASSF1A, 3OST2 and PRDM14 detected 28% (95% CI 11% to 44%) of lung cancer cases within 2years, with specificity of 90% (95% CI 86% to 94%). Sputum cytology did not detect any lung cancers.

Conclusions In a lung cancer screening setting with maximum screening interval of 2years, DNA hypermethylation analysis in sputum may play a role in the detection of preclinical disease, but complementary diagnostic markers are needed to improve sensitivity.

Original language	English
Pages (from-to)	250-254
Number of pages	5
Journal	Journal of Clinical Pathology
Volume	70
Issue number	3
DOIs	https://doi.org/10.1136/jclinpath-2016-203734
Publication status	Published - Mar-2017

Keywords

LUNG CANCER
SPUTUM
PCR
ONCOGENES
PROMOTER HYPERMETHYLATION
DIAGNOSIS
SMOKERS
CT

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DNA hypermethylation analysis in sputum of asymptomatic subjects at risk for lung cancer participating in the NELSON trial: argument for maximum screening interval of 2 years
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Nederlands-Leuvens Longkanker Screenings Onderzoek (NELSON)
Oudkerk, M. (Creator), Groen, H. J. M. (Creator), Van Klaveren, R. J. (Creator), de Koning, H. J. (Creator), Mali, W. P. T. M. (Creator) & Lammers, J.-W. J. (Creator), University of Groningen, 2018
http://www.nelsonproject.nl/infobrochure.html
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Hubers, A. J., Heideman, D. A. M., Duin, S., Witte, B. I., de Koning, H. J., Groen, H., Prinsen, C. F. M., Bolijn, A. S., Wouters, M., van der Meer, S. E., Steenbergen, R. D. M., Snijders, P. J. F., Uyterlinde, A., Berkhof, H., Smit, E. F., & Thunnissen, E. (2017). DNA hypermethylation analysis in sputum of asymptomatic subjects at risk for lung cancer participating in the NELSON trial: Argument for maximum screening interval of 2years. Journal of Clinical Pathology, 70(3), 250-254. https://doi.org/10.1136/jclinpath-2016-203734

@article{43ebe151ce7d451985610819c1b8b9ed,

title = "DNA hypermethylation analysis in sputum of asymptomatic subjects at risk for lung cancer participating in the NELSON trial: Argument for maximum screening interval of 2years",

abstract = "Aims Lung cancer is the major contributor to cancer mortality due to metastasised disease at time of presentation. The current study investigated DNA hypermethylation of biomarkers RASSF1A, APC, cytoglobin, 3OST2, FAM19A4, PHACTR3 and PRDM14 in sputum of asymptomatic high-risk individuals from the NELSON lung cancer low-dose spiral CT screening trial to detect lung cancer at preclinical stage.Methods Subjects were selected with (i) lung cancer in follow-up (cases; n=65), (ii) minor cytological aberrations (controls; n=120) and (iii) a random selection of subjects without cytological aberrations (controls; n=99). Median follow-up time for controls was 80months. Cut-off values were based on high specificity to assess diagnostic value of the biomarkers.ResultsRASSF1A may denote presence of invasive cancer because of its high specificity (93% (95% CI 89% to 96%); sensitivity 17% (95% CI 4% to 31%), with best performance in a screening interval of 2 years. The panel of RASSF1A, 3OST2 and PRDM14 detected 28% (95% CI 11% to 44%) of lung cancer cases within 2years, with specificity of 90% (95% CI 86% to 94%). Sputum cytology did not detect any lung cancers.Conclusions In a lung cancer screening setting with maximum screening interval of 2years, DNA hypermethylation analysis in sputum may play a role in the detection of preclinical disease, but complementary diagnostic markers are needed to improve sensitivity.",

keywords = "LUNG CANCER, SPUTUM, PCR, ONCOGENES, PROMOTER HYPERMETHYLATION, DIAGNOSIS, SMOKERS, CT",

author = "Hubers, {A. Jasmijn} and Heideman, {Danielle A. M.} and Sylvia Duin and Witte, {Birgit I.} and {de Koning}, {Harry J.} and Hendricus Groen and Prinsen, {Clemens F. M.} and Bolijn, {Anne S.} and Mandy Wouters and {van der Meer}, {Susanne E.} and Steenbergen, {Renske D. M.} and Snijders, {Peter J. F.} and Anne Uyterlinde and Hans Berkhof and Smit, {Egbert F.} and Erik Thunnissen",

note = "Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/",

year = "2017",

month = mar,

doi = "10.1136/jclinpath-2016-203734",

language = "English",

volume = "70",

pages = "250--254",

journal = "Journal of Clinical Pathology",

issn = "0021-9746",

publisher = "BMJ Publishing Group",

number = "3",

}

Hubers, AJ, Heideman, DAM, Duin, S, Witte, BI, de Koning, HJ, Groen, H, Prinsen, CFM, Bolijn, AS, Wouters, M, van der Meer, SE, Steenbergen, RDM, Snijders, PJF, Uyterlinde, A, Berkhof, H, Smit, EF & Thunnissen, E 2017, 'DNA hypermethylation analysis in sputum of asymptomatic subjects at risk for lung cancer participating in the NELSON trial: Argument for maximum screening interval of 2years', Journal of Clinical Pathology, vol. 70, no. 3, pp. 250-254. https://doi.org/10.1136/jclinpath-2016-203734

DNA hypermethylation analysis in sputum of asymptomatic subjects at risk for lung cancer participating in the NELSON trial: Argument for maximum screening interval of 2years. / Hubers, A. Jasmijn; Heideman, Danielle A. M.; Duin, Sylvia et al.
In: Journal of Clinical Pathology, Vol. 70, No. 3, 03.2017, p. 250-254.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - DNA hypermethylation analysis in sputum of asymptomatic subjects at risk for lung cancer participating in the NELSON trial

T2 - Argument for maximum screening interval of 2years

AU - Hubers, A. Jasmijn

AU - Heideman, Danielle A. M.

AU - Duin, Sylvia

AU - Witte, Birgit I.

AU - de Koning, Harry J.

AU - Groen, Hendricus

AU - Prinsen, Clemens F. M.

AU - Bolijn, Anne S.

AU - Wouters, Mandy

AU - van der Meer, Susanne E.

AU - Steenbergen, Renske D. M.

AU - Snijders, Peter J. F.

AU - Uyterlinde, Anne

AU - Berkhof, Hans

AU - Smit, Egbert F.

AU - Thunnissen, Erik

N1 - Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

PY - 2017/3

Y1 - 2017/3

N2 - Aims Lung cancer is the major contributor to cancer mortality due to metastasised disease at time of presentation. The current study investigated DNA hypermethylation of biomarkers RASSF1A, APC, cytoglobin, 3OST2, FAM19A4, PHACTR3 and PRDM14 in sputum of asymptomatic high-risk individuals from the NELSON lung cancer low-dose spiral CT screening trial to detect lung cancer at preclinical stage.Methods Subjects were selected with (i) lung cancer in follow-up (cases; n=65), (ii) minor cytological aberrations (controls; n=120) and (iii) a random selection of subjects without cytological aberrations (controls; n=99). Median follow-up time for controls was 80months. Cut-off values were based on high specificity to assess diagnostic value of the biomarkers.ResultsRASSF1A may denote presence of invasive cancer because of its high specificity (93% (95% CI 89% to 96%); sensitivity 17% (95% CI 4% to 31%), with best performance in a screening interval of 2 years. The panel of RASSF1A, 3OST2 and PRDM14 detected 28% (95% CI 11% to 44%) of lung cancer cases within 2years, with specificity of 90% (95% CI 86% to 94%). Sputum cytology did not detect any lung cancers.Conclusions In a lung cancer screening setting with maximum screening interval of 2years, DNA hypermethylation analysis in sputum may play a role in the detection of preclinical disease, but complementary diagnostic markers are needed to improve sensitivity.

AB - Aims Lung cancer is the major contributor to cancer mortality due to metastasised disease at time of presentation. The current study investigated DNA hypermethylation of biomarkers RASSF1A, APC, cytoglobin, 3OST2, FAM19A4, PHACTR3 and PRDM14 in sputum of asymptomatic high-risk individuals from the NELSON lung cancer low-dose spiral CT screening trial to detect lung cancer at preclinical stage.Methods Subjects were selected with (i) lung cancer in follow-up (cases; n=65), (ii) minor cytological aberrations (controls; n=120) and (iii) a random selection of subjects without cytological aberrations (controls; n=99). Median follow-up time for controls was 80months. Cut-off values were based on high specificity to assess diagnostic value of the biomarkers.ResultsRASSF1A may denote presence of invasive cancer because of its high specificity (93% (95% CI 89% to 96%); sensitivity 17% (95% CI 4% to 31%), with best performance in a screening interval of 2 years. The panel of RASSF1A, 3OST2 and PRDM14 detected 28% (95% CI 11% to 44%) of lung cancer cases within 2years, with specificity of 90% (95% CI 86% to 94%). Sputum cytology did not detect any lung cancers.Conclusions In a lung cancer screening setting with maximum screening interval of 2years, DNA hypermethylation analysis in sputum may play a role in the detection of preclinical disease, but complementary diagnostic markers are needed to improve sensitivity.

KW - LUNG CANCER

KW - SPUTUM

KW - PCR

KW - ONCOGENES

KW - PROMOTER HYPERMETHYLATION

KW - DIAGNOSIS

KW - SMOKERS

KW - CT

U2 - 10.1136/jclinpath-2016-203734

DO - 10.1136/jclinpath-2016-203734

M3 - Article

SN - 0021-9746

VL - 70

SP - 250

EP - 254

JO - Journal of Clinical Pathology

JF - Journal of Clinical Pathology

IS - 3

ER -

DNA hypermethylation analysis in sputum of asymptomatic subjects at risk for lung cancer participating in the NELSON trial: Argument for maximum screening interval of 2years

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Keywords

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Nederlands-Leuvens Longkanker Screenings Onderzoek (NELSON)

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