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

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.

Strain differences in carcinogenic and hematopoietic responses of mice after injection of plutonium citrate.

The carcinogenicity of injected (239)Pu citrate was compared in female mice of the C3H, C57BL/6 and BC3F(1) hybrid strains with different spectra of spontaneous or radiation-induced tumors. A significant reduction in survival due to early death caused particularly by the induction of osteosarcomas was noted in each strain after injection of 500 Bq or more. The dose response of osteosarcomas appeared to have a similar pattern in each strain except for the differences in the skeletal dose ranges for the maximum induction. While the incidence of lymphoid tumors decreased as that of osteosarcomas increased sharply to the maximum at higher doses, their histological phenotypes were predominantly non-thymic, pre-B-cell leukemic lymphomas compared to the controls in each strain. Myeloid leukemias were not highly induced in any of the control and (239)Pu-injected mice, and solid tumors involving the other organs were reduced in each strain after injection of 500 Bq or more. To follow up the hematological kinetics related to alpha-particle irradiation of bone marrow stem cells, sequential examinations were done in mice of each strain within 1 year after injection of 5000 Bq. The numbers of peripheral white blood cells and bone marrow cells were consistently reduced in each strain from 90 days on, while spleen cells increased from 180 days on. Granulocyte-macrophage and macrophage colony-forming cells were also consistently reduced in the bone marrow, with a compensatory increase in the spleen from 90 days on. These findings indicate that the carcinogenic and hematopoietic responses were specific to alpha-particle irradiation and were independent of mouse strain after injection with (239)Pu citrate.

Effects of wind and electric fields on 218Po deposition from the atmosphere.

PURPOSE: To estimate, under atmospheric conditions, 218Po deposition on a sphere representing the human head and compare with the effects of the maximum electric field to be found under a transmission line. METHOD: The effect of the wind in the absence of electric fields was calculated using the Reynolds Analogy between heat and mass transfer. The effect of the electric field was shown to be large compared with that of turbulence. A 'capture radius' due to the field was then estimated and charged 218Po particles blown into this region were assumed to be captured. RESULTS: The deposition ratio was proportional to gammaV0.4E0(0.67), where gamma = charged fraction of 218Po, V = velocity and E0 = surface electric field. With the charged fraction ranging from 0.9% to 3.2%, a surface field on 280 kV m(-1) and a wind speed of 3 m s(-1), the deposition ratio ranged from 3.4 to 9.3. The surface field is several orders of magnitude higher than the average personal exposures that have been measured in epidemiological studies and the effect does not appear to be of epidemiological significance. At low velocities, the predictions of this model are in agreement with the measurements of Henshaw et al. CONCLUSIONS: 218Po deposition by environmental AC fields cannot be advanced as an explanation for the reported associations between childhood leukaemia and electrical installations.

1987 Douglas Lea memorial lecture. Particle dosimetry in bone and the toxicity of bone-seeking radionuclides.

Consideration is given to the tissues at risk in bone and a Monte Carlo method is described which determines the absorbed dose to endosteal tissues and marrow in trabecular bone. The method synthesizes random tracks through the trabecular structures that deposit energy along a path through any given trabecular cavity. The path lengths through the trabeculae and marrow cavities are measured with a bone-scanning microscope and other bone data, such as trabecular surface areas, can also be derived. Results are given for human bones and for bones of the beagle, miniature pig and rhesus monkey. They show that, for the same radionuclide concentration, the doses to endosteal tissues and bone marrow are several times greater in animal than in human bone, and that higher doses in human bone from the Ca and Sr radionuclides are obtained if the initial deposition on bone surfaces is allowed for. Other studies show that the occurrence of osteosarcoma in the human long bones correlates well with trabecular surface area and also that, unlike the case of beta-particles from 90Sr+90Y, leukaemia is not a significant consequence of the alpha-particle doses from 226Ra in human bone or from 226Ra, 239Pu and other alpha emitters in beagle bone.

Reversal of gamma-radiation-induced leukemogenesis in mice by immunomodulation with thiabendazole and dinitrofluorobenzene.

The effect of thiabendazole (TBZ) and dinitrofluorobenzene (DNFB) on radiation-induced leukemogenesis was investigated in the C57BL/6 mouse model. Administration of TBZ-DNFB during, post, or during and post irradiation successfully blocked leukemogenesis, as indicated by the absence of leukemia blast cells in thymus and peripheral blood, as well as prevented thymic lymphoma. TBZ-DNFB treatment prevented the development of leukemia when studies were terminated both after 7 months of last irradiation (disease fully developed) and after 5 months of last irradiation (disease in the process of development). This TBZ-DNFB treatment also resulted in a significant increase in survival.