A study of Telomerase Reverse Transcriptase rare variants in myeloid neoplasia

Gurnari, Carmelo; Wahida, Adam; Pagliuca, Simona; Durmaz, Arda; Zawit, Misam; Haferlach, Torsten; Maciejewski, Jaroslaw P.; Visconte, Valeria

doi:10.1002/hon.2967

Cited by 3 publications

(3 citation statements)

References 19 publications

(28 reference statements)

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“…Locally, we performed a next‐generation sequencing based diagnostic custom‐made panel sequencing of around 600 genes associated with cancer and hematological and immune disorders. Apart from the same expected PTPN11 variant, this yielded a rare telomerase gene ( TERT) variant (c.2177C>T, p.Thr726Met) with potential pathogenicity predictions (in nine of 20 used prediction tools) and literature reports of both association with cryptic TBD, severe AA, or MDS as well as biochemical data for partially compromised telomerase activity 2,4,5,8,9 . Table 1 presents the reported p.Thr726Met TERT associations with hematological phenotypes or compromised telomerase activity in vitro.…”

Section: Case Description and Discussionmentioning

confidence: 95%

Challenges in the interpretation of a germline TERT variant in a patient with juvenile myelomonocytic leukemia

Janczar

Kirschner

Beier

et al. 2022

Pediatric Blood & Cancer

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Dyskeratosis congenita (DC) is a bone marrow failure syndrome with extrahematopoietic abnormalities. DC is a paradigmatic telomere biology disorder (TBD) caused by germline mutations in genes responsible for telomere maintenance including TERT. Cryptic TBD is a bone marrow failure syndrome due to premature telomere shortening but without additional symptoms, frequently clinically indistinguishable from severe aplastic anemia (SAA) or hypoplastic myelodysplastic syndrome. We present the complex diagnostic pathway in a boy with a rare germline p.Thr726MetTERT variant with previous reports of SAA association and compromised enzymatic function who presented with juvenile myelomonocytic leukemia, which is a rare myelodysplastic/myeloproliferative neoplasm of childhood.

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Section: Case Description and Discussionmentioning

confidence: 95%

Challenges in the interpretation of a germline TERT variant in a patient with juvenile myelomonocytic leukemia

Janczar

Kirschner

Beier

et al. 2022

Pediatric Blood & Cancer

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“…Two sequencing platforms were used for specimen processing: targeted sequencing for a total of 1007 and whole exome and genome sequencing (WES, WGS) for a total of 1103 specimens analyzed. Targeted sequencing was performed as previously described [19][20][21] using a custom panel for detection of GL variants from TruSeq or Nextera platforms (Illumina, San Diego, CA, USA). Sequencing libraries were generated according to an Illumina paired-end library protocol.…”

Section: Next-generation Sequencingmentioning

confidence: 99%

Significance of hereditary gene alterations for the pathogenesis of adult bone marrow failure versus myeloid neoplasia

Kubota

Zawit²,

Durrani³

et al. 2022

Leukemia

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Broader genetic screening has led to the growing recognition of the role of germline variants associated with adult bone marrow failure (BMF) and myeloid neoplasia (MN) not exclusively in children and young adults. In this study, we applied a germline variant panel to 3008 adult BMF and MN cases to assess the importance of germline genetics and its impact on disease phenotype and prognosis. In our cohort, up to 9.7% of BMF and 5.3% of MN cases carried germline variants. Our cohort also included heterozygous carriers of recessive traits, suggesting they contribute to the risk of BMF and MN. By gene category, variants of Fanconi anemia gene family represented the highest-frequency category for both BMF and MN cases, found in 4.9% and 1.7% cases, respectively. In addition, about 1.4% of BMF and 0.19% of MN cases harbored multiple germline variants affecting often functionally related genes as compound heterozygous. The burden of germline variants in BMF and MN was clearly associated with acquisition of monosomy 7. While BMF cases carrying germline variants showed similar overall survival as compared to the wild-type (WT) cases, MN cases with germline variants experienced a significantly shorter overall survival as compared to WT cases.

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“…The disease's incidence ranges from 4 per 100,000 in the general population to 25-40 per 100,000 in people aged > 65 years [2,3]. The rare instances in younger patients (< 50 years of age) should prompt genetic testing for inherited conditions, in order to adequately address familial counseling and potential donor choice for allogeneic hematopoietic stem cell (HSCT) purposes [4][5][6][7]. The latter represents the only curative treatment to date, but its wide application is limited by the disease demographics, and only eligible patients can benefit from this procedure [8,9].…”

Section: Introductionmentioning

confidence: 99%

How I Manage Transplant Ineligible Patients with Myelodysplastic Neoplasms

2022

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Myelodysplastic neoplasms, formerly known as myelodysplastic syndromes (MDS), represent a group of clonal disorders characterized by a high degree of clinical and molecular heterogeneity, and an invariable tendency to progress to acute myeloid leukemia. MDS typically present in the elderly with cytopenias of different degrees and bone marrow dysplasia, the hallmarks of the disease. Allogeneic hematopoietic stem cell transplant is the sole curative approach to date. Nonetheless, given the disease’s demographics, only a minority of patients can benefit from this procedure. Currently used prognostic schemes such as the Revised International Prognostic Scoring System (R-IPSS), and most recently the molecular IPSS (IPSS-M), guide clinical management by dividing MDS into two big categories: lower- and higher-risk cases, based on a cut-off score of 3.5. The main clinical problem of the lower-risk group is represented by the management of cytopenias, whereas the prevention of secondary leukemia progression is the goal for the latter. Herein, we discuss the non-transplant treatment of MDS, focusing on current practice and available therapeutic options, while also presenting new investigational agents potentially entering the MDS therapeutic arsenal in the near future.

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A study of Telomerase Reverse Transcriptase rare variants in myeloid neoplasia

Cited by 3 publications

References 19 publications

Challenges in the interpretation of a germline TERT variant in a patient with juvenile myelomonocytic leukemia

Challenges in the interpretation of a germline TERT variant in a patient with juvenile myelomonocytic leukemia

Significance of hereditary gene alterations for the pathogenesis of adult bone marrow failure versus myeloid neoplasia

How I Manage Transplant Ineligible Patients with Myelodysplastic Neoplasms

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