Sausville Lindsay N, Jones Carissa C, Aldrich Melinda C, Blot William J, Pozzi Ambra, Williams Scott M
Department of Genetics, Geisel School of Medicine, Dartmouth College, Hanover, NH, United States of America.
Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, United States of America.
PLoS One. 2017 Jul 13;12(7):e0180471. doi: 10.1371/journal.pone.0180471. eCollection 2017.
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.
在全球范围内，肺癌导致的死亡人数比其他任何癌症都多，这表明需要更好的治疗方法。类花生酸代谢途径的成员是很有前景的治疗靶点，因为许多参与这些脂质生成的酶在多种癌症中失调，并且抑制这些酶可减少小鼠模型中的肺癌生长。然而，尚未充分研究参与类花生酸代谢的酶的基因变异与肺癌的关联。本研究的目的是确定改变类花生酸生成酶功能和/或表达的种系基因变异是否与肺癌生存率的差异相关。我们在南方社区队列研究（SCCS）的395例非小细胞肺癌（NSCLC）病例中，研究了类花生酸代谢基因内基因变异与死亡率的关联。共检测了19个基因中的108个单核苷酸多态性（SNP），包括常见和罕见的SNP，以确定其关联性。在整个研究人群中，没有常见或罕见变异与肺癌生存率相关。然而，ALOX15B（花生四烯酸15-脂氧合酶，B型）中的罕见变异和AKR1C3（前列腺素F合酶）中的常见变异rs12529分别与女性和非裔美国人的NSCLC死亡率相关。ALOX15B中的罕见变异与女性更高的死亡率相关（风险比[HR]=2.10，95%置信区间[CI]=1.25-3.54，p值=0.005）。AKCR1C3中rs12529的主要等位基因与非裔美国人生存率的提高相关（HR=0.74，95%CI=0.59-0.92，p值=0.008）。所有NSCLC病例中缺乏基因关联以及仅在女性中发现ALOX15B罕见变异的关联，可能部分解释了女性中观察到的更好的NSCLC生存率。这些结果增加了NSCLC人群中的一些亚组可能从靶向类花生酸代谢的药物中获益的可能性。
