Identification of genetic polymorphisms modulating nausea and vomiting in two series of opioid-treated cancer patients

Abstract

Nausea and vomiting are often associated with opioid analgesia in cancer patients; however, only a subset of patients develop such side effects. Here, we tested the hypothesis that the occurrence of nausea and vomiting is modulated by the genetic background of the patients. Whole exome sequencing of DNA pools from patients with either low (n = 937) or high (n = 557) nausea and vomiting intensity, recruited in the European Pharmacogenetic Opioid Study, revealed a preliminary association of 53 polymorphisms. PCR-based genotyping of 45 of these polymorphisms in the individual patients of the same series confirmed the association for six SNPs in AIM1L, CLCC1, MUC16, PDE3A, POM121L2, and ZNF165 genes. Genotyping of the same 45 polymorphisms in 264 patients of the Italian CERP study, also treated with opioids for cancer pain, instead confirmed the association for two SNPs in ZNF568 and PDE3A genes. Only one SNP, rs12305038 in PDE3A, was confirmed in both series, although with opposite effects of the minor allele on the investigated phenotype. Overall, our findings suggest that genetic factors are indeed associated with nausea and vomiting in opioid-treated cancer patients, but the role of individual polymorphisms may be weak. Opioid treatment is a standard and consolidated therapy for relieving pain in advanced cancer patients 1. However, a variable percentage of patients experience poor treatment benefit and also develop side effects 2,3. Nausea and vomiting occur frequently in opioid therapy for cancer-related pain. A recent systematic review of 25 prospective studies 4 found that approximately 50% of patients who took morphine, oxycodone, fentanyl, methadone, or hydromorphone for cancer-related pain experienced nausea (ranging from 3% to 85%), whereas the occurrence of vomiting in the same patients ranged from 4% to 50% in the various studies. The wide range in occurrence of nausea and vomiting suggests that genetic factors are involved in individual susceptibility to these side effects. So far, only a few studies have reported genetic polymorphisms associated with the variability in nausea and vomiting among cancer patients receiving opioids. One multicenter European study that examined polymorphisms in genes related to opioid and nausea/vomiting signaling pathways, in 1579 patients receiving opioids for cancer pain, found associations between these side effects and polymorphisms in HTR3B, COMT, and CHRM3 genes 5. Another study looked specifically at polymorphisms in CYP2D6, a gene that encodes an opioid-metabolizing enzyme, and found no effect of CYP2D6 genotypes on nausea 6. Both of these studies followed a candidate-gene approach, involving the analysis of known polymorphisms in genes already shown to participate in opioid action or metabolism or in the expression of nausea and vomiting. A candidate-gene approach, which permits the analysis of only a few genes, has major limitations in the study of the genetics of complex

Predicting Opioid Therapy Safety In Pancreatic Cancer Patients

“…Genotyping of 45 ONVs demonstrated the association of SNVs of AIM1L, CLCC1, MUC16, PDE3A, POM121L2 and ZNF165 genes with the risk of opioidassociated constipation [20]. In Italian cancer patients, the presence of an association of two SNVs in the ZNF568 and PDE3A genes with the risk of opioid-associated constipation was also shown [20]. The diversity of the studied genes, as well as ethnic and territorial characteristics, could explain the inconsistency of our results.…”

“…The limited sample size of patients with pancreatic cancer in our study may have also provided the specificity of the collected data only for this category of patients. Genotyping of 45 ONVs demonstrated the association of SNVs of AIM1L, CLCC1, MUC16, PDE3A, POM121L2 and ZNF165 genes with the risk of opioidassociated constipation [20]. In Italian cancer patients, the presence of an association of two SNVs in the ZNF568 and PDE3A genes with the risk of opioid-associated constipation was also shown [20].…”

Absent in melanoma 1-like (AIM1L) serves as a novel candidate for overall survival in hepatocellular carcinoma

“…Whole exome sequencing of DNA pools revealed that six single nucleotide polymorphisms in some genes including AIM1L were associated with nausea and vomiting in opioid-treated cancer patients [47]. Unfortunately, impact of AIM1L on tumorigenesis is rarely investigated.…”

“…A pharmacogenomics study indicated that the risk of nausea and vomiting in opioid-treated cancer patients has a genetic component. Whole exome sequencing of DNA pools revealed that six single nucleotide polymorphisms in some genes including AIM1L were associated with nausea and vomiting in opioid-treated cancer patients [ 47 ]. Unfortunately, impact of AIM1L on tumorigenesis is rarely investigated.…”

Progress, Challenges, and Prospects of Research on the Effect of Gene Polymorphisms on Adverse Reactions to Opioids

“…In the European Opioid Genetics Study (EPS), Colombo et al [46] calculated and analyzed the nausea and vomiting score (NVS) after opioid analgesia in 1494 cancer patients and found a strong correlation between PDE3A rs12305038 and NVS. Thus, mutations in these taste-altering enzymes may also modulate the response to nausea and vomiting.…”