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

<div><p>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 <i>ALOX15B</i> (arachidonate 15-lipoxygenase, type B) and the common variant rs12529 in <i>AKR1C3</i> (prostaglandin F synthase) were associated with NSCLC mortality in women and African Americans, respectively. Rare variants in <i>ALOX15B</i> 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 <i>AKCR1C3</i> 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 <i>ALOX15B</i> 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.</p></div

Metabolism of COX-derived eicosanoids.

<p>Arachidonic acid is first metabolized by COX-1 or COX-2 to synthesize PGH₂. Five different types of prostaglandin synthases act on this intermediate to generate the various eicosanoids shown above. In addition, subsequent dehydration/isomerization of PGD₂ can create 15d-PGJ₂. With the exception of three eicosanoids, 15d-PGJ₂, PGD₂, and PGI₂, all of the COX-derived eicosanoids are thought to be pro-tumorigenic. COX-derived eicosanoids in green are pro-tumorigenic, while those in blue are anti-tumorigenic. Abbreviations are as followed: 15-deoxy-Δ^12,14-PGJ₂ (15d-PGJ₂), arachidonic acid (AA), prostaglandin D₂ (PGD₂), prostaglandin E₂ (PGE₂), prostaglandin F_2α (PGF_2α), prostaglandin H₂ (PGH₂), prostaglandin I₂ (PGI₂), and thromboxane A₂ (TXA₂).</p

Description of combination of treatment variables.

<p>Description of combination of treatment variables.</p

Eicosanoid metabolism.

<p>(A) Eicosanoid metabolite generation begins with the metabolism of arachidonic acid by cyclooxygenase (COX), lipooxygenase (LOX), or the cytochrome P450 monooxygenases, which includes both the cytochrome P450 epoxygenases and cytochrome p450 ω-hydroxylases. Each of these enzymes produces its own major metabolites displayed here according to the first enzyme acting on arachidonic acid. Abbreviations are as followed: prostaglandin D₂ (PGD₂), prostaglandin E₂ (PGE₂), prostaglandin F_2α (PGF_2α), prostaglandin I₂ (PGI₂), thromboxane (TXA₂), hydroxyeicosatetraenoic acids (HETEs), and epoxyeicosatrienoic acids (EETs). (B) The genes encoding the enzymes responsible for metabolism of major metabolites are shown here with the number of common and rare SNPs in blue and gray, respectively.</p

Association of a common <i>AKR1C3</i> SNP, rs12529, with NSCLC survival in African Americans, (N = 265).

<p>Survival curves for each genotypic class are plotted based on the multivariate Cox proportional model, which included adjustment for sex, cigarettes per day, resection, and NSCLC stage.</p

Univariate association of clinical and demographic variables with mortality in NSCLC cases.

<p>Univariate association of clinical and demographic variables with mortality in NSCLC cases.</p

Description of clinical and demographic variables in NSCLC cases from the SCCS cohort.

<p>Description of clinical and demographic variables in NSCLC cases from the SCCS cohort.</p

Association of common variants adjusted for prognostic variables.

<p>Association of common variants adjusted for prognostic variables.</p

Metabolism of LOX-derived eicosanoids.

<p>The initial reaction in the LOX pathway can be carried out by 5-LOX, 12-LOX, or 15-LOX, with each LOX synthesizing its own corresponding HpETE. Subsequent reduction of these HpETEs generates HETEs. However, 5-HpETE and 15-HpETE can undergo other reactions as well. More specially, 5-LOX further metabolizes 5-HpETE to LTA₄ that serves a precursor for LXs, LTB₄, or cysteinyl leukotrienes. 5-LOX can also act on 15-HpETE to synthesize LXs. LOX-derived eicosanoids are color coded to indicate their effect on tumors. Blue metabolites are anti-tumorigeneic, green metabolites are pro-tumorigenic, and gray metabolites are unknown. Abbreviations are as followed: arachidonic acid (AA), hydroperoxyeicosatetraenoic acid (HpETE), hydroxyeicosatetraenoic acid (HETE), leukotriene A4 (LTA₄), leukotriene B4 (LTB₄), and lipoxins (LXs).</p

Common SNPs interaction with sex in African Americans unadjusted for covariates, N = 265.

<p>Common SNPs interaction with sex in African Americans unadjusted for covariates, N = 265.</p