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. 2021 Sep;15(9):2273-2284.
doi: 10.1002/1878-0261.12921. Epub 2021 Jul 16.

Clinical utility of targeted next-generation sequencing for the diagnosis of myeloid neoplasms with germline predisposition

Cristina Andrés-Zayas  1   2 , Julia Suárez-González  1   2 , Gabriela Rodríguez-Macías  3 , Nieves Dorado  2   3 , Santiago Osorio  2   3 , Patricia Font  2   3 , Diego Carbonell  2   3 , María Chicano  2   3 , Paula Muñiz  2   3 , Mariana Bastos  2   3 , Mi Kwon  2   3 , José Luis Díez-Martín  2   3   4 , Ismael Buño  1   2   3   5 , Carolina Martínez-Laperche  2   3
Affiliations

Clinical utility of targeted next-generation sequencing for the diagnosis of myeloid neoplasms with germline predisposition

Cristina Andrés-Zayas et al. Mol Oncol. 2021 Sep.

Abstract

Myeloid neoplasms (MN) with germline predisposition (MNGP) are likely to be more common than currently appreciated. Many of the genes involved in MNGP are also recurrently mutated in sporadic MN. Therefore, routine analysis of gene panels by next-generation sequencing provides an effective approach to detect germline variants with clinical significance in patients with hematological malignancies. Gene panel sequencing was performed in 88 consecutive and five nonconsecutive patients with MN diagnosis. Disease-causing germline mutations in CEBPα, ASXL1, TP53, MPL, GATA2, DDX41, and ETV6 genes were identified in nine patients. Six out of the nine patients with germline variants had a strong family history. These patients presented great heterogeneity in the age of diagnosis and phenotypic characteristics. In our study, there were families in which all the affected members presented the same subtype of disease, whereas members of other families presented various disease phenotypes. This intrafamiliar heterogeneity suggests that the acquisition of particular somatic variants may drive the evolution of the disease. This approach enabled high-throughput detection of MNGP in patients with MN diagnosis, which is of great relevance for both the patients themselves and the asymptomatic mutation carriers within the family. It is crucial to make a proper diagnosis of these patients to provide them with the most suitable treatment, follow-up, and genetic counseling.

Keywords: family history; genetic counseling; hereditary cancer; myeloid neoplasms with germline predisposition; next-generation sequencing.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1
Fig. 1
Workflow for the analysis of variants in the 93 patients studied (88 with MN diagnosis and five with suspected MNGP). BWA, Burrows‐Wheeler Aligner; FB, fibroblasts; R‐PB, remission PB; R‐BM, remission bone marrow.
Fig. 2
Fig. 2
Pedigrees of patients with a confirmed MNGP. (A) AML (germline CEBPα p.His24Alafs). (B) MPN (germline ASXL1 p.Gly704Arg). (C) AML (germline ETV6 p.Arg49Cys). (D) AML (germline TP53 p.Arg282Trp). (E) MPN (germline MPL p.Phe105Leu). (F) MDS/Mono‐Mac syndrome (germline GATA2 p.Arg396Gln). (G) MDS/Mono‐Mac syndrome (germline GATA2 p.Arg396Trp). (H) MDS (germline DDX41 p.Arg339Cys). Arrowhead indicates index proband. Pedigree for Family I is not shown because no detailed family information was collected. nt, not tested.
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