Inherited mutations in cancer susceptibility genes are common among survivors of breast cancer who develop therapy‐related leukemia

Abstract

Background Risk factors for therapy-related leukemia (TRL) development, an often lethal late complication of cytotoxic therapy, remain poorly understood and may differ for survivors of different malignancies. Breast cancer (BC) survivors now account for the majority of TRL cases, making study of TRL risk factors in this population a priority. Methods Patients with TRL following cytotoxic therapy for a primary BC were identified from The University of Chicago TRL registry. 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 are described. Results Nineteen (22%) of 88 BC survivors with TRL had an additional primary cancer and 40 (57%) of the 70 with available family history 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 (n=3, 6%), BRCA2 (n=2, 4%), TP53 (n=3, 6%), CHEK2 (n=1, 2%), and PALB2 (n=1, 2%). Conclusions BC survivors with TRL have personal and family histories suggestive of inherited cancer susceptibility and frequently carry germline mutations in BC susceptibility genes. These data support the role of these genes in TRL risk and suggest that long term follow-up studies of women with germline mutations treated for BC and functional studies of the effects of heterozygous mutations in these genes on bone marrow function following cytotoxic exposures are warranted.

Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel

“…§Mutations in genes associated with cancer predisposition genes such as TP53 and BRCA1/2 appear to be frequent in therapy-related myeloid neoplasms. 256 …”

Introduction to cancer genetic susceptibility syndromes

“…25 Consistent with these data, a study of breast cancer survivors with therapy-related leukemia identified germ line mutations in BRCA1, BRCA2, TP53, CHEK2, and PALB2 that collectively accounted for 21% of cases. 26 Interestingly, in this second study, there were 7 patients with therapy-associated ALL, with 2 (50%) of 4 tested harboring germ line TP53 mutations. 26 Together, the data from these studies suggest that individuals with therapy-associated leukemia should be considered as candidates for a possible genetic evaluation.…”

“…26 Interestingly, in this second study, there were 7 patients with therapy-associated ALL, with 2 (50%) of 4 tested harboring germ line TP53 mutations. 26 Together, the data from these studies suggest that individuals with therapy-associated leukemia should be considered as candidates for a possible genetic evaluation.…”

Initial Diagnostic Workup of Acute Leukemia: Guideline From the College of American Pathologists and the American Society of Hematology

“…74,75 Thus, the history of previous cytotoxic therapy in a patient with t-AML or therapy-related lymphoblastic leukemia is important for diagnosis and classification but also, perhaps, for identification of an inherited predisposition to drug-induced cancer. 76 As noted in the preceding section, a history of radiation therapy-either alone or in combination with chemotherapy for prior neoplastic or nonneoplastic conditions-is recognized as being associated with an increased risk for AL, particularly AML. Radiation exposure for individuals near natural disasters or atomic bomb explosions is also associated with an increased risk of leukemia, 77,78 and reportedly, radiation exposure after diagnostic procedures, including computed tomography scans in children, increases the risk for leukemia.…”