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

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.

Interaction between leukocyte aldo-keto reductase 1C3 activity, genotypes, biological, lifestyle and clinical features in a prostate cancer cohort from New Zealand

“…The frequencies between the AKR1C3 rs12529 genotypes are similar to that of the European Americans and African Americans recorded before [20, 28]. The frequency of the AKR1C3 rs12529 G allele in our cohort was 0.463 which is marginally lower than the frequencies recorded in the Genome Aggregation Database (0.499); but similar to the Trans-Omics for Precision Medicine Database (0.476); and higher than the TWINSUK Database (0.385) and Avon Longitudinal Study of parents and Children Database from the University of Bristol (0.382) (https://www.ncbi.nlm.nih.gov/snp/rs12529).…”

Overview of AKR1C3: Inhibitor Achievements and Disease Insights

“…Both AKR1B10 or AKR1C3 can effectively reduce HNE to the less toxic alcohol 1,4-Table 1. Summary of AKR1C3-Related Diseases disease types detailed classification endocrine system disease polycystic ovary syndrome 6,62 ovarian dysfunction 63 hyperandrogenism 63 ovarian neoplasm 61,64 adenocarcinoma 65 prostate adenocarcinoma 66 renal cell adenocarcinoma 67−69 invasive breast ductal carcinoma 20,70 breast cancer 6 triple-negative breast cancer 71 estrogen-receptor positive breast cancer 20 breast ductal carcinoma in situ 72,73 invasive breast carcinoma 72 invasive lobular carcinoma 74 cervical adenocarcinoma 75 pancreatic adenocarcinoma 65 endometrium adenocarcinoma 76 breast ductal carcinoma in situ 72 lung cancer 77,78 nonsmall-cell lung cancer 23,79 neuroendocrine neoplasm 65 melanoma 80 nonmelanoma skin carcinoma 81 esophageal squamous cell carcinoma 82 head and neck squamous cell carcinoma 83 oral squamous cell carcinoma 84 squamous cell carcinoma 65 dihydroxynonene, and knockout of these two AKR isoforms significantly increases the sensitivity of cells to DTX toxicity. The combined inhibition of three upregulated proteins reversed the sensitivity of drug-resistant cells to DTX, providing a new approach for the adjuvant treatment of DTX.…”

Selenium Supplementation and Prostate Health in a New Zealand Cohort

“…The aldo-keto reductase 1C3 (AKR1C3) encoding gene is located in the chromosomal region 10p15 and the rs12529 C>G polymorphism produces a nonsynonymous amino acid change from histidine to glutamine [34]. This rs12529 polymorphism is also associated with various cancers [20,35,36]. The kallikrein-related peptidase 3 (KLK3) gene encodes the serine protease PSA and this gene is located in the chromosomal region 19q13 [37].…”