DNMT3A Co-Mutation with SF3B1, ASXL1 and TET2 in Indian Patients with Myelodysplastic Syndrome (MDS)

Syed Sultan Beevi; Rahul Yadav; Vinod Kumar Verma; Radhika Chowdary Darapuneni; Sukrutha Gopal Reddy; Sujatha Paduval; Sonali Sadawarte; Dharshani Jayashanker

doi:doi:10.11648/j.bmb.20220701.11

DNMT3A Co-Mutation with SF3B1, ASXL1 and TET2 in Indian Patients with Myelodysplastic Syndrome (MDS)

Syed Sultan Beevi, Rahul Yadav, Vinod Kumar Verma, Radhika Chowdary Darapuneni, Sukrutha Gopal Reddy, Sujatha Paduval, Sonali Sadawarte, Dharshani Jayashanker

Published in Biochemistry and Molecular Biology (Volume 7, Issue 1)

Received: 1 December 2021 Accepted: 28 December 2021 Published: 8 January 2022

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Abstract

Myelodysplastic syndrome (MDS) encompasses a diverse group of closely related clonal hematopoietic disorders. Several genes are often mutated in MDS, of which only five (DNMT3A, SF3B1, ASXL1, TET2 and SRSF2) are known to be mutated in >10% of cases. In this perspective, we studied the frequency of somatic mutations in DNMT3A, SF3B1, ASXL1 and TET2 genes and also the impact of DNMT3A co-mutation with SF3B1, ASXL1 and TET2 genes in a series of 21 Indian patients primarily diagnosed with MDS. Patients with de novo MDS were examined for mutations in DNMT3A, SF3B1, ASXL1 and TET2 genes by Sanger’s sequencing. The prognostic impact of DNMT3A mutations was evaluated in juxtaposition with SF3B1, ASXL1 and TET2 gene. Around 62% patients (13 out of 21) were found to have a somatic mutation in at least one of the genes studied herein. Of the 13 patients, 2 patients had single mutation of DNMT3A, 5 carried SF3B1 mutation and one patient each had ASXL1 and TET2 mutation. Likewise, 2 patients carried double mutation of DNMT3A/TET2 and one each carried DNMT3A/SF3B1 and DNMT3A/ASXL1 co-mutation. Our study identified novel missense, nonsense and frameshift mutations in DNMT3A, SF3B1, ASXL1 and TET2 genes for the first time in Indian MDS patients. Distinct mutations of DNMT3A in juxtaposition with SF3B1, ASXL1 and TET2 gene were predictive of clinical status.

Published in	Biochemistry and Molecular Biology (Volume 7, Issue 1)
DOI	10.11648/j.bmb.20220701.11
Page(s)	1-5
Creative Commons	This is an Open Access article, distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium or format, provided the original work is properly cited.
Copyright	Copyright © The Author(s), 2024. Published by Science Publishing Group

Keywords

Sangers’ Sequencing, Co-mutations, Stop-gained Frameshift Mutation, IPSS Risk Score

References

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[2]	Kennedy J. A., and Ebert B. L. 2017 Clinical Implications of Genetic Mutations in Myelodysplastic Syndrome. J. Clin. Oncol. 35, 968-974.
[3]	Ogawa S. 2019 Genetics of MDS. Blood. 133, 1049-1059.
[4]	Cazzola M., Della Porta M. G., and Malcovati L. 2013 The genetic basis of myelodysplasia and its clinical relevance. Blood. 122, 4021-4034.
[5]	Liang S., Zhou X., Pan H., Yang Y., Shi L., and Wang L. 2019 Prognostic value of mutations in myelodysplastic syndromes: a meta-analysis. Hematology. 24, 613 – 622.
[6]	Cancer Genome Atlas Research Network. 2013 Genomic and epigenomic landscapes of adult de novo acute myeloid leukaemia. N. Engl. J. Med. 368, 2059 – 2074.
[7]	Walter M. J., Ding L., Shen D., et al. 2011 Recurrent DNMT3A mutations in patients with myelodysplastic syndromes. Leukemia. 25, 1153–1158.
[8]	Lin M. E., Hou H. A., Tsai C. H., et al. 2018 Dynamics of DNMT3A mutation and prognostic relevance in patients with primary myelodysplastic syndrome. Clin. Epigenetics. 10, 42.
[9]	Yan X. J., Xu J., Gu Z. H., et al. 2011 Exome sequencing identifies somatic mutations of DNA methyltransferase gene DNMT3A in acute monocytic leukaemia. Nat. Genet. 43, 309–15.
[10]	Martín I., Such E., Navarro B., et al. 2017 Negative impact on clinical outcome of the mutational co-occurrence of SF3B1 and DNMT3A in refractory anemia with ring sideroblasts (RARS). Leuk. Lymphoma. 58, 1686-1693.
[11]	Song J., Hussaini M., Qin D., et al. 2020 Comparison of SF3B1/DNMT3A Comutations With DNMT3A or SF3B1 Mutation Alone in Myelodysplastic Syndrome and Clonal Cytopenia of Undetermined Significance. Am. J. Clin. Pathol. XX, 1–9.
[12]	Yoshizato T., Dumitriu B., Hosokawa K., et al. 2015 Somatic Mutations and Clonal Haematopoiesis in Aplastic Anaemia. N. Engl. J. Med. 373, 35–47.
[13]	Hayette S., Thomas X., Jallades L., et al. 2012 High DNA Methyltransferase DNMT3B Levels: A Poor Prognostic Marker in Acute Myeloid Leukemia. PLoS ONE. 7, e51527.
[14]	Papaemmanuil E., Gerstung M., Malcovati L., et al. 2013 Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood. 122, 3616–3627.
[15]	Russler-Germain D. A., Spencer D. H., and Young M. A. 2014 The R882H DNMT3A mutation associated with AML dominantly inhibits wild-type DNMT3A by blocking its ability to form active tetramers. Cancer Cell 25, 442-454.
[16]	Zhou Z., Gong Q., Wang Y., et al. 2020 The biological function and clinical significance of SF3B1 mutations in cancer. Biomark. Res. 8, 38.
[17]	Visconte V., Tabarroki A., Hasrouni E., et al. 2012 Patients with SF3B1 mutation have good prognosis even in the presence of other poor prognostic MDS features and have better outcomes during treatment with low intensity chemotherapy. Blood. 120, 3831.
[18]	Abdel-Wahab O., Adli M., LaFave L. M., et al. 2012 ASXL1 mutations promote myeloid transformation through loss of PRC2-mediated gene repression. Cancer. Cell. 22, 180–193.

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APA Style

Syed Sultan Beevi, Rahul Yadav, Vinod Kumar Verma, Radhika Chowdary Darapuneni, Sukrutha Gopal Reddy, et al. (2022). DNMT3A Co-Mutation with SF3B1, ASXL1 and TET2 in Indian Patients with Myelodysplastic Syndrome (MDS). Biochemistry and Molecular Biology, 7(1), 1-5. https://doi.org/10.11648/j.bmb.20220701.11

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ACS Style

Syed Sultan Beevi; Rahul Yadav; Vinod Kumar Verma; Radhika Chowdary Darapuneni; Sukrutha Gopal Reddy, et al. DNMT3A Co-Mutation with SF3B1, ASXL1 and TET2 in Indian Patients with Myelodysplastic Syndrome (MDS). Biochem. Mol. Biol. 2022, 7(1), 1-5. doi: 10.11648/j.bmb.20220701.11

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AMA Style

Syed Sultan Beevi, Rahul Yadav, Vinod Kumar Verma, Radhika Chowdary Darapuneni, Sukrutha Gopal Reddy, et al. DNMT3A Co-Mutation with SF3B1, ASXL1 and TET2 in Indian Patients with Myelodysplastic Syndrome (MDS). Biochem Mol Biol. 2022;7(1):1-5. doi: 10.11648/j.bmb.20220701.11

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@article{10.11648/j.bmb.20220701.11,
  author = {Syed Sultan Beevi and Rahul Yadav and Vinod Kumar Verma and Radhika Chowdary Darapuneni and Sukrutha Gopal Reddy and Sujatha Paduval and Sonali Sadawarte and Dharshani Jayashanker},
  title = {DNMT3A Co-Mutation with SF3B1, ASXL1 and TET2 in Indian Patients with Myelodysplastic Syndrome (MDS)},
  journal = {Biochemistry and Molecular Biology},
  volume = {7},
  number = {1},
  pages = {1-5},
  doi = {10.11648/j.bmb.20220701.11},
  url = {https://doi.org/10.11648/j.bmb.20220701.11},
  eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.bmb.20220701.11},
  abstract = {Myelodysplastic syndrome (MDS) encompasses a diverse group of closely related clonal hematopoietic disorders. Several genes are often mutated in MDS, of which only five (DNMT3A, SF3B1, ASXL1, TET2 and SRSF2) are known to be mutated in >10% of cases. In this perspective, we studied the frequency of somatic mutations in DNMT3A, SF3B1, ASXL1 and TET2 genes and also the impact of DNMT3A co-mutation with SF3B1, ASXL1 and TET2 genes in a series of 21 Indian patients primarily diagnosed with MDS. Patients with de novo MDS were examined for mutations in DNMT3A, SF3B1, ASXL1 and TET2 genes by Sanger’s sequencing. The prognostic impact of DNMT3A mutations was evaluated in juxtaposition with SF3B1, ASXL1 and TET2 gene. Around 62% patients (13 out of 21) were found to have a somatic mutation in at least one of the genes studied herein. Of the 13 patients, 2 patients had single mutation of DNMT3A, 5 carried SF3B1 mutation and one patient each had ASXL1 and TET2 mutation. Likewise, 2 patients carried double mutation of DNMT3A/TET2 and one each carried DNMT3A/SF3B1 and DNMT3A/ASXL1 co-mutation. Our study identified novel missense, nonsense and frameshift mutations in DNMT3A, SF3B1, ASXL1 and TET2 genes for the first time in Indian MDS patients. Distinct mutations of DNMT3A in juxtaposition with SF3B1, ASXL1 and TET2 gene were predictive of clinical status.},
 year = {2022}
}

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TY  - JOUR
T1  - DNMT3A Co-Mutation with SF3B1, ASXL1 and TET2 in Indian Patients with Myelodysplastic Syndrome (MDS)
AU  - Syed Sultan Beevi
AU  - Rahul Yadav
AU  - Vinod Kumar Verma
AU  - Radhika Chowdary Darapuneni
AU  - Sukrutha Gopal Reddy
AU  - Sujatha Paduval
AU  - Sonali Sadawarte
AU  - Dharshani Jayashanker
Y1  - 2022/01/08
PY  - 2022
N1  - https://doi.org/10.11648/j.bmb.20220701.11
DO  - 10.11648/j.bmb.20220701.11
T2  - Biochemistry and Molecular Biology
JF  - Biochemistry and Molecular Biology
JO  - Biochemistry and Molecular Biology
SP  - 1
EP  - 5
PB  - Science Publishing Group
SN  - 2575-5048
UR  - https://doi.org/10.11648/j.bmb.20220701.11
AB  - Myelodysplastic syndrome (MDS) encompasses a diverse group of closely related clonal hematopoietic disorders. Several genes are often mutated in MDS, of which only five (DNMT3A, SF3B1, ASXL1, TET2 and SRSF2) are known to be mutated in >10% of cases. In this perspective, we studied the frequency of somatic mutations in DNMT3A, SF3B1, ASXL1 and TET2 genes and also the impact of DNMT3A co-mutation with SF3B1, ASXL1 and TET2 genes in a series of 21 Indian patients primarily diagnosed with MDS. Patients with de novo MDS were examined for mutations in DNMT3A, SF3B1, ASXL1 and TET2 genes by Sanger’s sequencing. The prognostic impact of DNMT3A mutations was evaluated in juxtaposition with SF3B1, ASXL1 and TET2 gene. Around 62% patients (13 out of 21) were found to have a somatic mutation in at least one of the genes studied herein. Of the 13 patients, 2 patients had single mutation of DNMT3A, 5 carried SF3B1 mutation and one patient each had ASXL1 and TET2 mutation. Likewise, 2 patients carried double mutation of DNMT3A/TET2 and one each carried DNMT3A/SF3B1 and DNMT3A/ASXL1 co-mutation. Our study identified novel missense, nonsense and frameshift mutations in DNMT3A, SF3B1, ASXL1 and TET2 genes for the first time in Indian MDS patients. Distinct mutations of DNMT3A in juxtaposition with SF3B1, ASXL1 and TET2 gene were predictive of clinical status.
VL  - 7
IS  - 1
ER  -

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Author Information

Syed Sultan Beevi

Krishna Institute of Medical Sciences Foundation and Research Centre, Krishna Institute of Medical Sciences, Secunderabad, India
Rahul Yadav

Krishna Institute of Medical Sciences Foundation and Research Centre, Krishna Institute of Medical Sciences, Secunderabad, India
Vinod Kumar Verma

Krishna Institute of Medical Sciences Foundation and Research Centre, Krishna Institute of Medical Sciences, Secunderabad, India
Radhika Chowdary Darapuneni

Diagnostics Division, Krishna Institute of Medical Sciences, Secunderabad, India
Sukrutha Gopal Reddy

Diagnostics Division, Krishna Institute of Medical Sciences, Secunderabad, India
Sujatha Paduval

Diagnostics Division, Krishna Institute of Medical Sciences, Secunderabad, India
Sonali Sadawarte

Department of Haematology, Krishna Institute of Medical Sciences, Secunderabad, India
Dharshani Jayashanker

Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, India

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APA Style

Syed Sultan Beevi, Rahul Yadav, Vinod Kumar Verma, Radhika Chowdary Darapuneni, Sukrutha Gopal Reddy, et al. (2022). DNMT3A Co-Mutation with SF3B1, ASXL1 and TET2 in Indian Patients with Myelodysplastic Syndrome (MDS). Biochemistry and Molecular Biology, 7(1), 1-5. https://doi.org/10.11648/j.bmb.20220701.11

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ACS Style

Syed Sultan Beevi; Rahul Yadav; Vinod Kumar Verma; Radhika Chowdary Darapuneni; Sukrutha Gopal Reddy, et al. DNMT3A Co-Mutation with SF3B1, ASXL1 and TET2 in Indian Patients with Myelodysplastic Syndrome (MDS). Biochem. Mol. Biol. 2022, 7(1), 1-5. doi: 10.11648/j.bmb.20220701.11

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AMA Style

Syed Sultan Beevi, Rahul Yadav, Vinod Kumar Verma, Radhika Chowdary Darapuneni, Sukrutha Gopal Reddy, et al. DNMT3A Co-Mutation with SF3B1, ASXL1 and TET2 in Indian Patients with Myelodysplastic Syndrome (MDS). Biochem Mol Biol. 2022;7(1):1-5. doi: 10.11648/j.bmb.20220701.11

Copy | Download

@article{10.11648/j.bmb.20220701.11,
  author = {Syed Sultan Beevi and Rahul Yadav and Vinod Kumar Verma and Radhika Chowdary Darapuneni and Sukrutha Gopal Reddy and Sujatha Paduval and Sonali Sadawarte and Dharshani Jayashanker},
  title = {DNMT3A Co-Mutation with SF3B1, ASXL1 and TET2 in Indian Patients with Myelodysplastic Syndrome (MDS)},
  journal = {Biochemistry and Molecular Biology},
  volume = {7},
  number = {1},
  pages = {1-5},
  doi = {10.11648/j.bmb.20220701.11},
  url = {https://doi.org/10.11648/j.bmb.20220701.11},
  eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.bmb.20220701.11},
  abstract = {Myelodysplastic syndrome (MDS) encompasses a diverse group of closely related clonal hematopoietic disorders. Several genes are often mutated in MDS, of which only five (DNMT3A, SF3B1, ASXL1, TET2 and SRSF2) are known to be mutated in >10% of cases. In this perspective, we studied the frequency of somatic mutations in DNMT3A, SF3B1, ASXL1 and TET2 genes and also the impact of DNMT3A co-mutation with SF3B1, ASXL1 and TET2 genes in a series of 21 Indian patients primarily diagnosed with MDS. Patients with de novo MDS were examined for mutations in DNMT3A, SF3B1, ASXL1 and TET2 genes by Sanger’s sequencing. The prognostic impact of DNMT3A mutations was evaluated in juxtaposition with SF3B1, ASXL1 and TET2 gene. Around 62% patients (13 out of 21) were found to have a somatic mutation in at least one of the genes studied herein. Of the 13 patients, 2 patients had single mutation of DNMT3A, 5 carried SF3B1 mutation and one patient each had ASXL1 and TET2 mutation. Likewise, 2 patients carried double mutation of DNMT3A/TET2 and one each carried DNMT3A/SF3B1 and DNMT3A/ASXL1 co-mutation. Our study identified novel missense, nonsense and frameshift mutations in DNMT3A, SF3B1, ASXL1 and TET2 genes for the first time in Indian MDS patients. Distinct mutations of DNMT3A in juxtaposition with SF3B1, ASXL1 and TET2 gene were predictive of clinical status.},
 year = {2022}
}

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TY  - JOUR
T1  - DNMT3A Co-Mutation with SF3B1, ASXL1 and TET2 in Indian Patients with Myelodysplastic Syndrome (MDS)
AU  - Syed Sultan Beevi
AU  - Rahul Yadav
AU  - Vinod Kumar Verma
AU  - Radhika Chowdary Darapuneni
AU  - Sukrutha Gopal Reddy
AU  - Sujatha Paduval
AU  - Sonali Sadawarte
AU  - Dharshani Jayashanker
Y1  - 2022/01/08
PY  - 2022
N1  - https://doi.org/10.11648/j.bmb.20220701.11
DO  - 10.11648/j.bmb.20220701.11
T2  - Biochemistry and Molecular Biology
JF  - Biochemistry and Molecular Biology
JO  - Biochemistry and Molecular Biology
SP  - 1
EP  - 5
PB  - Science Publishing Group
SN  - 2575-5048
UR  - https://doi.org/10.11648/j.bmb.20220701.11
AB  - Myelodysplastic syndrome (MDS) encompasses a diverse group of closely related clonal hematopoietic disorders. Several genes are often mutated in MDS, of which only five (DNMT3A, SF3B1, ASXL1, TET2 and SRSF2) are known to be mutated in >10% of cases. In this perspective, we studied the frequency of somatic mutations in DNMT3A, SF3B1, ASXL1 and TET2 genes and also the impact of DNMT3A co-mutation with SF3B1, ASXL1 and TET2 genes in a series of 21 Indian patients primarily diagnosed with MDS. Patients with de novo MDS were examined for mutations in DNMT3A, SF3B1, ASXL1 and TET2 genes by Sanger’s sequencing. The prognostic impact of DNMT3A mutations was evaluated in juxtaposition with SF3B1, ASXL1 and TET2 gene. Around 62% patients (13 out of 21) were found to have a somatic mutation in at least one of the genes studied herein. Of the 13 patients, 2 patients had single mutation of DNMT3A, 5 carried SF3B1 mutation and one patient each had ASXL1 and TET2 mutation. Likewise, 2 patients carried double mutation of DNMT3A/TET2 and one each carried DNMT3A/SF3B1 and DNMT3A/ASXL1 co-mutation. Our study identified novel missense, nonsense and frameshift mutations in DNMT3A, SF3B1, ASXL1 and TET2 genes for the first time in Indian MDS patients. Distinct mutations of DNMT3A in juxtaposition with SF3B1, ASXL1 and TET2 gene were predictive of clinical status.
VL  - 7
IS  - 1
ER  -

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