Pathogenic mutations in the TSC1 and TSC2 genes are frequent in insulinomas
https://doi.org/10.25557/2073-7998.2018.10.26-30
Abstract
Background. Insulinomas are rare (1-4 cases per million people) and typically sporadic neuroendocrine tumors of the pancreas, manifesting mainly by hypoglycemia caused by endogenous hyperinsulinism. So far, only a few studies of the genomes of these tumors have been carried out, and a generally accepted idea of their etiopathogenesis at the molecular genetic level has not been developed. Hypothesis. Recently, studies in the field of insulinomas drug therapy have demonstrated the effectiveness of everolimus, an inhibitor of a protein kinase of the serine-threonine specificity mTOR. Everolimus is known as a targeted drug for the treatment of tuberous sclerosis, a key role in the etiopathogenesis of which is played by alterations of the TSC1 and TSC2 genes. We hypothesized that the high therapeutic efficacy of everolimus against insulinomas, by analogy, may be due to the pivotal involvement of mutations in the TSC1 and TSC2 genes in the development of these tumors. Material and methods. To test the hypothesis, we performed NGS of exons and adjacent introns of the TSC1 and TSC2 genes in order to identify point mutations and losses of heterozygosity in 9 pancreatic insulinomas. Result. Totally in 9 samples we have identified eight point mutations and seven cases of loss of heterozygosity. In 4 samples, the tumor genotype corresponds to a two-hit tumorigenesis model (two different mutational events in the TSC2 gene). In two samples, losses of heterozygosity encompassing simultaneously the TSC1 and TSC2 genes were identified. In only one case, no point mutations nor losses of heterozygosity in the TSC1 or TSC2 genes were found. Conclusion. This is the first report of a high occurrence of mutations in the genes of the tuberous sclerosis complex in insulinomas of the pancreas, indicating possible involvement of the TSC1/TSC2 protein complex disruption in the development of most tumors of this type. Further research should lead to a deeper understanding of the causes of pancreatic neuroendocrine tumors and to the improvement of their treatment, including that with mTOR inhibitors.
About the Authors
K. I. Anoshkin
Research Centre for Medical Genetics, Moscow, Russian Federation, 115522, Moskvorechie st.1, e-mail: anoshkiri@gmail.com
Russian Federation
Russian Federation
I. A. Vasiliev
I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation, 119991, Trubetskaya st. 8, e-mail: sekachrab@mail.ru
Russian Federation
Russian Federation
K. O. Karandasheva
Research Centre for Medical Genetics, Moscow, Russian Federation, 115522, Moskvorechie st.1, e-mail: anoshkiri@gmail.com
Russian Federation
Russian Federation
A. S. Tanas
Research Centre for Medical Genetics, Moscow, Russian Federation, 115522, Moskvorechie st.1, e-mail: anoshkiri@gmail.com
Russian Federation
Russian Federation
M. M. Byakhova
State budgetary healthcare institution of the Moscow region «Moscow Regional Scientific Research Clinical Institute. MF Vladimirsky», Moscow, Russian Federation, 129110, Shchepkina street 61/2: e-mail: biakhovamm@mail.ru
Russian Federation
Russian Federation
L. E. Gurevich
State budgetary healthcare institution of the Moscow region «Moscow Regional Scientific Research Clinical Institute. MF Vladimirsky», Moscow, Russian Federation, 129110, Shchepkina street 61/2: e-mail: biakhovamm@mail.ru
Russian Federation
Russian Federation
Yu. V. Doludin
I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation, 119991, Trubetskaya st. 8, e-mail: sekachrab@mail.ru
Russian Federation
Russian Federation
N. N. Bagmet
Federal State Budget Scientific Institution «Russian Research Center for Surgery named after Academician B.V. Petrovsky», Moscow, Russian Federation, 119991, Abrikosovsky lane house 2, e-mail: gshatverian@mail.ru
Russian Federation
Russian Federation
G. A. Shatveryan
Federal State Budget Scientific Institution «Russian Research Center for Surgery named after Academician B.V. Petrovsky», Moscow, Russian Federation, 119991, Abrikosovsky lane house 2, e-mail: gshatverian@mail.ru
Russian Federation
Russian Federation
A. V. Yegorov
I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation, 119991, Trubetskaya st. 8, e-mail: sekachrab@mail.ru
Russian Federation
Russian Federation
M. V. Nemtsova
Research Centre for Medical Genetics, Moscow, Russian Federation, 115522, Moskvorechie st.1, e-mail: anoshkiri@gmail.com
Russian Federation
Russian Federation
M. I. Sekacheva
Federal State Budget Scientific Institution «Russian Research Center for Surgery named after Academician B.V. Petrovsky», Moscow, Russian Federation, 119991, Abrikosovsky lane house 2, e-mail: gshatverian@mail.ru
Russian Federation
Russian Federation
V. V. Strelnikov
Research Centre for Medical Genetics, Moscow, Russian Federation, 115522, Moskvorechie st.1, e-mail: anoshkiri@gmail.com
Russian Federation
Russian Federation
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Review
For citations:
Anoshkin K.I., Vasiliev I.A., Karandasheva K.O., Tanas A.S., Byakhova M.M., Gurevich L.E., Doludin Yu.V., Bagmet N.N., Shatveryan G.A., Yegorov A.V., Nemtsova M.V., Sekacheva M.I., Strelnikov V.V. Pathogenic mutations in the TSC1 and TSC2 genes are frequent in insulinomas. Medical Genetics. 2018;17(10):26-30. (In Russ.) https://doi.org/10.25557/2073-7998.2018.10.26-30
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