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PLoS One. 2017 Jul 13;12(7):e0180471. doi: 10.1371/journal.pone.0180471. eCollection 2017.

Genetic variation in the eicosanoid pathway is associated with non-small-cell lung cancer (NSCLC) survival.

Author information

1
Department of Genetics, Geisel School of Medicine, Dartmouth College, Hanover, NH, United States of America.
2
Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, United States of America.
3
Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, United States of America.
4
Department of Thoracic Surgery, Vanderbilt University Medical Center, Nashville, TN, United States of America.
5
Division of Epidemiology, Vanderbilt University School of Medicine, Nashville, TN, United States of America.
6
International Epidemiology Institute, Rockville, MD, United States of America.
7
Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States of America.
8
Department of Medicine, Veterans Affairs Hospital, Nashville, TN, United States of America.

Abstract

Globally, lung cancer results in more deaths worldwide than any other cancer, indicating a need for better treatments. Members of the eicosanoid metabolism pathway represent promising therapeutic targets, as several enzymes involved in the generation of these lipids are dysregulated in many cancers and their inhibition reduces lung cancer growth in mouse models. However, genetic variation of enzymes involved in eicosanoid metabolism has not been adequately examined for association with lung cancer. The goal of this study was to determine whether germline genetic variation altering eicosanoid producing enzyme function and/or expression are associated with differences in lung cancer survival. We examined the association of genetic variation with mortality within eicosanoid metabolism genes in 395 non-small-cell lung cancer (NSCLC) cases from the Southern Community Cohort Study (SCCS). A total of 108 SNPs, both common and rare, in 19 genes, were examined for association. No common or rare variants were associated with lung cancer survival across the entire study population. However, rare variants in ALOX15B (arachidonate 15-lipoxygenase, type B) and the common variant rs12529 in AKR1C3 (prostaglandin F synthase) were associated with NSCLC mortality in women and African Americans, respectively. Rare variants in ALOX15B were associated with greater mortality in women (HR = 2.10, 95% CI = 1.25-3.54, p-value = 0.005). The major allele of rs12529 in AKCR1C3 associated with improved survival in African Americans (HR = 0.74, 95% CI = 0.59-0.92, p-value = 0.008). The lack of genetic associations among all NSCLC cases and the association among women only for rare variants in ALOX15B may, in part, explain the better NSCLC survival observed among women. These results raise the possibility that some subgroups within the NSCLC population may benefit from drugs targeting eicosanoid metabolism.

PMID:
28704416
PMCID:
PMC5509150
DOI:
10.1371/journal.pone.0180471
[Indexed for MEDLINE]
Free PMC Article

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