Mol Gen Microbiol Virol, 2013, Vol.28, No.2, pp.52–55. DOI: 10.3103/S0891416813020031

Analysis of the –238(G/A)TNF Polymorphism in Breast Cancer Patients.

Malivanova TF, Skoromyslova EV, Yurchenko VA, Kononenko IB, Manzyuk LV, Mazurenko NN.

ABSTRACT

Tumor necrosis factor (TNF) is an inflammatory cytokine that is involved in pathogenesis of different malignancies. The single nucleotide polymorphism –238(G/A)TNF (rs361525) has been investigated for detection of a predisposition to infectious, autoimmune, and oncological diseases. The goal of the study was to investigate the association of –238(G/A)TNF polymorphism with breast cancer (BC) prognosis. TNF allelic variants were detected by restriction fragment length polymorphism polymerase chain reaction (RFLP-PCR). We did not reveal genotype distribution disparities among groups with various stages of the disease and various levels of expression of ER, PR and Her2/neu. The AG genotype frequency was about 10%, and there were no BC patients with the AA genotype in all groups. However, the 5-year overall survival was significantly lower for AG than GG carriers with stage II or ER positive BC. Our data suggest that –238(G/A)TNF polymorphism is not involved in the initiation of malignancies but is a substantial factor of BC prognosis.

PMID: 24003507

 

SUPPLEMENT

BC is very heterogeneous disease. Molecular subtypes connected with such molecules involved in BC pathogenesis as estrogen receptors (ER), progesterone receptors (PR), and HER2/neu have been isolated. At the same time, the levels of expression of these molecules in tumor tissue are traditionally used markers and therapeutic targets defining the approach to treatment. TNF is an inflammatory cytokine which is involved in pathogenesis of different malignancies including BC. High doses of TNF are able to induce apoptosis, while a chronically low production of it results in proliferation of tumor cells. Single nucleotide substitution of G for A at –238 bp (rs361525) in the TNF promoter region decreased transcription of this cytokine in vitro. The purpose of this work was to investigate the association of –238(G/A)TNF with known prognosis factors (stage of the disease and ER, PR, and HER2/neu status) and to determine the BC prognostic value of the polymorphism.

The obtained distribution of BC patient’s genotypes did not differ from the healthy women. Also we did not reveal the difference in genotype distribution in groups with different disease stages and ER, PR, and HER2/neu statuses. The analysis of 5-year survival was carried out on 268 BC patients (see table). When samples were ranging according to the stage of the disease, the survival of patients with AG genotype was two-fold lower than in GG patients in the BC stage II group. In the case of a sample ranging according to the receptor status, a significant difference between AG and GG genotype carriers was observed in the ER-positive BC, but not in ER-negative group. It seems that the disease state is more aggressive in low expression AG genotype carriers than in GG patients. Consequently, the low expression AG genotype is associated with unfavorable prognosis of BC. The low endogenous TNF production seems not to provide antitumor effect of this cytokine already at an early (II) stage of disease. At the same time, lower survival for AG genotype carriers with ER-positive tumors can be indicative of a resistance to hormone therapy that is normally assigned in case of this type of tumors.

Tatyana Malivanova-tab1

Contact: Tatyana Malivanova, MD, PhD, Blokhin Russian Cancer Research Center, Russian Academy of Medical Sciences, Russia. tmalivanova@yandex.ru

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