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.
Highlights
Lung cancer causes more than one million deaths annually worldwide, with most cases being non-small-cell lung cancer (NSCLC) [1,2,3]
We evaluated the effect of genetic variation within 20 genes that encode eicosanoid metabolism enzymes on NSCLC survival in the Southern Community Cohort Study (SCCS) (Fig 1B, S1 Table)
From the years of 2002 to 2010, a total of 395 incident cases of NSCLC with smoking history were diagnosed in the SCCS cohort (Table 1)
Summary
Lung cancer causes more than one million deaths annually worldwide, with most cases being non-small-cell lung cancer (NSCLC) [1,2,3]. A major cause of the high mortality is that most patients present with advanced-stage disease, precluding the possibility of successful surgical resection. In this case alternative treatment modalities, such as chemotherapy and radiation, are used, but they are less effective than resection of localized disease [4, 5]. A major group of secreted factors altering these processes are the eicosanoids. These molecules are produced by either the tumor cells or TME cells, affecting processes such as inflammation, angiogenesis, and tumor cell growth/dissemination [7]
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