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Germline variants in DNA repair genes, including BRCA1/2, may cause familial myeloproliferative neoplasms

Authors :
Tim H. Brümmendorf
Kim Kricheldorf
Beate Betz
Ulrich Germing
Deniz Gezer
Susanne Isfort
Robert Meyer
Eggermann Thomas
Ingo Kurth
Steffen Koschmieder
Miriam Elbracht
Lino L. Teichmann
Source :
Blood Adv
Publication Year :
2021
Publisher :
American Society of Hematology, 2021.

Abstract

The molecular causes of myeloproliferative neoplasms (MPNs) have not yet been fully elucidated. Approximately 7% to 8% of the patients carry predisposing genetic germline variants that lead to driver mutations, which enhance JAK-STAT signaling. To identify additional predisposing genetic germline variants, we performed whole-exome sequencing in 5 families, each with parent-child or sibling pairs affected by MPNs and carrying the somatic JAK2 V617F mutation. In 4 families, we detected rare germline variants in known tumor predisposition genes of the DNA repair pathway, including the highly penetrant BRCA1 and BRCA2 genes. The identification of an underlying hereditary tumor predisposition is of major relevance for the individual patients as well as for their families in the context of therapeutic options and preventive care. Two patients with essential thrombocythemia or polycythemia vera experienced progression to acute myeloid leukemia, which may suggest a high risk of leukemic transformation in these familial MPNs. Our study demonstrates the relevance of genetic germline diagnostics in elucidating the causes of MPNs and suggests novel therapeutic options (eg, PARP inhibitors) in MPNs. Furthermore, we uncover a broader tumor spectrum upon the detection of a germline mutation in genes of the DNA repair pathway.

Details

ISSN :
24739537 and 24739529
Volume :
5
Database :
OpenAIRE
Journal :
Blood Advances
Accession number :
edsair.doi.dedup.....1b78e8ef61b12acdde59b543b9ab2ecc
Full Text :
https://doi.org/10.1182/bloodadvances.2021004811