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PLoS One. 2018 Apr 16;13(4):e0195497. doi: 10.1371/journal.pone.0195497. eCollection 2018.

Can chimerism explain breast/ovarian cancers in BRCA non-carriers from BRCA-positive families?

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Department of Internal Medicine, Division of Hematology, Oncology and Cell Therapy, Rush University Medical Center, Chicago, Illinois, United States of America.
Department of Pathology, Division of Medical Laboratory Science, Rush University Medical Center, Chicago, Illinois, United States of America.
Department of Obstetrics and Gynecology, Division of Gynecologic, Rush University Medical Center, Chicago, Illinois, United States of America.


Hereditary breast and ovarian cancer syndrome (HBOC) is most frequently caused by mutations in BRCA1 or BRCA2 (in short, BRCA) genes. The incidence of hereditary breast and ovarian cancer in relatives of BRCA mutation carriers who test negative for the familial mutation (non-carriers) may be increased. However, the data is controversial, and at this time, these individuals are recommended the same cancer surveillance as general population. One possible explanation for BRCA phenocopies (close relatives of BRCA carriers who have developed cancer consistent with HBOC but tested negative for a familial mutation) is natural chimerism where lack of detectable mutation in blood may not rule out the presence of the mutation in the other tissues. To test this hypothesis, archival tumor tissue from eleven BRCA phenocopies was investigated. DNA from the tumor tissue was analyzed using sequence-specific PCR, capillary electrophoresis, and pyrosequencing. The familial mutations were originally detected in the patients' first-degree relatives by commercial testing. The same testing detected no mutations in the blood of the patients under study. The test methods targeted only the known familial mutation in the tumor tissue. Tumor diagnoses included breast, ovarian, endometrial and primary peritoneal carcinoma. None of the familial mutations were found in the tumor samples tested. These results do not support, but do not completely exclude, the possibility of chimerism in these patients. Further studies with comprehensive sequence analysis in a larger patient group are warranted as a chimeric state would further refine the predictive value of genetic testing to include BRCA phenocopies.

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