Date Published: July 13, 2017
Publisher: Public Library of Science
Author(s): Lindsay N. Sausville, Carissa C. Jones, Melinda C. Aldrich, William J. Blot, Ambra Pozzi, Scott M. Williams, Daotai Nie.
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.
Lung cancer causes more than one million deaths annually worldwide, with most cases being non-small-cell lung cancer (NSCLC) [1–3]. 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]. The late stage of diagnosis and the aggressive nature of NSCLC together lead to a 5-year survival of only 18% and clearly point to the need for more effective therapies . To target NSCLC for treatment it is necessary to better understand processes that affect tumor progression.
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). At presentation of disease, 55.2% of the NSCLC cases were diagnosed with distant stage disease. Histology was predominately adenocarcinoma (37.0%), followed by squamous cell carcinoma and NSCLC not otherwise specified (27.9% and 27.6%, respectively). Treatment for NSCLC broadly consisted of surgical resection, chemotherapy, and radiation. Distribution of treatments reflects the restriction of a given treatment to certain stages of NSCLC with no single treatment received by the majority of the population. For example, surgical resection is typically limited to local and regional stage disease. For individuals who underwent the above treatments a combination of chemotherapy and radiation was the most common treatment (21.3%), which is consistent with the frequency of advanced stage disease in this population. Of the NSCLC cases, 22% did not receive any of these three types of treatments. Finally, approximately 15% of the individuals were missing information for one or more treatment variables (Table 3).
The goal of this study was to determine whether exonic variation in the eicosanoid pathway is associated with NSCLC survival. To do this, we investigated the association of genetic variation in eicosanoid metabolism genes with NSCLC prognosis in the Southern Community Cohort Study. No genetic variants were significantly associated with NSCLC mortality. The lack of an association for the entire population is not unexpected since prognosis differs by sex. However, variation within ALOX15B and the prostaglandin F synthase AKR1C3 associated significantly with NSCLC survival in certain subgroups of the NSCLC cases. We found that rare exonic ALOX15B variants were associated with poorer survival among women with NSCLC and rs12529 in AKR1C3 was associated with better prognosis in African Americans with NSCLC. Despite the decreased survival in women with rare ALOX15B variants, overall women still survive longer than men. This may be because the SNPs we studied were too rare to affect outcome averaged across all women. Although this may also be due to women being more proactive in their treatment, data indicates that under equal treatment women still survive better than men indicating some still unknown factors impacting survival [35–37].