Top

27-04-2024 | Nausea | Original Article

Gene polymorphisms of TACR1 serve as the potential pharmacogenetic predictors of response to the neurokinin-1 receptor antagonist-based antiemetic regimens: a candidate-gene association study in breast cancer patients

Authors: Marziyeh Ghorbani, Soha Namazi, Mehdi Dehghani, Farideh Razi, Bahman Khalvati, Ali Dehshahri

Published in: Cancer Chemotherapy and Pharmacology

Abstract

Purpose

The current candidate gene association study aims to investigate tag SNPs from the TACR1 gene as pharmacogenetic predictors of response to the antiemetic guidelines-recommended, NK-1 receptor antagonist-based, triple antiemetic regimens.

Methods

A set of eighteen tag SNPs of TACR1 were genotyped in breast cancer patients receiving anthracycline and cyclophosphamide (with/without docetaxel) applying real-time PCR-HRMA.

Data analysis for 121 ultimately enrolled patients was initiated by defining haplotype blocks using PHASE v.2.1. The association of each tag SNP and haplotype alleles with failure to achieve the defined antiemetic regimen efficacy endpoints was tested using PLINK (v.1.9 and v.1.07, respectively) based on the logistic regression, adjusting for the previously known chemotherapy-induced nausea and vomiting (CINV) prognostic factors. All reported p-values were corrected using the permutation test (n = 100,000).

Results

Four variants of rs881, rs17010730, rs727156, and rs3755462, as well as haplotypes containing the mentioned variants, were significantly associated with failure to achieve at least one of the defined efficacy endpoints. Variant annotation via in-silico studies revealed that the non-seed sequence variant, rs881, is located in the miRNA (hsa-miR-613) binding site. The other three variants or a variant in complete linkage disequilibrium with them overlap a region of high H3K9ac-promoter-like signature or regions of high enhancer-like signature in the brain or gastrointestinal tissue.

Conclusion

Playing an essential role in regulating TACR1 expression, gene polymorphisms of TACR1 serve as the potential pharmacogenetic predictors of response to the NK-1 receptor antagonist-based, triple antiemetic regimens. If clinically approved, modifying the NK-1 receptor antagonist dose leads to better management of CINV in risk-allele carriers.

Available only for authorised users

Aapro M (2018) CINV: still troubling patients after all these years. Support Care Cancer 26(Suppl 1):5–9. https://doi.org/10.1007/s00520-018-4131-3CrossRefPubMedPubMedCentral

Yeo W, Mo FKF, Yip CCH et al (2021) Quality of life associated with nausea and vomiting from anthracycline-based chemotherapy: a pooled data analysis from three prospective trials. Oncologist 26(12):e2288–e2296. https://doi.org/10.1002/onco.13978CrossRefPubMedPubMedCentral

Kuchuk I, Bouganim N, Beusterien K et al (2013) Preference weights for chemotherapy side effects from the perspective of women with breast cancer. Breast Cancer Res Treat 142(1):101–107. https://doi.org/10.1007/s10549-013-2727-3CrossRefPubMed

Schwartzberg L, Harrow B, Lal LS et al (2015) Resource utilization for chemotherapy-induced nausea and vomiting events in patients with solid tumors treated with antiemetic regimens. Am Health Drug Benefits 8(5):273–282PubMedPubMedCentral

Roeland EJ, Ruddy KJ, LeBlanc TW et al (2020) What the HEC? Clinician adherence to evidence-based antiemetic prophylaxis for highly emetogenic chemotherapy. J Natl Compr Canc Netw 18(6):676–681. https://doi.org/10.6004/jnccn.2019.7526CrossRefPubMed

Navari RM, Aapro M (2016) Antiemetic prophylaxis for chemotherapy-induced nausea and vomiting. N Engl J Med 374(14):1356–1367. https://doi.org/10.1056/NEJMra1515442CrossRefPubMed

Hesketh PJ, Van Belle S, Aapro M et al (2003) Differential involvement of neurotransmitters through the time course of cisplatin-induced emesis as revealed by therapy with specific receptor antagonists. Eur J Cancer 39(8):1074–1080. https://doi.org/10.1016/S0959-8049(02)00674-3CrossRefPubMed

Warr D (2014) Prognostic factors for chemotherapy induced nausea and vomiting. Eur J Pharmacol 722:192–196. https://doi.org/10.1016/j.ejphar.2013.10.015CrossRefPubMed

Ettinger DS, Armstrong DK, Barbour S et al (2012) Antiemesis. JNCCN J Natl Compr Cancer Netw 10(4):456–485CrossRef

10.

Navari RM (2020) Nausea and vomiting in advanced cancer. Curr Treat Options Oncol 21(2):14. https://doi.org/10.1007/s11864-020-0704-8CrossRefPubMed

11.

Ghorbani M, Dehghani M, Fahimfar N et al (2022) FLOT (a chemotherapy regimen for gastric/esophagogastric junction cancer): to be treated as a highly emetogenic regimen or a moderately emetogenic one? Comparison of the emetogenic potential of FLOT versus FOLFOX and TAC regimens. Support Care Cancer 30(5):3865–3873. https://doi.org/10.1007/s00520-022-06832-xCrossRefPubMed

12.

Trammel M, Roederer M, Patel J et al (2013) Does pharmacogenomics account for variability in control of acute chemotherapy-induced nausea and vomiting with 5-hydroxytryptamine type 3 receptor antagonists? Curr Oncol Rep 15(3):276–285. https://doi.org/10.1007/s11912-013-0312-xCrossRefPubMedPubMedCentral

13.

Hashimoto H, Abe M, Tokuyama O et al (2020) Olanzapine 5 mg plus standard antiemetic therapy for the prevention of chemotherapy-induced nausea and vomiting (J-FORCE): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 21(2):242–249. https://doi.org/10.1016/s1470-2045(19)30678-3CrossRefPubMed

14.

Nishimura J, Satoh T, Fukunaga M et al (2015) Combination antiemetic therapy with aprepitant/fosaprepitant in patients with colorectal cancer receiving oxaliplatin-based chemotherapy (SENRI trial): a multicentre, randomised, controlled phase 3 trial. Eur J Cancer 51(10):1274–1282. https://doi.org/10.1016/j.ejca.2015.03.024CrossRefPubMed

15.

Bubalo JS, Herrington JD, Takemoto M et al (2018) Phase II open label pilot trial of aprepitant and palonosetron for the prevention of chemotherapy-induced nausea and vomiting (CINV) in patients receiving moderately emetogenic FOLFOX chemotherapy for the treatment of colorectal cancer. Support Care Cancer 26(4):1273–1279. https://doi.org/10.1007/s00520-017-3950-yCrossRefPubMed

16.

Zhang L, Lu S, Feng J et al (2018) A randomized phase III study evaluating the efficacy of single-dose NEPA, a fixed antiemetic combination of netupitant and palonosetron, versus an aprepitant regimen for prevention of chemotherapy-induced nausea and vomiting (CINV) in patients receiving highly emetogenic chemotherapy (HEC). Ann Oncol 29(2):452–458. https://doi.org/10.1093/annonc/mdx698CrossRefPubMed

17.

Moradian S, Shahidsales S, Ghavam Nasiri MR et al (2014) Translation and psychometric assessment of the Persian version of the Rhodes Index of Nausea, Vomiting and Retching (INVR) scale for the assessment of chemotherapy-induced nausea and vomiting. Eur J Cancer Care (Engl Lang Ed) 23(6):811–818. https://doi.org/10.1111/ecc.12147CrossRef

18.

Ahmadi KR, Weale ME, Xue ZY et al (2005) A single-nucleotide polymorphism tagging set for human drug metabolism and transport. Nat Genet 37(1):84–89. https://doi.org/10.1038/ng1488CrossRefPubMed

19.

Ding K, Kullo IJ (2007) Methods for the selection of tagging SNPs: a comparison of tagging efficiency and performance. Eur J Hum Genet 15(2):228–236. https://doi.org/10.1038/sj.ejhg.5201755CrossRefPubMed

20.

The International HapMap Project (2003) Nature 426(6968):789–796. https://doi.org/10.1038/nature02168

21.

Xu Z, Taylor JA (2009) SNPinfo: integrating GWAS and candidate gene information into functional SNP selection for genetic association studies. Nucl Acids Res 37(Web Server issue):W600-605. https://doi.org/10.1093/nar/gkp290CrossRefPubMedPubMedCentral

22.

Conrad DF, Jakobsson M, Coop G et al (2006) A worldwide survey of haplotype variation and linkage disequilibrium in the human genome. Nat Genet 38(11):1251–1260. https://doi.org/10.1038/ng1911CrossRefPubMed

23.

de Bakker PIW, Burtt NP, Graham RR et al (2006) Transferability of tag SNPs in genetic association studies in multiple populations. Nat Genet 38(11):1298–1303. https://doi.org/10.1038/ng1899CrossRefPubMed

24.

Hayase T, Sugino S, Moriya H et al (2015) TACR1 gene polymorphism and sex differences in postoperative nausea and vomiting. Anaesthesia 70(10):1148–1159. https://doi.org/10.1111/anae.13082CrossRefPubMed

25.

Fattahi Z, Beheshtian M, Mohseni M et al (2019) Iranome: a catalog of genomic variations in the Iranian population. Hum Mutat 40(11):1968–1984CrossRefPubMed

26.

Reed GH, Kent JO, Wittwer CT (2007) High-resolution DNA melting analysis for simple and efficient molecular diagnostics. Pharmacogenomics 8(6):597–608. https://doi.org/10.2217/14622416.8.6.597CrossRefPubMed

27.

Vossen RH, Aten E, Roos A et al (2009) High-resolution melting analysis (HRMA): more than just sequence variant screening. Hum Mutat 30(6):860–866. https://doi.org/10.1002/humu.21019CrossRefPubMed

28.

Słomka M, Sobalska-Kwapis M, Wachulec M et al (2017) High resolution melting (HRM) for high-throughput genotyping-limitations and caveats in practical case studies. Int J Mol Sci 18(11):2316. https://doi.org/10.3390/ijms18112316CrossRefPubMedPubMedCentral

29.

Er TK, Chang JG (2012) High-resolution melting: applications in genetic disorders. Clin Chim Acta 414:197–201. https://doi.org/10.1016/j.cca.2012.09.012CrossRefPubMed

30.

Reed GH, Wittwer CT (2004) Sensitivity and specificity of single-nucleotide polymorphism scanning by high-resolution melting analysis. Clin Chem 50(10):1748–1754. https://doi.org/10.1373/clinchem.2003.029751CrossRefPubMed

31.

Wojdacz TK, Dobrovic A, Hansen LL (2008) Methylation-sensitive high-resolution melting. Nat Protoc 3(12):1903–1908. https://doi.org/10.1038/nprot.2008.191CrossRefPubMed

32.

Erali M, Voelkerding KV, Wittwer CT (2008) High resolution melting applications for clinical laboratory medicine. Exp Mol Pathol 85(1):50–58. https://doi.org/10.1016/j.yexmp.2008.03.012CrossRefPubMedPubMedCentral

33.

Auton A, Abecasis GR, Altshuler DM et al (2015) A global reference for human genetic variation. Nature 526(7571):68–74. https://doi.org/10.1038/nature15393CrossRefPubMed

34.

Untergasser A, Cutcutache I, Koressaar T et al (2012) Primer3—new capabilities and interfaces. Nucl Acids Res 40(15):e115–e115. https://doi.org/10.1093/nar/gks596CrossRefPubMedPubMedCentral

35.

Ye J, Coulouris G, Zaretskaya I et al (2012) Primer-BLAST: a tool to design target-specific primers for polymerase chain reaction. BMC Bioinform 13:134. https://doi.org/10.1186/1471-2105-13-134CrossRef

36.

Owczarzy R, Tataurov AV, Wu Y et al (2008) IDT SciTools: a suite for analysis and design of nucleic acid oligomers. Nucl Acids Res 36(Web Server issue):W163–W169. https://doi.org/10.1093/nar/gkn198CrossRefPubMedPubMedCentral

37.

Ziegler A, Van Steen K, Wellek S (2011) Investigating Hardy–Weinberg equilibrium in case–control or cohort studies or meta-analysis. Breast Cancer Res Treat 128(1):197–201. https://doi.org/10.1007/s10549-010-1295-zCrossRefPubMed

38.

Barrett JC, Fry B, Maller J et al (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21(2):263–265. https://doi.org/10.1093/bioinformatics/bth457CrossRefPubMed

39.

Stephens M, Smith NJ, Donnelly P (2001) A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 68(4):978–989. https://doi.org/10.1086/319501CrossRefPubMedPubMedCentral

40.

Stephens M, Scheet P (2005) Accounting for decay of linkage disequilibrium in haplotype inference and missing-data imputation. Am J Hum Genet 76(3):449–462. https://doi.org/10.1086/428594CrossRefPubMedPubMedCentral

41.

Chang CC, Chow CC, Tellier LC et al (2015) Second-generation PLINK: rising to the challenge of larger and richer datasets. GigaScience. https://doi.org/10.1186/s13742-015-0047-8CrossRefPubMedPubMedCentral

42.

Purcell S, Neale B, Todd-Brown K et al (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81(3):559–575. https://doi.org/10.1086/519795CrossRefPubMedPubMedCentral

43.

Purcell S, Cherny SS, Sham PC (2003) Genetic power calculator: design of linkage and association genetic mapping studies of complex traits. Bioinformatics 19(1):149–150. https://doi.org/10.1093/bioinformatics/19.1.149CrossRefPubMed

44.

ENCODE Project Consortium (2012) An integrated encyclopedia of DNA elements in the human genome. Nature 489(7414):57–74. https://doi.org/10.1038/nature11247CrossRef

45.

Moore JE, Purcaro MJ, Pratt HE et al (2020) Expanded encyclopaedias of DNA elements in the human and mouse genomes. Nature 583(7818):699–710. https://doi.org/10.1038/s41586-020-2493-4CrossRefPubMedPubMedCentral

46.

Tak YG, Farnham PJ (2015) Making sense of GWAS: using epigenomics and genome engineering to understand the functional relevance of SNPs in non-coding regions of the human genome. Epigenetics Chromatin 8:57. https://doi.org/10.1186/s13072-015-0050-4CrossRefPubMedPubMedCentral

47.

Saunders MA, Liang H, Li W-H (2007) Human polymorphism at microRNAs and microRNA target sites. Proc Natl Acad Sci USA 104(9):3300–3305. https://doi.org/10.1073/pnas.0611347104CrossRefPubMedPubMedCentral

48.

McGeary SE, Lin KS, Shi CY et al (2019) The biochemical basis of microRNA targeting efficacy. Science. https://doi.org/10.1126/science.aav1741CrossRefPubMedPubMedCentral

49.

Cummins JM, He Y, Leary RJ et al (2006) The colorectal microRNAome. Proc Natl Acad Sci USA 103(10):3687–3692. https://doi.org/10.1073/pnas.0511155103CrossRefPubMedPubMedCentral

50.

Kozomara A, Birgaoanu M, Griffiths-Jones S (2018) miRBase: from microRNA sequences to function. Nucl Acids Res 47(D1):D155–D162. https://doi.org/10.1093/nar/gky1141CrossRefPubMedCentral

51.

Ludwig N, Leidinger P, Becker K et al (2016) Distribution of miRNA expression across human tissues. Nucl Acids Res 44(8):3865–3877. https://doi.org/10.1093/nar/gkw116CrossRefPubMedPubMedCentral

52.

Duan Y, Veksler-Lublinsky I, Ambros V (2022) Critical contribution of 3′ non-seed base pairing to the in vivo function of the evolutionarily conserved let-7a microRNA. Cell Rep 39(4):110745. https://doi.org/10.1016/j.celrep.2022.110745CrossRefPubMedPubMedCentral

53.

Ward LD, Kellis M (2011) HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucl Acids Res 40(D1):D930–D934. https://doi.org/10.1093/nar/gkr917CrossRefPubMedPubMedCentral

54.

Boyle AP, Hong EL, Hariharan M et al (2012) Annotation of functional variation in personal genomes using RegulomeDB. Genome Res 22(9):1790–1797. https://doi.org/10.1101/gr.137323.112CrossRefPubMedPubMedCentral

55.

Van Laere K, De Hoon J, Bormans G et al (2012) Equivalent dynamic human brain NK1-receptor occupancy following single-dose i.v. fosaprepitant vs. oral aprepitant as assessed by PET imaging. Clin Pharmacol Therap 92(2):243–250. https://doi.org/10.1038/clpt.2012.62CrossRef

56.

Renner SP, Ekici AB, Maihöfner C et al (2009) Neurokinin 1 receptor gene polymorphism might be correlated with recurrence rates in endometriosis. Gynecol Endocrinol 25(11):726–733. https://doi.org/10.3109/09513590903159631CrossRefPubMed

57.

Seneviratne C, Ait-Daoud N, Ma JZ et al (2009) Susceptibility locus in neurokinin-1 receptor gene associated with alcohol dependence. Neuropsychopharmacol Offi Publ Am Coll Neuropsychopharmacol 34(11):2442–2449. https://doi.org/10.1038/npp.2009.65CrossRef

58.

Singh KP, Dhruva AA, Flowers E et al (2018) A review of the literature on the relationships between genetic polymorphisms and chemotherapy-induced nausea and vomiting. Crit Rev Oncol Hematol 121:51–61. https://doi.org/10.1016/j.critrevonc.2017.11.012CrossRefPubMed

59.

Tsuji D, Matsumoto M, Kawasaki Y et al (2021) Analysis of pharmacogenomic factors for chemotherapy-induced nausea and vomiting in patients with breast cancer receiving doxorubicin and cyclophosphamide chemotherapy. Cancer Chemother Pharmacol 87(1):73–83. https://doi.org/10.1007/s00280-020-04177-yCrossRefPubMed

Title: Gene polymorphisms of TACR1 serve as the potential pharmacogenetic predictors of response to the neurokinin-1 receptor antagonist-based antiemetic regimens: a candidate-gene association study in breast cancer patients
Authors: Marziyeh Ghorbani
Soha Namazi
Mehdi Dehghani
Farideh Razi
Bahman Khalvati
Ali Dehshahri
Publication date: 27-04-2024
Publisher: Springer Berlin Heidelberg
Keywords: Nausea
Breast Cancer
Breast Cancer
Vomiting
Cytostatic Therapy
Published in: Cancer Chemotherapy and Pharmacology
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-024-04661-9

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine