Genetic testing in severe aplastic anemia is required for optimal hematopoietic cell transplant outcomes.

Autor:	McReynolds LJ; Clinical Genetics Branch and., Rafati M; Clinical Genetics Branch and., Wang Y; Clinical Genetics Branch and., Ballew BJ; Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD.; Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD., Kim J; Clinical Genetics Branch and., Williams VV; Clinical Genetics Branch and., Zhou W; Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD.; Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD., Hendricks RM; Clinical Genetics Branch and., Dagnall C; Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD.; Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD., Freedman ND; Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD., Carter B; Department of Population Science, American Cancer Society, Atlanta, GA., Strollo S; Department of Population Science, American Cancer Society, Atlanta, GA., Hicks B; Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD.; Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD., Zhu B; Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD.; Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD., Jones K; Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD.; Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD., Paczesny S; Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC., Marsh SGE; Anthony Nolan Research Institute and University College London Cancer Institute, London, United Kingdom., Spellman SR; Center for International Blood and Marrow Transplant Research, National Marrow Donor Program, Minneapolis, MN., He M; Center for International Blood and Marrow Transplant Research, National Marrow Donor Program, Minneapolis, MN., Wang T; Center for International Blood and Marrow Transplant Research and.; Division of Biostatistics, Medical College of Wisconsin, Milwaukee, WI; and., Lee SJ; Center for International Blood and Marrow Transplant Research and.; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA., Savage SA; Clinical Genetics Branch and., Gadalla SM; Clinical Genetics Branch and.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2022 Aug 25; Vol. 140 (8), pp. 909-921.
DOI:	10.1182/blood.2022016508
Abstrakt:	Patients with severe aplastic anemia (SAA) can have an unrecognized inherited bone marrow failure syndrome (IBMFS) because of phenotypic heterogeneity. We curated germline genetic variants in 104 IBMFS-associated genes from exome sequencing performed on 732 patients who underwent hematopoietic cell transplant (HCT) between 1989 and 2015 for acquired SAA. Patients with pathogenic or likely pathogenic (P/LP) variants fitting known disease zygosity patterns were deemed unrecognized IBMFS. Carriers were defined as patients with a single P/LP variant in an autosomal recessive gene or females with an X-linked recessive P/LP variant. Cox proportional hazard models were used for survival analysis with follow-up until 2017. We identified 113 P/LP single-nucleotide variants or small insertions/deletions and 10 copy number variants across 42 genes in 121 patients. Ninety-one patients had 105 in silico predicted deleterious variants of uncertain significance (dVUS). Forty-eight patients (6.6%) had an unrecognized IBMFS (33% adults), and 73 (10%) were carriers. No survival difference between dVUS and acquired SAA was noted. Compared with acquired SAA (no P/LP variants), patients with unrecognized IBMFS, but not carriers, had worse survival after HCT (IBMFS hazard ratio [HR], 2.13; 95% confidence interval[CI], 1.40-3.24; P = .0004; carriers HR, 0.96; 95% CI, 0.62-1.50; P = .86). Results were similar in analyses restricted to patients receiving reduced-intensity conditioning (n = 448; HR IBMFS = 2.39; P = .01). The excess mortality risk in unrecognized IBMFS attributed to death from organ failure (HR = 4.88; P < .0001). Genetic testing should be part of the diagnostic evaluation for all patients with SAA to tailor therapeutic regimens. Carriers of a pathogenic variant in an IBMFS gene can follow HCT regimens for acquired SAA. (© 2022 by The American Society of Hematology.)
Databáze:	MEDLINE
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