title: Evaluation of Patients and Families With Concern for Predispositions to Hematologic Malignancies Within the Hereditary Hematologic Malignancy Clinic (HHMC).
abstract: Although multiple predispositions to hematologic malignancies exist, evaluations for hereditary cancer syndromes (HCS) are underperformed by most hematologist/oncologists. Criteria for initiating HCS evaluation are poorly defined, and results of genetic testing for hereditary hematologic malignancies have not been systematically reported.
  
  
  
  From April 2014 to August 2015, 67 patients were referred to the Hereditary Hematologic Malignancy Clinic (HHMC). Referral reasons included (1) bone marrow failure or myelodysplastic syndrome in patients ≤ 50 years, (2) evaluation for germ-line inheritance of identified RUNX1, GATA2, or CEBPA mutations on targeted next-generation sequencing panels, and (3) strong personal and/or family history of malignancy. Cultured skin fibroblasts were utilized for germ-line DNA in all patients with hematologic malignancy.
  
  
  
  Eight patients (12%) were clinically diagnosed with a HCS: 4 patients with RUNX1-related familial platelet disorder (FPD)/acute myeloid leukemia (AML), and 1 patient each with dyskeratosis congenita, Fanconi anemia, germ-line DDX41, and Li-Fraumeni syndrome (LFS). Two patients with concern for FPD/AML and LFS, respectively, had RUNX1 and TP53 variants of unknown significance. Additionally, 4 patients with prior HCS diagnosis (1 LFS, 3 FPD/AML) were referred for further evaluation and surveillance.
  
  
  
  In this HHMC-referred hematologic malignancy cohort, HCS was confirmed in 12 patients (18%). HCS identification provides insight for improved and individualized treatment, as well as screening/surveillance opportunities for family members. The HHMC has facilitated HCS diagnosis; with increased clinical awareness of hematologic malignancy predisposition syndromes, more patients who may benefit from evaluation can be identified. Mutation panels intended for prognostication may provide increased clinical suspicion for germ-line testing.
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX. Electronic address: cdinardo@mdanderson.org.
authors.forename: Courtney D
authors.initials: CD
authors.lastname: DiNardo
authors.affiliation: Department of Clinical Cancer Genetics, University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Bannon
authors.affiliation: Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Mark
authors.initials: M
authors.lastname: Routbort
authors.affiliation: Department of Pediatrics, University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Anna
authors.initials: A
authors.lastname: Franklin
authors.affiliation: Department of Clinical Cancer Genetics, University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Maureen
authors.initials: M
authors.lastname: Mork
authors.affiliation: Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Mary
authors.initials: M
authors.lastname: Armanios
authors.affiliation: Center for Human Immunobiology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX.
authors.forename: Emily M
authors.initials: EM
authors.lastname: Mace
authors.affiliation: Center for Human Immunobiology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX.
authors.forename: Jordan S
authors.initials: JS
authors.lastname: Orange
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, Comprehensive Cancer Research Center, University of Chicago, Chicago, IL.
authors.forename: Meselle
authors.initials: M
authors.lastname: Jeff-Eke
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, Comprehensive Cancer Research Center, University of Chicago, Chicago, IL.
authors.forename: Jane E
authors.initials: JE
authors.lastname: Churpek
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Koichi
authors.initials: K
authors.lastname: Takahashi
authors.affiliation: Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Jorgensen
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Garcia-Manero
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Steve
authors.initials: S
authors.lastname: Kornblau
authors.affiliation: Department of Pediatrics, Texas Children's Cancer & Hematology Center, Baylor College of Medicine, Houston, TX.
authors.forename: Alison
authors.initials: A
authors.lastname: Bertuch
authors.affiliation: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Hannah
authors.initials: H
authors.lastname: Cheung
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Kapil
authors.initials: K
authors.lastname: Bhalla
authors.affiliation: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Andrew
authors.initials: A
authors.lastname: Futreal
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, Comprehensive Cancer Research Center, University of Chicago, Chicago, IL.
authors.forename: Lucy A
authors.initials: LA
authors.lastname: Godley
authors.affiliation: Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Keyur P
authors.initials: KP
authors.lastname: Patel
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor; D005190:Family / Q000523:psychology*; D005260:Female; D005817:Genetic Counseling; D020022:Genetic Predisposition to Disease / Q000523:psychology*; D018095:Germ-Line Mutation; D019337:Hematologic Neoplasms / Q000175:diagnosis / Q000453:epidemiology* / Q000235:genetics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D009386:Neoplastic Syndromes, Hereditary / Q000175:diagnosis / Q000453:epidemiology* / Q000235:genetics; D010361:Patients / Q000523:psychology*; D010375:Pedigree; D012017:Referral and Consultation; D013781:Texas; D057188:Workflow; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor
keywords: AML; Germ line; HCS; Inherited; MDS; Predisposition