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Identification of novel potential predisposing variants in familial acute myeloid leukemia
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  • Chiara Ronchini,
  • Federica Gigli,
  • Martina Fontanini,
  • Raffaella Furgi,
  • Viviana Amato,
  • Fabio Giglio,
  • Giuliana Gregato,
  • Francesco Bertolini,
  • Michela Rondoni,
  • Francesco Lanza,
  • Atto Billio,
  • Enrico Derenzini,
  • Corrado Tarella,
  • P. G. Pelicci,
  • Myriam Alcalay,
  • Elisabetta Todisco
Chiara Ronchini
Istituto Europeo di Oncologia
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Federica Gigli
Istituto Europeo di Oncologia
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Martina Fontanini
Istituto Europeo di Oncologia
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Raffaella Furgi
Istituto Europeo di Oncologia
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Viviana Amato
Istituto Europeo di Oncologia
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Fabio Giglio
Istituto Europeo di Oncologia
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Giuliana Gregato
Istituto Europeo di Oncologia
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Francesco Bertolini
Istituto Europeo di Oncologia
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Michela Rondoni
Universita degli Studi di Bologna - Campus di Ravenna
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Francesco Lanza
Universita degli Studi di Bologna - Campus di Ravenna
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Atto Billio
Ospedale di Bolzano
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Enrico Derenzini
Istituto Europeo di Oncologia
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Corrado Tarella
Istituto Europeo di Oncologia
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P. G. Pelicci
Istituto Europeo di Oncologia
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Myriam Alcalay
Istituto Europeo di Oncologia
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Elisabetta Todisco
Istituto Europeo di Oncologia

Corresponding Author:[email protected]

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Abstract

Myeloid neoplasms, including acute myeloid leukemia, have been traditionally among the less investigated cancer types concerning germline predisposition. Indeed, myeloid neoplasms with germline predisposition are challenging to identify because often display similar clinical and morphological characteristics of sporadic cases and have similar age at diagnosis. However, a misidentification of familiarity in myeloid neoplasms have a critical impact on clinical management both for the carriers and their relatives. We performed a thorough genomic analysis using a large custom gene panel, the Myelo-Panel, targeted on cancer predisposing genes. In particular, we assessed both germline and somatic variants in 4 families, each with two siblings, who developed hematological neoplasms: 7 acute myeloid leukemia and 1 Philadelphia-positive chronic myeloid leukemia. In each family, we identified at least one novel potentially predisposing variant, affecting also genes not included in the current European LeukemiaNet guidelines for AML management. Moreover, we suggest reclassification of 2 germline variants as pathogenic: likely pathogenic p.S21Tfs*139 in CEPBA and VUS p.K392Afs*66 in DDX41. Our data underline how familiar predisposition to hematological neoplasms is currently underestimated and call for revision of clinical practices that should include thorough reconstruction of family history and genetic testing with gene panels targeted for cancer predisposing genes.
29 Feb 2024Submitted to Cancer Reports
04 Mar 2024Submission Checks Completed
04 Mar 2024Assigned to Editor
04 Mar 2024Review(s) Completed, Editorial Evaluation Pending
07 Mar 2024Reviewer(s) Assigned
15 May 2024Submission Checks Completed
15 May 2024Assigned to Editor
15 May 2024Review(s) Completed, Editorial Evaluation Pending
05 Jun 2024Editorial Decision: Revise Minor
07 Jun 2024Submission Checks Completed
07 Jun 2024Assigned to Editor
30 Jun 2024Editorial Decision: Accept