• Мclinical application of polymorphic variants of the genes ESR1 and CYP2D6*4 in patients with breast and endometrial cancer

Мclinical application of polymorphic variants of the genes ESR1 and CYP2D6*4 in patients with breast and endometrial cancer

HEALTH OF WOMAN. 2017.2(118):132–138; doi 10.15574/HW.2017.118.132

Paliychuk O. V., Polishchuk L. Z., Rossokha Z. I.
Institute of experimental pathology, Oncology and radiobiology R.E. Kavetsky NAS of Ukraine, Kyiv
SI «Reference-centre on molecular diagnostic MH of Ukraine», Kyiv
SI «Cherkasy regional Oncology dispensary» CRC

The objective: determining gene polymorphism features ERS1, CYP2D6 in patients with breast cancer (RHZ) and endometrial cancer (EC) and the impact assessment studied genetic characteristics compared to receptor status (immunohistochemical determination of expression levels of ER, PR) tumors and the results of the treatment.

Patients and methods. article presents the results of complex clinical, morphological, clinical-genealogical, and molecular-genetic examination of 28 females: 19 patients with breast cancer (BC), 9 patients with endometrial cancer (EC), including 5 patients with primary-multiple tumors (PMT) with and without tumor pathology aggregation in families.

Results. The It was determined that in patients’ families malignant tumors of breast, uterine body and/or ovaries prevail that corresponds to Lynch type II syndrome (family cancer syndrome). Molecular-genetic examination of genomic DNA of peripheral blood and histological sections for the presence of SNPs of ESR and CYP2D6*4 genes comparing with the results of immunohistochemical study of tumors for receptors ER and PR status have not found associations between these characteristics; although among EC patients the occurrence of genotypes 397ТТ and 351АА was significantly higher comparing with BC patients (55.55% and 10.5% for genotype 397ТТ,and 15.8% for genotype 351АА, respectively). At the same time the patients with BC and primary-multiple tumors (PMT) of female reproductive system organs (FRSO) that carried mutations in BRCA1 in all the cases demonstrated positive ER and PR receptor status and adverse combinations of polymorphous variants of the genes ESR1 (397СС, 397ТС) and CYP2D6*4 (1846G, 1846GA), suggesting combined effect of these factors on the development of malignant neoplasias of FRSO in families with positive family cancer history. In BC patients, receiving standard hormone therapy with tamoxifen, those, who had genotype 1846GG of the gene CYP2D6*4, in 3 patients (15.8%) of 19 (100%) patients disease recurrence was diagnosed.

Conclusion. The obtained results allow clinical use of the assessment of polymorphism frequency of the genes ESR1 and CYP2D6*4 for selection of individual hormone therapy regimens schemes for BC patients, to increase efficacy of dispensary observation after finishing of special therapy for such patients, and also personalization of complex and combined treatment regimens.

Key words: breast cancer, endometrial cancer, family cancer syndrome, single nucleotide polymorphisms (SNPs) of the genes ESR1, CYP2D6*4.

REFERENCES

1. Paliichuk OV, Rossokha ZI, Halkin FM, Polishchuk LZ. 2015. Otsinka asotsiatsii kliniko-patolohichnykh osoblyvostei pukhlynnoho protsesu z rezultatamy kliniko-henealohichnoho obstezhennia khvorykh na rak yaiechnyka ta hrudnoi zalozy – nosiiv mutatsii 5382insC u heni BRCA1. Klynycheskaia onkolohiya 4(20):23–28.

2. Paliichuk OV, Polishchuk LZ, Rossokha ZI, Chekhun VV. 2016. Doslidzhennia polimorfizmiv hena ESR1 u khvorykh na rak orhaniv zhinochoi reproduktyvnoi systemy z obtiazhenym simeinym anamnezom. Onkolohiya 18(70);4:316–324.

3. Paliichuk OV, Polishchuk LZ, Rossokha ZI, Chekhun VV. 2017. Testuvannia na polimorfni varianty hena CYP2D6*4 u patsiientok z dobroiakisnoiu patolohiieiu ta khvorykh na rak orhaniv zhinochoi reproduktyvnoi systemy z rodyn iz simeinym rakovym syndromom. Onkolohiya 19(71):1.

4. Lee YH, Kim JH, Song GG. 2014. Genome-wide path way analysis of breast cancer.TumourBiol. 35(8):7699–705. https://doi.org/10.1007/s13277-014-2027-5; PMid:24805830

5. Mancini-Di Nardo D, Judkins T, Woolstenhulme N et al. 2014, Sep 11. Design and validation of an oligonucleotide microarray for the detection of genomic rearrangements associated with common hereditary cancer syndromes.J Exp Clin Cancer Res. 33:74. https://doi.org/10.1186/s13046-014-0074-9.

6. Hoskins  JM, Carey LA, McLeod HL. 2009. CYP2D6 and tamoxifen: DNA matters in breast cancer.Nat Rev Cancer. 9(8):576-86. https://doi.org/10.1038/nrc2683; PMid:19629072

7. Hennig EE, Piatkowska M, Karczmarski J et al. 2015. Limited predictive value of achieving beneficial plasma (Z)-endoxifen threshold level by CYP2D6 genotyping intamoxifen-treated Polish women with breast cancer. BMC Cancer. 15:570. https://doi.org/10.1186/s12885-015-1575-4.

8. Mürdter TE1, Schroth W, Bacchus-Gerybadze L et al. 2011, May. Activity levels of tamoxifen metabolites at the estrogen receptor and the impact of genetic polymorphisms of phase I and II enzymes on their concentration levels in plasma. Clin Pharmacol Ther. 89(5):708-17. https://doi.org/10.1038/clpt.2011.27; PMid:21451508

9. Hennig EE, Piatkowska M, Karczmarski J et al. 2015. Limited predictive value of achieving beneficial plasma (Z)-endoxifen threshold level by CYP2D6 genotyping in tamoxifen-treated Polish women with breast cancer. BMC Cancer. 15:570. https://doi.org/10.1186/s12885-015-1575-4.

10. Xu Y, Sun Y, Yao L et al. 2008. Association between CYP2D6 *10 genotype and survival of breast cancer patients receiving tamoxifen treatment. Ann Oncol 19:1423-1429. https://doi.org/10.1093/annonc/mdn155; PMid:18407954

11. Dezentjé VO, van Blijderveen NJ, Gelderblom H et al. 2010. Effect of concomitant CYP2D6 inhibitor use and tamoxifen adherence on breast cancer recurrence in early-stage breast cancer. J Clin Oncol 28:2423–2429. https://doi.org/10.1200/JCO.2009.25.0894; PMid:20385997

12. Hartman M, Loy EY, Ku CS et al. 2010. Molecular epidemiology and its current clinical use in cancer management. The Lancet Oncology. Ukranian Edition tissue 3;41: 01–51. https://doi.org/10.1016/s1470-2045(10)70005-x

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