title: Inherited mutations in cancer susceptibility genes are common among survivors of breast cancer who develop therapy-related leukemia.
abstract: BACKGROUND
  Risk factors for the development of therapy-related leukemia (TRL), an often lethal late complication of cytotoxic therapy, remain poorly understood and may differ for survivors of different malignancies. Survivors of breast cancer (BC) now account for the majority of TRL cases, making the study of TRL risk factors in this population a priority.
  
  
  METHODS
  Subjects with TRL after cytotoxic therapy for a primary BC were identified from the TRL registry at The University of Chicago. Those with an available germline DNA sample were screened with a comprehensive gene panel covering known inherited BC susceptibility genes. Clinical and TRL characteristics of all subjects and those with identified germline mutations were described.
  
  
  RESULTS
  Nineteen of 88 survivors of BC with TRL (22%) had an additional primary cancer and 40 of the 70 survivors with an available family history (57%) had a close relative with breast, ovarian, or pancreatic cancer. Of the 47 subjects with available DNA, 10 (21%) were found to carry a deleterious inherited mutation in BRCA1 (3 subjects; 6%), BRCA2 (2 subjects; 4%), TP53 (tumor protein p53) (3 subjects; 6%), CHEK2 (checkpoint kinase 2) (1 subject; 2%), and PALB2 (partner and localizer of BRCA2) (1 subject; 2%).
  
  
  CONCLUSIONS
  Survivors of BC with TRL have personal and family histories suggestive of inherited cancer susceptibility and frequently carry germline mutations in BC susceptibility genes. The data from the current study support the role of these genes in TRL risk and suggest that long-term follow-up studies of women with germline mutations who are treated for BC and functional studies of the effects of heterozygous mutations in these genes on bone marrow function after cytotoxic exposures are warranted. Cancer 2016;122:304-311. © 2015 American Cancer Society.
authors.affiliation: Center for Clinical Cancer Genetics, The University of Chicago, Chicago, Illinois.|Department of Medicine, The University of Chicago, Chicago, Illinois.|Comprehensive Cancer Center, The University of Chicago, Chicago, Illinois.
authors.forename: Jane E
authors.initials: JE
authors.lastname: Churpek
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, Illinois.
authors.forename: Rafael
authors.initials: R
authors.lastname: Marquez
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, Illinois.
authors.forename: Barbara
authors.initials: B
authors.lastname: Neistadt
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, Illinois.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Claussen
authors.affiliation: Division of Medical Genetics, Department of Medicine, University of Washington School of Medicine, Seattle, Washington.
authors.forename: Ming K
authors.initials: MK
authors.lastname: Lee
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, Illinois.|Department of Health Studies, The University of Chicago, Chicago, Illinois.
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Churpek
authors.affiliation: Department of Health Studies, The University of Chicago, Chicago, Illinois.
authors.forename: Dezheng
authors.initials: D
authors.lastname: Huo
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, Illinois.
authors.forename: Howard
authors.initials: H
authors.lastname: Weiner
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, Illinois.
authors.forename: Mekhala
authors.initials: M
authors.lastname: Bannerjee
authors.affiliation: Center for Clinical Cancer Genetics, The University of Chicago, Chicago, Illinois.|Department of Medicine, The University of Chicago, Chicago, Illinois.|Comprehensive Cancer Center, The University of Chicago, Chicago, Illinois.
authors.forename: Lucy A
authors.initials: LA
authors.lastname: Godley
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, Illinois.|Comprehensive Cancer Center, The University of Chicago, Chicago, Illinois.
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Le Beau
authors.affiliation: Department of Laboratory Medicine, University of Washington, Seattle, Washington.
authors.forename: Colin C
authors.initials: CC
authors.lastname: Pritchard
authors.affiliation: Division of Medical Genetics, Department of Medicine, University of Washington School of Medicine, Seattle, Washington.
authors.forename: Tom
authors.initials: T
authors.lastname: Walsh
authors.affiliation: Division of Medical Genetics, Department of Medicine, University of Washington School of Medicine, Seattle, Washington.
authors.forename: Mary-Claire
authors.initials: MC
authors.lastname: King
authors.affiliation: Center for Clinical Cancer Genetics, The University of Chicago, Chicago, Illinois.|Department of Medicine, The University of Chicago, Chicago, Illinois.|Comprehensive Cancer Center, The University of Chicago, Chicago, Illinois.
authors.forename: Olufunmilayo I
authors.initials: OI
authors.lastname: Olopade
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, Illinois.|Comprehensive Cancer Center, The University of Chicago, Chicago, Illinois.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Larson
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000235:genetics / Q000628:therapy; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D020022:Genetic Predisposition to Disease / Q000453:epidemiology*; D018095:Germ-Line Mutation; D006801:Humans; D007953:Leukemia, Radiation-Induced / Q000139:chemically induced / Q000235:genetics*; D008875:Middle Aged; D011379:Prognosis; D012042:Registries; D012189:Retrospective Studies; D018570:Risk Assessment; D017741:Survivors
chemical_list: D000970:Antineoplastic Agents
keywords: breast cancer; inherited; leukemia; therapy-related