TY - JOUR
T1 - MDS-287 Genetic Landscape of Somatic Myeloid Mutations in the Presence of Rare TERT Variants and Their Relation to Myeloid Neoplasia
AU - Ferrer, Alejandro
AU - Mangaonkar, Abhishek M.
AU - Lasho, Terra L.
AU - Wylam, Mark E.
AU - Finke, Christy M.
AU - Fernandez, Jenna A.
AU - He, Rong
AU - Viswanatha, David S.
AU - Patnaik, Mrinal M.
N1 - Publisher Copyright:
© 2022 Elsevier Inc.
PY - 2022/10
Y1 - 2022/10
N2 - Context: Germline variants in the TERT gene may lead to impaired telomere maintenance implicated in the pathogenesis of myelodysplastic syndromes (MDS) by unknown mechanisms. Objective: To explore the clinical and genetic associations of germline TERT variants in patients with suspicion of myeloid neoplasm. Design: We selected patients tested through our institutional amplicon-based sequencing panel (42 myeloid genes, including exons 2 to 16 of TERT, read depth >250X) that carried a TERT variant with allele frequency between 35% and 65%. Variants were classified into those with CADD score?>20 and <20 to identify the top 1% according to predicted deleteriousness. Results were correlated with MDS diagnosis and clinical and survival information. Setting: Division of Hematology (Mayo Clinic). Research protocol approved by Institutional Review Board. Patients: Unselected cohort of patients screened with a myeloid mutation gene panel due to clinical suspicion of myeloid neoplasia. Results: 55 different TERT variants (46 missense, 3 splice sites, 4 synonymous, and 2 in-frame deletions) were identified in 148 individuals from April 2016 to November 2021. None of these patients were diagnosed with a telomere biology disorder and no telomere length measurement was available. All variants were clinically classified as uncertain significance. 17 (12%) patients carried CADD>20 TERT variants of which, 59% (10 patients) were diagnosed with MDS. [5 with <5% bone marrow blasts (4 with normal karyotype) and 5 with 5-19% blasts (all with complex karyotype)] This percentage was higher compared to CADD<20 TERT carriers (34%, 49 patients, p=0.048 by Chi-square test). No major differences were found in age at diagnosis (median 70 vs 73-year-old, p=0.2305), AML-free survival (median 10 vs 15.5 months since diagnosis, p=0.4674), or percentage of carriers of additional variants in myeloid-related genes (60% vs 64%). The most frequently mutated genes in CADD>20 carriers were TP53 (22%), TET2 (18%) and RUNX1 (9%) while in CADD<20 carriers were TET2 (14%), ASXL1 (11%), and SRSF2 (9%). TP53 variants were significantly enriched in CADD>20 TERT carriers. (22.7% vs 7.4%, p=0.0169) Conclusions: CADD>20 TERT variant carriers were more likely to be associated with a diagnosis of MDS and with somatic TP53 mutations than CADD<20 carriers.
AB - Context: Germline variants in the TERT gene may lead to impaired telomere maintenance implicated in the pathogenesis of myelodysplastic syndromes (MDS) by unknown mechanisms. Objective: To explore the clinical and genetic associations of germline TERT variants in patients with suspicion of myeloid neoplasm. Design: We selected patients tested through our institutional amplicon-based sequencing panel (42 myeloid genes, including exons 2 to 16 of TERT, read depth >250X) that carried a TERT variant with allele frequency between 35% and 65%. Variants were classified into those with CADD score?>20 and <20 to identify the top 1% according to predicted deleteriousness. Results were correlated with MDS diagnosis and clinical and survival information. Setting: Division of Hematology (Mayo Clinic). Research protocol approved by Institutional Review Board. Patients: Unselected cohort of patients screened with a myeloid mutation gene panel due to clinical suspicion of myeloid neoplasia. Results: 55 different TERT variants (46 missense, 3 splice sites, 4 synonymous, and 2 in-frame deletions) were identified in 148 individuals from April 2016 to November 2021. None of these patients were diagnosed with a telomere biology disorder and no telomere length measurement was available. All variants were clinically classified as uncertain significance. 17 (12%) patients carried CADD>20 TERT variants of which, 59% (10 patients) were diagnosed with MDS. [5 with <5% bone marrow blasts (4 with normal karyotype) and 5 with 5-19% blasts (all with complex karyotype)] This percentage was higher compared to CADD<20 TERT carriers (34%, 49 patients, p=0.048 by Chi-square test). No major differences were found in age at diagnosis (median 70 vs 73-year-old, p=0.2305), AML-free survival (median 10 vs 15.5 months since diagnosis, p=0.4674), or percentage of carriers of additional variants in myeloid-related genes (60% vs 64%). The most frequently mutated genes in CADD>20 carriers were TP53 (22%), TET2 (18%) and RUNX1 (9%) while in CADD<20 carriers were TET2 (14%), ASXL1 (11%), and SRSF2 (9%). TP53 variants were significantly enriched in CADD>20 TERT carriers. (22.7% vs 7.4%, p=0.0169) Conclusions: CADD>20 TERT variant carriers were more likely to be associated with a diagnosis of MDS and with somatic TP53 mutations than CADD<20 carriers.
KW - MDS
KW - TERT
KW - TP53
KW - Telomere
KW - next-generation sequencing
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U2 - 10.1016/S2152-2650(22)01404-5
DO - 10.1016/S2152-2650(22)01404-5
M3 - Article
C2 - 36163953
AN - SCOPUS:85138188483
SN - 2152-2650
VL - 22
SP - S309
JO - Clinical Lymphoma, Myeloma and Leukemia
JF - Clinical Lymphoma, Myeloma and Leukemia
ER -