Germline variants in DNA repair genes, including BRCA1/2, may cause familial myeloproliferative neoplasms.
Miriam ElbrachtRobert MeyerKim KricheldorfDeniz GezerEggermann ThomasBeate BetzIngo KurthLino L TeichmannTim Henrik BrümmendorfUlrich GermingSusanne IsfortSteffen KoschmiederPublished in: Blood advances (2021)
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.
Keyphrases
- dna repair
- dna damage
- copy number
- genome wide
- dna damage response
- end stage renal disease
- acute myeloid leukemia
- chronic kidney disease
- ejection fraction
- bioinformatics analysis
- newly diagnosed
- peritoneal dialysis
- oxidative stress
- genome wide identification
- early onset
- gene expression
- pain management
- acute lymphoblastic leukemia
- patient reported outcomes
- genome wide analysis
- allogeneic hematopoietic stem cell transplantation
- sensitive detection
- label free