Genes associated with genetic and rare lung diseases and the risk of lung cancer

doi:10.1186/s12885-026-15934-2

Genes associated with genetic and rare lung diseases and the risk of lung cancer

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Abstract

Background: We investigated whether markers, genes or terms of the Human Phenotype Ontology associated with genetic or rare diseases (GARDs) that affect airway or lung function are associated with lung cancer. Methods: Genes of interest were extracted from GARD (Genetic and Rare Diseases Information Center), OMIM (Online Mendelian Inheritance in Man®), ORPHANET and Monarch Initiative. Individual SNP, gene level and gene-set analyses were performed for 52,207 SNPs, 1677 genes or for 620 terms of the Human Phenotype Ontology. The analysis included 14,068 lung cancer cases and 12,390 cancer-free control subjects of European descent from the International Lung Cancer Consortium ILCCO. Results: The marker rs56113850 (OR=0.893, 95%CI: 0.862-0.924) was associated with lung cancer (p=1.2x10^-10). This marker is located in CYP2A6 as well as in an enhancer region of LTBP4, which is associated with cutis laxa. A suggestive significant association was observed for two markers associated with the DMD gene, which is linked to Duchenne muscular dystrophy. The gene sets "Abnormal circulating adrenocorticotropin concentration" and "Central nervous system neoplasm" were found to be significantly enriched with GARD genes, and can therefore be considered to be associated with lung cancer. Conclusions: Genes associated with genetic and rare lung diseases do not generally appear to carry risk factors for lung cancer. However, genes associated with the hypothalamic-pituitary-adrenal axis show some, but rather weak or complex, associations with lung cancer. Tests at the gene level provide extremely inhomogeneous results, even when applied to the same data.

Original language	English
Article number	461
Journal	BMC Cancer
Volume	26
Issue number	1
DOIs	https://doi.org/10.1186/s12885-026-15934-2
State	Published - Dec 2026

Bibliographical note

Publisher Copyright:
© The Author(s) 2026.

Funding

Open Access funding enabled and organized by Projekt DEAL. The National Institutes of Health (7U19CA203654-02/397 114564-5111078 Integrative Analysis of Lung Cancer Etiology and Risk) supported this work. Other individual funding sources for participating studies and members of INTEGRAL-ILCCO are listed elsewhere. [24] The funders played no role in the study design, data collection and analysis, decision to publish, or manuscript preparation. The funders had no role in study design, data collection, data analysis, or data interpretation.

Funders	Funder number
National Institutes of Health (NIH)	7U19CA203654-02/397 114564-5111078

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Adrenocorticotropic hormone
CYP2A6
DMD
GARD
Gene-based test
Gene-set analysis
Genomic marker
Hypothalamic-Pituitary-Adrenal axis
LTBP4
Lung cancer
OMIM
Orphanet
Rare disease

ASJC Scopus subject areas

Oncology
Genetics
Cancer Research

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10.1186/s12885-026-15934-2

Cite this

@article{dbe9c443a2784c0cbad3912a20fd3423,

title = "Genes associated with genetic and rare lung diseases and the risk of lung cancer",

abstract = "Background: We investigated whether markers, genes or terms of the Human Phenotype Ontology associated with genetic or rare diseases (GARDs) that affect airway or lung function are associated with lung cancer. Methods: Genes of interest were extracted from GARD (Genetic and Rare Diseases Information Center), OMIM (Online Mendelian Inheritance in Man{\textregistered}), ORPHANET and Monarch Initiative. Individual SNP, gene level and gene-set analyses were performed for 52,207 SNPs, 1677 genes or for 620 terms of the Human Phenotype Ontology. The analysis included 14,068 lung cancer cases and 12,390 cancer-free control subjects of European descent from the International Lung Cancer Consortium ILCCO. Results: The marker rs56113850 (OR=0.893, 95\%CI: 0.862-0.924) was associated with lung cancer (p=1.2x10-10). This marker is located in CYP2A6 as well as in an enhancer region of LTBP4, which is associated with cutis laxa. A suggestive significant association was observed for two markers associated with the DMD gene, which is linked to Duchenne muscular dystrophy. The gene sets {"}Abnormal circulating adrenocorticotropin concentration{"} and {"}Central nervous system neoplasm{"} were found to be significantly enriched with GARD genes, and can therefore be considered to be associated with lung cancer. Conclusions: Genes associated with genetic and rare lung diseases do not generally appear to carry risk factors for lung cancer. However, genes associated with the hypothalamic-pituitary-adrenal axis show some, but rather weak or complex, associations with lung cancer. Tests at the gene level provide extremely inhomogeneous results, even when applied to the same data.",

keywords = "Adrenocorticotropic hormone, CYP2A6, DMD, GARD, Gene-based test, Gene-set analysis, Genomic marker, Hypothalamic-Pituitary-Adrenal axis, LTBP4, Lung cancer, OMIM, Orphanet, Rare disease",

author = "Albert Rosenberger and Heike Bickeb{\"o}ller and Christiani, \{David C.\} and Caporaso, \{Neil E.\} and Geoffrey Liu and Bojesen, \{Stig E.\} and \{Le Marchand\}, Loic and Demetrios Albanes and Aldrich, \{Melinda C.\} and Adonina Tardon and Guillermo Fern{\'a}ndez‐Tard{\'o}n and Gad Rennert and Field, \{John K.\} and Davies, \{Michael P.A.\} and Kiemeney, \{Lambertus A.\} and Philip Lazarus and Shanbeh Zienolddiny and Stephen Lam and Schabath, \{Matthew B.\} and Andrew, \{Angeline S.\} and Arnold, \{Susanne M.\} and Goodman, \{Gary E.\} and Doherty, \{Jennifer A.\} and Fiona Taylor and Angela Cox and Woll, \{Penella J.\} and Angela Risch and Mikael Johansson and Paul Brennan and Landi, \{Maria Teresa\} and Shete, \{Sanjay S.\} and Hung, \{Rayjean J.\} and Amos, \{Christopher I.\}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2026.",

year = "2026",

month = dec,

doi = "10.1186/s12885-026-15934-2",

language = "English",

volume = "26",

number = "1",

}

TY - JOUR

T1 - Genes associated with genetic and rare lung diseases and the risk of lung cancer

AU - Rosenberger, Albert

AU - Bickeböller, Heike

AU - Christiani, David C.

AU - Caporaso, Neil E.

AU - Liu, Geoffrey

AU - Bojesen, Stig E.

AU - Le Marchand, Loic

AU - Albanes, Demetrios

AU - Aldrich, Melinda C.

AU - Tardon, Adonina

AU - Fernández‐Tardón, Guillermo

AU - Rennert, Gad

AU - Field, John K.

AU - Davies, Michael P.A.

AU - Kiemeney, Lambertus A.

AU - Lazarus, Philip

AU - Zienolddiny, Shanbeh

AU - Lam, Stephen

AU - Schabath, Matthew B.

AU - Andrew, Angeline S.

AU - Arnold, Susanne M.

AU - Goodman, Gary E.

AU - Doherty, Jennifer A.

AU - Taylor, Fiona

AU - Cox, Angela

AU - Woll, Penella J.

AU - Risch, Angela

AU - Johansson, Mikael

AU - Brennan, Paul

AU - Landi, Maria Teresa

AU - Shete, Sanjay S.

AU - Hung, Rayjean J.

AU - Amos, Christopher I.

PY - 2026/12

Y1 - 2026/12

N2 - Background: We investigated whether markers, genes or terms of the Human Phenotype Ontology associated with genetic or rare diseases (GARDs) that affect airway or lung function are associated with lung cancer. Methods: Genes of interest were extracted from GARD (Genetic and Rare Diseases Information Center), OMIM (Online Mendelian Inheritance in Man®), ORPHANET and Monarch Initiative. Individual SNP, gene level and gene-set analyses were performed for 52,207 SNPs, 1677 genes or for 620 terms of the Human Phenotype Ontology. The analysis included 14,068 lung cancer cases and 12,390 cancer-free control subjects of European descent from the International Lung Cancer Consortium ILCCO. Results: The marker rs56113850 (OR=0.893, 95%CI: 0.862-0.924) was associated with lung cancer (p=1.2x10-10). This marker is located in CYP2A6 as well as in an enhancer region of LTBP4, which is associated with cutis laxa. A suggestive significant association was observed for two markers associated with the DMD gene, which is linked to Duchenne muscular dystrophy. The gene sets "Abnormal circulating adrenocorticotropin concentration" and "Central nervous system neoplasm" were found to be significantly enriched with GARD genes, and can therefore be considered to be associated with lung cancer. Conclusions: Genes associated with genetic and rare lung diseases do not generally appear to carry risk factors for lung cancer. However, genes associated with the hypothalamic-pituitary-adrenal axis show some, but rather weak or complex, associations with lung cancer. Tests at the gene level provide extremely inhomogeneous results, even when applied to the same data.

AB - Background: We investigated whether markers, genes or terms of the Human Phenotype Ontology associated with genetic or rare diseases (GARDs) that affect airway or lung function are associated with lung cancer. Methods: Genes of interest were extracted from GARD (Genetic and Rare Diseases Information Center), OMIM (Online Mendelian Inheritance in Man®), ORPHANET and Monarch Initiative. Individual SNP, gene level and gene-set analyses were performed for 52,207 SNPs, 1677 genes or for 620 terms of the Human Phenotype Ontology. The analysis included 14,068 lung cancer cases and 12,390 cancer-free control subjects of European descent from the International Lung Cancer Consortium ILCCO. Results: The marker rs56113850 (OR=0.893, 95%CI: 0.862-0.924) was associated with lung cancer (p=1.2x10-10). This marker is located in CYP2A6 as well as in an enhancer region of LTBP4, which is associated with cutis laxa. A suggestive significant association was observed for two markers associated with the DMD gene, which is linked to Duchenne muscular dystrophy. The gene sets "Abnormal circulating adrenocorticotropin concentration" and "Central nervous system neoplasm" were found to be significantly enriched with GARD genes, and can therefore be considered to be associated with lung cancer. Conclusions: Genes associated with genetic and rare lung diseases do not generally appear to carry risk factors for lung cancer. However, genes associated with the hypothalamic-pituitary-adrenal axis show some, but rather weak or complex, associations with lung cancer. Tests at the gene level provide extremely inhomogeneous results, even when applied to the same data.

KW - Adrenocorticotropic hormone

KW - CYP2A6

KW - DMD

KW - GARD

KW - Gene-based test

KW - Gene-set analysis

KW - Genomic marker

KW - Hypothalamic-Pituitary-Adrenal axis

KW - LTBP4

KW - Lung cancer

KW - OMIM

KW - Orphanet

KW - Rare disease

UR - https://www.scopus.com/pages/publications/105035555569

UR - https://www.scopus.com/pages/publications/105035555569#tab=citedBy

U2 - 10.1186/s12885-026-15934-2

DO - 10.1186/s12885-026-15934-2

M3 - Article

C2 - 41917862

AN - SCOPUS:105035555569

SN - 1471-2407

VL - 26

JO - BMC Cancer

JF - BMC Cancer

IS - 1

M1 - 461

ER -

Genes associated with genetic and rare lung diseases and the risk of lung cancer

Abstract

Bibliographical note

Funding

UN SDGs

Keywords

ASJC Scopus subject areas

Access to Document

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