TY - JOUR
T1 - Next-Generation Sequencing of DDX41 in Myeloid Neoplasms Leads to Increased Detection of Germline Alterations
AU - Bannon, Sarah A.
AU - Routbort, Mark J.
AU - Montalban-Bravo, Guillermo
AU - Mehta, Rohtesh S.
AU - Jelloul, Fatima Zahra
AU - Takahashi, Koichi
AU - Daver, Naval
AU - Oran, Betul
AU - Pemmaraju, Naveen
AU - Borthakur, Gautam
AU - Naqvi, Kiran
AU - Issa, Ghayas
AU - Sasaki, Koji
AU - Alvarado, Yesid
AU - Kadia, Tapan M.
AU - Konopleva, Marina
AU - Shamanna, Rashmi Kanagal
AU - Khoury, Joseph
AU - Ravandi, Farhad
AU - Champlin, Richard
AU - Kantarjian, Hagop M.
AU - Bhalla, Kapil
AU - Garcia-Manero, Guillermo
AU - Patel, Keyur P.
AU - DiNardo, Courtney D.
N1 - Publisher Copyright:
© Copyright © 2021 Bannon, Routbort, Montalban-Bravo, Mehta, Jelloul, Takahashi, Daver, Oran, Pemmaraju, Borthakur, Naqvi, Issa, Sasaki, Alvarado, Kadia, Konopleva, Shamanna, Khoury, Ravandi, Champlin, Kantarjian, Bhalla, Garcia-Manero, Patel and DiNardo.
PY - 2021/1/28
Y1 - 2021/1/28
N2 - Previously considered rare, inherited hematologic malignancies are increasingly identified. Germline mutations in the RNA helicase DDX41 predispose to increased lifetime risks of myeloid neoplasms with disease often occurring later in life which presents challenges for germline recognition. To improve identification of germline DDX41, individuals presenting with ≥1 DDX41 alteration on an institutional MDS/AML next-generation sequencing based panel with at least one at >40% variant allele frequency were flagged for review and genetic counseling referral. Of 5,801 individuals, 90 (1.5%) had ≥1 DDX41 mutation(s) identified. Thirty-eight (42%) patients with a median age of 66 years were referred for genetic counseling; thirty-one were male (81.5%). Thirty-five (92%) referred patients elected to pursue germline evaluation and in 33/35 (94%) a germline DDX41 variant was confirmed. Twenty-two patients (66%) with germline variants reported antecedent cytopenias, seven (21%) had a prior history of malignancy, and twenty-seven (82%) reported a family history of cancer. Predictive genetic testing for healthy family members under consideration as stem cell transplant donors was successfully performed in 11 family members, taking an average of 15 days. Near-heterozygous DDX41 mutations identified on next-generation sequencing, particularly nonsense/frameshift variants or those at recurrent germline “hot spots” are highly suggestive of a germline mutation. Next-generation sequencing screening is a feasible tool to screen unselected myeloid neoplasms for germline DDX41 mutations, enabling timely and appropriate care.
AB - Previously considered rare, inherited hematologic malignancies are increasingly identified. Germline mutations in the RNA helicase DDX41 predispose to increased lifetime risks of myeloid neoplasms with disease often occurring later in life which presents challenges for germline recognition. To improve identification of germline DDX41, individuals presenting with ≥1 DDX41 alteration on an institutional MDS/AML next-generation sequencing based panel with at least one at >40% variant allele frequency were flagged for review and genetic counseling referral. Of 5,801 individuals, 90 (1.5%) had ≥1 DDX41 mutation(s) identified. Thirty-eight (42%) patients with a median age of 66 years were referred for genetic counseling; thirty-one were male (81.5%). Thirty-five (92%) referred patients elected to pursue germline evaluation and in 33/35 (94%) a germline DDX41 variant was confirmed. Twenty-two patients (66%) with germline variants reported antecedent cytopenias, seven (21%) had a prior history of malignancy, and twenty-seven (82%) reported a family history of cancer. Predictive genetic testing for healthy family members under consideration as stem cell transplant donors was successfully performed in 11 family members, taking an average of 15 days. Near-heterozygous DDX41 mutations identified on next-generation sequencing, particularly nonsense/frameshift variants or those at recurrent germline “hot spots” are highly suggestive of a germline mutation. Next-generation sequencing screening is a feasible tool to screen unselected myeloid neoplasms for germline DDX41 mutations, enabling timely and appropriate care.
KW - AML
KW - DDX41
KW - MDS
KW - germline
KW - hereditary
UR - http://www.scopus.com/inward/record.url?scp=85100831880&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85100831880&partnerID=8YFLogxK
U2 - 10.3389/fonc.2020.582213
DO - 10.3389/fonc.2020.582213
M3 - Article
C2 - 33585199
AN - SCOPUS:85100831880
SN - 2234-943X
VL - 10
JO - Frontiers in Oncology
JF - Frontiers in Oncology
M1 - 582213
ER -