ARTICLE
Epidemiolgy
Nested case–control study of telomere length and lung cancer
risk among heavy smokers in the β-Carotene and Retinol
Efficacy Trial
Jennifer Anne Doherty
1,2
, Laurie Grieshober
1
, John R. Houck
2
, Matt J. Barnett
2
, Jean De Dieu Tapsoba
2
, Mark D. Thornquist
2
,
Ching-Yun Wang
2
, Gary E. Goodman
2
and Chu Chen
2,3,4
BACKGROUND: Telomeres protect cells from genomic instability. We examined telomere length and lung cancer risk prospectively
in heavy smokers.
METHODS: In a nested case–control study with 709 cases and 1313 controls, conditional logistic regression was used to evaluate
associations between telomere length (global, chromosome 5p, and 13q) and lung cancer risk by histotype, controlling for detailed
smoking history.
RESULTS: Risks of overall lung cancer and adenocarcinoma were suggestively elevated among individuals with telomere length in
the longest tertile. No clear patterns were observed for other histotypes, or for chromosome 5p or 13q telomere length.
Associations with adenocarcinoma were strongest among (OR, 95% CI for longest versus shortest tertile): former smokers (2.26,
1.03–4.96), individuals <65 years (2.22, 1.13–4.35), and women (2.21, 0.99–4.93).
CONCLUSIONS: Our large study of heavy smokers adds additional evidence that long telomere length prior to diagnosis is
associated with risk of lung adenocarcinoma, but not other histotypes.
British Journal of Cancer (2018) 118:1513–1517; https://doi.org/10.1038/s41416-018-0075-0
INTRODUCTION
Telomeres are chromatin structures that cap chromosomes, and
critically short telomeres can cause chromosomal instability, enabling
genetic changes in favor of carcinogenesis.
1
Atthesametime,longer
telomeres could result in enhanced proliferative potential, increasing
the chance of accumulating mutations.
2,3
Telomere length decreases
with age, cigarette smoking,
4,5
and oxidative stress and inflamma-
tion,
6–10
and varies by chromosome arm.
11–13
While three
case–control studies suggested that short telomere length was
associated with increased lung cancer risk,
14–16
and a cohort study
observed no association,
17
alargecase–control study
18
and a pooled
analysis of three nested case–control studies
19
reported that longer
telomere length is associated with increased risk, particularly for
adenocarcinoma. Although the majority (80–90%) of lung cancers
develop in current or former cigarette smokers,
20
most smokers do
not develop lung cancer. We evaluated whether telomere length
(overall, and chromosome arms 5p and 13q), measured prior to
diagnosis, was associated with lung cancer risk in heavy smokers, and
if associations varied by histotype and other factors.
MATERIALS AND METHODS
Study population
The β-Carotene and Retinol Efficacy Trial (CARET) was a
randomised, double-blinded, placebo-controlled chemoprevention
trial of β-carotene and retinyl palmitate among 18,314 men and
women at high risk of developing lung cancer.
21–23
The interven-
tion was stopped due to higher lung cancer incidence and overall
mortality in the intervention arm after average follow-up of 4 years.
Reports of cancer were confirmed through review of clinical
records and pathology reports following a detailed protocol. The
present study includes a subset of a previous nested case–control
study designed using endpoint information collected during active
follow-up (1985–2005).
24
Briefly, participants who were free of lung
cancer and provided a blood specimen (between 1994 and 1997)
were eligible. Two lung cancer-free controls were matched to the
793 lung cancer cases on age (±4 years), sex, race/ethnicity,
enrollment year (2-year intervals), baseline smoking status (current/
former), occupational asbestos exposure, and length of follow-up.
The current study includes the 717 cases and 1343 controls with
sufficient DNA for telomere length assays. Institutional Review
Boards for the CARET institutions approved study protocols, and all
participants provided written informed consent.
Laboratory methods
Blood was extracted using QIAamp DNA Blood Midi kits (Qiagen,
Valencia, USA). Relative telomere length was measured using
modified singleplex qPCR and normalisation per Aviv et al.,
25
and
the telomere to single-copy control gene ratio approach in
McGrath et al.
26
Individuals were measured in duplicate on two
www.nature.com/bjc
Received: 23 September 2017 Revised: 8 March 2018 Accepted: 14 March 2018
Published online: 19 April 2018
1
Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112-5550, USA;
2
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA
98109-1024, USA;
3
Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA 98195, USA and
4
Department of Otolaryngology: Head and Neck
Surgery, School of Medicine, University of Washington, Seattle, WA 98195, USA
Correspondence: Jennifer Anne Doherty (jen.doherty@hci.utah.edu)
© Cancer Research UK 2018
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