PF582 PARTICIPATION OF IMMUNE RESPONSE GENES POLYMORPHISM IN THE OCCURRENCE OF SOLID TUMORS IN PATIENTS WITH MULTIPLE MYELOMA
Authors: E. Nazarova, J. Suhorukova, N. Minaeva, A. Dubrovina, A. Rylov, I. Paramonov
Journal: HemaSphere (2019)

Background: Modern treatment regimens, including the use of immunomodulatory drugs and high-dose chemotherapy followed by transplantation of autologous hematopoietic stem cells, have increased the duration of overall and relapse-free survival in patients with multiple myeloma (MM). However, the presence of a previous or subsequent MM onset another malignancies, can have a negative impact on the life expectancy of these patients. According to the IMWG [2017], the frequency of second tumors development in MM patients varies from 3 to 5% and is directly dependent on the effectiveness of the mechanisms of antitumor immunity implementation, controlled by the immune response genes. Aims: To determine the role of immune response genes polymorphic status in the development of solid tumors in MM patients. Methods: 170 patients with MM in age from 27 to 85 years (median-57 years) in the onset of the disease, 81 men (47.6%), women 89 (52.4%) were examined. Genotyping of the 20 loci in the 14 immune response genes (TLR2, TLR3, TLR4, TLR6, TLR9, IL1β, IL2, IL4, IL6, IL10, IL17A, CD14, TNFα, FCGR2A) was carried out by the PCR-ASP. The MDR program version 3.0.2 was used to search for optimal models of intergenic interaction susceptibility to the development of second tumors in MM patients, http://www.mybiosoftware.com/mdr-2-0-multifactor-dimensionality-reduction.html. Results: Patients were divided into 3 groups. The 1st group included 3 (1.8%) patients who had other malignancies: in 2 cases - thyroid and in one – breast cancer, from 1 to 384 mo. (median-144 mo.) before onset MM. The 2nd - consisted of 164 (96.4%) patients with MM without previous or secondary malignant tumors. In the 3rd group, 3 (1.8%) patients were observed, 2 of whom had breast and one bladder cancer after 12–96 mo. from the start of MM treatment (median-36 mo.) in the remission of myeloma. All groups were comparable in gender and age. In the process of modeling for 1st group patients, 2 statistically significant models of the previous MM malignant tumors development were identified: single- IL17A(G197A) (p = 0.0286) and three-locus models: IL17A(G197A)/IL10(C819T)/IL6(G174C) (p < 0.0001). On the other hand, for the group of patients with MM and secondary tumors, 2 models were also characteristic: single- TLR4(T1196C) (p = 0.003) and two-locus: IL1β(T31C)/IL1β(T511C) (p < 0.0001). In the intergenic interaction analysis for the 1st group of patients with MM 3 combinations of genotypes were found, the detection of which significantly increases the risk of previous solid tumors: TLR9-1237TT/IL17A-197GG; IL6-174CG/IL17A-197GG/IL10-819CT; IL6-174GG/IL17A-197GG/IL10-819CC. A group of patients, where a solid tumor was detected past MM, was characterized by 4 genotypes combinations: IL1β-511CT/IL1β-31CC; IL1β-511CT/IL1β-31TT; IL1β-511CT/TLR9-1237CC/IL1β-31CC; IL1β-511CT/TLR9-1237TC IL1β-31TT. It is interesting to note that in one patient (not included in the number 170 examined), we observed 3 malignancies: 108 mo. before MM was detected and treated bladder cancer, and 8 mo. after MM onset - prostate cancer. In general, the development of primary and second solid tumors in patients with MM was detected at different times (144 and 36 mo.) from MM onset. Undoubtedly, in the second case, the previous program therapy of MM had a certain role. Summary/Conclusion: The involvement of the immune response genes in the coexistence of solid tumors with MM was found. Determining the polymorphic status of the genes IL1β IL6, IL10, IL17A, TLR9 will make it possible to select among patients with MM a group with an increased risk of developing second tumors.