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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.
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