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Clinical Trial
. 2021 Jan 8:11:602482.
doi: 10.3389/fimmu.2020.602482. eCollection 2020.

Geographical Distribution, Incidence, Malignancies, and Outcome of 136 Eastern Slavic Patients With Nijmegen Breakage Syndrome and NBN Founder Variant c.657_661del5

Svetlana O Sharapova  1 , Olga E Pashchenko  2 , Anastasiia V Bondarenko  3 , Svetlana S Vakhlyarskaya  4 , Tatjana Prokofjeva  5 , Alina S Fedorova  1 , Ihor Savchak  6 , Yuliya Mareika  1 , Timur T Valiev  7 , Alexander Popa  8 , Irina A Tuzankina  9 , Elena V Vlasova  10 , Inga S Sakovich  1 , Ekaterina A Polyakova  1 , Natalia V Rumiantseva  11 , Irina V Naumchik  11 , Svetlana A Kulyova  12 , Svetlana N Aleshkevich  1 , Elena I Golovataya  11 , Nina V Minakovskaya  1 , Mikhail V Belevtsev  1 , Elena A Latysheva  13 , Tatiana V Latysheva  13 , Alexander G Beznoshchenko  14 , Hayane Akopyan  15 , Halyna Makukh  15 , Olena Kozlova  16 , Dzmitry S Varabyou  17 , Mark Ballow  18 , Mei-Sing Ong  19 , Jolan E Walter  20 , Irina V Kondratenko  4 , Larysa V Kostyuchenko  6 , Olga V Aleinikova  1
Affiliations
Clinical Trial

Geographical Distribution, Incidence, Malignancies, and Outcome of 136 Eastern Slavic Patients With Nijmegen Breakage Syndrome and NBN Founder Variant c.657_661del5

Svetlana O Sharapova et al. Front Immunol. .

Abstract

Nijmegen breakage syndrome (NBS) is a DNA repair disorder characterized by combined immunodeficiency and a high predisposition to lymphoid malignancies. The majority of NBS patients are identified with a homozygous five base pair deletion in the Nibrin (NBN) gene (c.657_661del5, p.K219fsX19) with a founder effect observed in Caucasian European populations, especially of Slavic origin. We present here an analysis of a cohort of 136 NBS patients of Eastern Slav origin across Belarus, Ukraine, Russia, and Latvia with a focus on understanding the geographic distribution, incidence of malignancy, and treatment outcomes of this cohort. Our analysis shows that Belarus had the highest prevalence of NBS (2.3 per 1,000,000), followed by Ukraine (1.3 per 1,000,000), and Russia (0.7 per 1,000,000). Of note, the highest concentration of NBS cases was observed in the western regions of Belarus and Ukraine, where NBS prevalence exceeds 20 cases per 1,000,000 people, suggesting the presence of an "Eastern Slavic NBS hot spot." The median age at diagnosis of this cohort ranged from 4 to 5 years, and delay in diagnosis was more pervasive in smaller cities and rural regions. A total of 62 (45%) patients developed malignancies, more commonly in males than females (55.2 vs. 34.2%; p=0.017). In 27 patients, NBS was diagnosed following the onset of malignancies (mean age: 8 years). Malignancies were mostly of lymphoid origin and predominantly non-Hodgkin lymphoma (NHL) (n=42, 68%); 38% of patients had diffuse large B-cell lymphoma. The 20-year overall survival rate of patients with malignancy was 24%. However, females with cancer experienced poorer event-free survival rates than males (16.6% vs. 46.8%, p=0.036). Of 136 NBS patients, 13 underwent hematopoietic stem cell transplantation (HSCT) with an overall survival of 3.5 years following treatment (range: 1 to 14 years). Indications for HSCT included malignancy (n=7) and immunodeficiency (n=6). Overall, 9% of patients in this cohort reached adulthood. Adult survivors reported diminished quality of life with significant physical and cognitive impairments. Our study highlights the need to improve timely diagnosis and clinical management of NBS among Eastern Slavs. Genetic counseling and screening should be offered to individuals with a family history of NBS, especially in hot spot regions.

Keywords: Nijmegen breakage syndrome (NBS); founder variants; geographical location; incidence in East Slavs; lymphomas, risk of malignancies; quality of life; social adaptation.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
The geographic distribution of NBS patients among East Slavs. Light gray zone on the map of Russia is the territory of predominant Russian settlement (18). The size of the full circle correlates to the number of patients diagnosed from one location (or region) (range 1 to 9). In blue is the NBN founder variant c.657_661del5, p.K219fsX19; in red: NBN c.657_661del5/c.681delT.
Figure 2
Figure 2
Number of patients with NBS in geographical hot spot region. In blue is the NBN founder variant c.657_661del5, p.K219fsX19. The size of the full circle correlates to the number of patients diagnosed from one location (or region). Blue circles represent number of cases (1 to >9).
Figure 3
Figure 3
Malignancy data of the NBS East Slavic cohort. (A) Cumulative incidence of any malignancy (%) from birth in the whole NBS East Slavic cohort. (B) Percentage of developed malignancy in boys and girls with NBS. (C) Cumulative incidence of any malignancy (%) among boys and girls in the NBS East Slavic cohort. (D) EFS displayed as Kaplan–Meier survival curves in males and females after first malignant diagnosis. *p < 0.05.
Figure 4
Figure 4
Survival probabilities of 136 East Slavic NBS. (A) OS displayed as Kaplan–Meier survival curve of cancer (+) and no cancer NBS patient groups. (B) The probability of the OS since NBS diagnosis in 13 patients who underwent HSCT and in 119 nontransplanted patients (expressed as a percentage, patients diagnosed postmortem were excluded from analysis). (C) Survival probabilities of 13 NBS patients after HSCT. (D) NBS patients’ appearance at different ages.
See this image and copyright information in PMC

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