Balkan Journal of Medical Genetics

IGHV MUTATIONAL STATUS IN A COHORT OF BULGARIAN CLL PATIENTS: HIGH UNMUTATED CLL PREVALENCE IN NORTH-EAST BULGARIA
Yosifova A, Micheva I, Donchev M, Tincheva S, Ormandjiev S, Genova J, Pavlova Z, Todorova A
*Corresponding Author: Angelina Yosifova, Genetic Medico-Diagnostic Laboratory “Genica”, Sofia, Bulgaria. Email: andjim91@gmail.com; Phone: +359888979313
page: 15

RESULTS ÀND DISCUSSION

Following the 98% identity cut-off value, a total of 57 patients were genotyped as unmutated IGHV (U-CLL), 44 – as mutated (M-CLL), and 4 – as borderline (B-CLL) (Figure 3). Different BCR stereotyped subsets were found in 7 out of 105 cases (6.67%) (Table 1). According to the published data, the expected ratio of unmutated and mutated cases at diagnosis are 40% vs. 60%, respectively [14,15]. Within the course of the analysis, a high prevalence of unmutated CLL patients was detected in the Varna district on the Black Sea (Northeast Bulgaria). From a total of 24 patients from the Varna region, 17 (75%) showed an unmutated status, hence more aggressive CLL, which we hypothesize might be related to the regional in- dustrial activities. For the rest of the 81 patients originating from different regions in Bulgaria, the unmutated patients were 41 (51%). Fisher’s Exact Test showed a statistically significant correlation between the region of origin of the patients and their IGHV mutational status (p=0.028, two- tailed Fisher’s Exact Test), but this finding might be biased by the small number of patients tested (Table 2). Furthermore, a difficult to categorize case with multiple rearrangements (triple productive rearrangements) was de- tected (Table 3). For diagnostic purposes, an analysis was per- formed on gDNA, and the obtained quality of the sequencing profiles was highly satisfactory, therefore RNA transcripts were not tested. This case was interpreted and reported as unmutated, based on the published data showing a shift in favor of unmutated IGHV in a majority of the discordant cases [16]. In such cases, when discordant multiple produc- tive rearrangements were detected, the resulting prognosis is inconclusive, and it is recommended to be considered and treated as a more aggressive unmutated status [16]. Following the current recommendations, cases with discordant multiple rearrangements, should be re-tested after six months [16]. In conclusion, the present data from IGHV genotyp- ing could aid in estimating the disease’s course and how to choose optimal initial treatment for Bulgarian CLL pa- tients. Patients with unmutated IGHV CLL tend to relapse earlier due to the more aggressive course of the disease [17,18]. These patients have also demonstrated less benefit from treatment with chemoimmunotherapy and BCL2 inhibitors compared to patients with mutated IGHV, while Bruton Tyrosine Kinase (BTK) inhibitors have the same efficacy irrespective of the IGHV mutational status.

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