PB1876 GENETIC MARKERS OF THE PRIMARY AND SECOND TUMORS RISK DEVELOPMENT IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA
Authors: Nazarova E. , Suhorukova J. , Minaeva N. , Dubrovina A. , Rylov A. , Paramonov I. 
Published: June 2019

Background:

Malignant tumors in patients with chronic lymphocytic leukemia (CLL) occur with equal frequency in both previously untreated patients and those receiving high‐dose therapy. This is due not only to the presence of CLL‐associated, but with drug‐induced immunodeficiency, and, probably, with modifications in the immune response genes.

Aims:

Identify the relationship of the several immune response genes mutational status with the development of primary and second tumors in patients with CLL.

Methods:

Surveyed 202 patients in the beginning of CLL at the age of 32 to 87 years (median‐63 years), 112 men (55.4%), 90 women (44.6%). Genotyping of 20 polymorphic regions of the 14 immune response genes (TLR2, TLR3, TLR4, TLR6, TLR9, IL1β, IL2, IL4, IL6, IL10, IL17A, CD14, TNFα, FCGR2A) in genomic DNA obtained from peripheral blood leukocytes was carried out by the PCR‐ASP. Intergenic interactions analysis was performed using the MDR program version 3.0.2, http://www.mybiosoftware.com/mdr‐2‐0‐multifactor‐dimensionality‐reduction.html.

Results:

Patients were divided into 3 groups. The first group consisted of 6 patients who had other malignancies before onset CLL. The appearance of CLL was preceded in 2 cases by the breast cancer and one: cancer of the testicle, ovary, skin and fungal mycosis from 36 to 252 months (median‐135.5 months). The second ‐ consisted of 190 CLL patients with no previous or second malignant tumors history. The third included 6 patients, who developed the second solid tumors in CLL remission after FCR treatment. Within 13‐94 months (median‐53.5 months) from the onset of CLL, they had skin cancer in 2 cases, colon cancer in 2 patients, melanoma and breast cancer in one case. In all selected groups, age and gender differences were not found. All possible combinations of the key immune response genes polymorphic variants were analyzed. It was found that the first group of patients is characterized by 2 statistically significant models: single‐ FCGR2A (A519C) (p = 0.0001) and two‐locus TLR4 (G896A)/FCGR2A (A519C) (p < 0.0001). Patients who had a second tumors after onset CLL also distinguished two models: single‐locus with the participation of the IL17A gene (G197A), p = 0.00006 and three‐locus model TLR6 (C745T)/TLR9 (A2848G)/IL1β (T511C) (p < 0.0001). It is very likely that the triggering factor for the second malignant tumors occurrence in these patients was high‐dose chemotherapy of CLL, which aggravated the existing CLL‐mediated immunodeficiency. As a result of the intergenic interactions evaluation, it was noted that in patients with a previous CLL cancer history, the risk factors for the development of primary tumors were 3 combined genotypes: FCGR2A‐519AA/TLR4‐896GG; FCGR2A‐519AA/TLR9‐2848AA/TLR4‐896GG; FCGR2A‐519AA/TLR9‐2848AG/TLR4‐896AG. For patients with CLL and second tumors detected in remission of leukemia, the most prognostically important were the combinations of genotypes: IL1β‐511CC/TLR9‐2848AA/TLR6‐745TT; IL1β‐511CC/TLR9‐2848AG/TLR6‐745TT; IL1β‐511TT/TLR9‐2848AG/TLR6‐745TT.

Summary/Conclusion:

Studies have confirmed the involvement of immune mechanisms in the carcinogenesis. Analysis of the polymorphic status genes FCGR2A, TLR6, TLR9 (A2848G), IL1β (T511C), IL17A, which are involved in the development and progression of various human tumors, will allow to select among patients with CLL a group with an increased risk of the development of previous and second malignant neoplasms.