TY - JOUR
T1 - Identification and prioritization of myeloid malignancy germline variants in a large cohort of adult patients with AML
AU - Yang, Fei
AU - Long, Nicola
AU - Anekpuritanang, Tauangtham
AU - Bottomly, Daniel
AU - Savage, Jonathan C.
AU - Lee, Tiffany
AU - Solis-Ruiz, Jose
AU - Borate, Uma
AU - Wilmot, Beth
AU - Tognon, Cristina
AU - Bock, Allison M.
AU - Pollyea, Daniel A.
AU - Radhakrishnan, Saikripa
AU - Radhakrishnan, Srinidhi
AU - Patel, Prapti
AU - Collins, Robert H.
AU - Tantravahi, Srinivas
AU - Deininger, Michael W.
AU - Fan, Guang
AU - Druker, Brian
AU - Shinde, Ujwal
AU - Tyner, Jeffrey W.
AU - Press, Richard
AU - McWeeney, Shannon
AU - Agarwal, Anupriya
N1 - Funding Information:
The authors thank all of our patients at all sites for donating precious time and tissue. DNA quality assessments, library creation, and short read sequencing assays were performed by the OHSU Massively Parallel Sequencing Shared Resource, as well as support from the Knight Diagnostic Laboratory and OHSU Clinical Pathology Core. Funding for this project was provided by the Oregon Health & Science University Knight Cancer Research Institute (F.Y. and A.A.), School of Medicine Exploratory Research Seed Grants (F.Y.), and Cancer early detection advanced research center (A.A.) as pilot research projects. The project in part is supported by a Leukemia Lymphoma Therapy Acceleration Grant to B.D. and J.W.T. A.A. is supported by grants from the National Cancer Institute (R01 CA229875-01A1), National Heart, Lung, and Blood Institute (R01 HL155426-01), American Cancer Society (RSG-17-187-01-LIB), Alex Lemonade/Babich RUNX1 Foundation, EvansMDS Foundation, and V foundation Scholar award (A.A.).
Funding Information:
Funding for this project was provided by the Oregon Health & Science University Knight Cancer Research Institute (F.Y. and A.A.), School of Medicine Exploratory Research Seed Grants (F.Y.), and Cancer early detection advanced research center (A.A.) as pilot research projects. The project in part is supported by a Leukemia Lymphoma Therapy Acceleration Grant to B.D. and J.W.T. A.A. is supported by grants from the National Cancer Institute (R01 CA229875-01A1), National Heart, Lung, and Blood Institute (R01 HL155426-01), American Cancer Society (RSG-17-187-01-LIB), Alex Lemonade/Babich RUNX1 Foundation, EvansMDS Foundation, and V foundation Scholar award (A.A.).
Funding Information:
Conflict-of-interest disclosure: B.D. potential competing interests–SAB: Aileron Therapeutics, Therapy Architects (ALLCRON), Cepheid, Vivid Biosciences, Celgene, RUNX1 Research Program, Nemucore Medical Innovations, Novartis, Gilead Sciences (inactive), Monojul (inactive); SAB & Stock: Aptose Biosciences, Blueprint Medicines, EnLiven Therapeutics, Iterion Therapeutics, GRAIL, Recludix Pharma; Scientific Founder: MolecularMD (inactive, acquired by ICON); Board of Directors & Stock: Amgen, Vincerx Pharma; Board of Directors: Burroughs Wellcome Fund, CureOne; Joint Steering Committee: Beat AML LLS; Founder: VB Therapeutics; Sponsored Research Agreement: EnLiven Therapeutics; Clinical Trial Funding: Novartis, Bristol-Myers Squibb, Pfizer; Royalties from Patent 6958335 (Novartis exclusive license) and OHSU and Dana-Farber Cancer Institute (1 Merck exclusive license and 1 CytoImage, Inc. exclusive license).
Publisher Copyright:
© 2022 American Society of Hematology
PY - 2022/2/24
Y1 - 2022/2/24
N2 - Inherited predisposition to myeloid malignancies is more common than previously appreciated. We analyzed the whole-exome sequencing data of paired leukemia and skin biopsy samples from 391 adult patients from the Beat AML 1.0 consortium. Using the 2015 American College of Medical Genetics and Genomics (ACMG) guidelines for variant interpretation, we curated 1547 unique variants from 228 genes. The pathogenic/likely pathogenic (P/LP) germline variants were identified in 53 acute myeloid leukemia (AML) patients (13.6%) in 34 genes, including 6.39% (25/391) of patients harboring P/LP variants in genes considered clinically actionable (tier 1). 41.5% of the 53 patients with P/LP variants were in genes associated with the DNA damage response. The most frequently mutated genes were CHEK2 (8 patients) and DDX41 (7 patients). Pathogenic germline variants were also found in new candidate genes (DNAH5, DNAH9, DNMT3A, and SUZ12). No strong correlation was found between the germline mutational rate and age of AML onset. Among 49 patients who have a reported history of at least one family member affected with hematological malignancies, 6 patients harbored known P/LP germline variants and the remaining patients had at least one variant of uncertain significance, suggesting a need for further functional validation studies. Using CHEK2 as an example, we show that three-dimensional protein modeling can be one of the effective methodologies to prioritize variants of unknown significance for functional studies. Further, we evaluated an in silico approach that applies ACMG curation in an automated manner using the tool for assessment and (TAPES) prioritization in exome studies, which can minimize manual curation time for variants. Overall, our findings suggest a need to comprehensively understand the predisposition potential of many germline variants in order to enable closer monitoring for disease management and treatment interventions for affected patients and families.
AB - Inherited predisposition to myeloid malignancies is more common than previously appreciated. We analyzed the whole-exome sequencing data of paired leukemia and skin biopsy samples from 391 adult patients from the Beat AML 1.0 consortium. Using the 2015 American College of Medical Genetics and Genomics (ACMG) guidelines for variant interpretation, we curated 1547 unique variants from 228 genes. The pathogenic/likely pathogenic (P/LP) germline variants were identified in 53 acute myeloid leukemia (AML) patients (13.6%) in 34 genes, including 6.39% (25/391) of patients harboring P/LP variants in genes considered clinically actionable (tier 1). 41.5% of the 53 patients with P/LP variants were in genes associated with the DNA damage response. The most frequently mutated genes were CHEK2 (8 patients) and DDX41 (7 patients). Pathogenic germline variants were also found in new candidate genes (DNAH5, DNAH9, DNMT3A, and SUZ12). No strong correlation was found between the germline mutational rate and age of AML onset. Among 49 patients who have a reported history of at least one family member affected with hematological malignancies, 6 patients harbored known P/LP germline variants and the remaining patients had at least one variant of uncertain significance, suggesting a need for further functional validation studies. Using CHEK2 as an example, we show that three-dimensional protein modeling can be one of the effective methodologies to prioritize variants of unknown significance for functional studies. Further, we evaluated an in silico approach that applies ACMG curation in an automated manner using the tool for assessment and (TAPES) prioritization in exome studies, which can minimize manual curation time for variants. Overall, our findings suggest a need to comprehensively understand the predisposition potential of many germline variants in order to enable closer monitoring for disease management and treatment interventions for affected patients and families.
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U2 - 10.1182/blood.2021011354
DO - 10.1182/blood.2021011354
M3 - Article
C2 - 34482403
AN - SCOPUS:85125130011
SN - 0006-4971
VL - 139
SP - 1208
EP - 1221
JO - Blood
JF - Blood
IS - 8
ER -