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

A Jasmijn Hubers, Daniëlle A M Heideman, Sylvia Duin, Birgit I Witte, Harry J de Koning, Harry J M 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

Research output: Contribution to journalArticleAcademicpeer-review

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 80 months. Cut-off values were based on high specificity to assess diagnostic value of the biomarkers.

RESULTS: RASSF1A 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 2 years, 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 2 years, 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 languageEnglish
JournalJournal of Clinical Pathology
DOIs
Publication statusPublished - 5 Aug 2016

Cite this

@article{643563e17fd34feea63145a6f2565fee,
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 2 years",
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 80 months. Cut-off values were based on high specificity to assess diagnostic value of the biomarkers.RESULTS: RASSF1A 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 2 years, 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 2 years, DNA hypermethylation analysis in sputum may play a role in the detection of preclinical disease, but complementary diagnostic markers are needed to improve sensitivity.",
author = "Hubers, {A Jasmijn} and Heideman, {Dani{\"e}lle A M} and Sylvia Duin and Witte, {Birgit I} and {de Koning}, {Harry J} and Groen, {Harry J M} 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 = "2016",
month = "8",
day = "5",
doi = "10.1136/jclinpath-2016-203734",
language = "English",
journal = "Journal of Clinical Pathology",
issn = "0021-9746",
publisher = "BMJ Publishing Group",

}

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

In: Journal of Clinical Pathology, 05.08.2016.

Research output: Contribution to journalArticleAcademicpeer-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 2 years

AU - Hubers, A Jasmijn

AU - Heideman, Daniëlle A M

AU - Duin, Sylvia

AU - Witte, Birgit I

AU - de Koning, Harry J

AU - Groen, Harry J M

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 - 2016/8/5

Y1 - 2016/8/5

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 80 months. Cut-off values were based on high specificity to assess diagnostic value of the biomarkers.RESULTS: RASSF1A 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 2 years, 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 2 years, 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 80 months. Cut-off values were based on high specificity to assess diagnostic value of the biomarkers.RESULTS: RASSF1A 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 2 years, 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 2 years, DNA hypermethylation analysis in sputum may play a role in the detection of preclinical disease, but complementary diagnostic markers are needed to improve sensitivity.

U2 - 10.1136/jclinpath-2016-203734

DO - 10.1136/jclinpath-2016-203734

M3 - Article

JO - Journal of Clinical Pathology

JF - Journal of Clinical Pathology

SN - 0021-9746

ER -