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

Abstract

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.

Somatic variants of potential clinical significance in the tumors of BRCA phenocopies

“…The current study addresses the origin of a disease phenocopy, an HBOC syndrome, in the absence of a familial (germline) gene pathogenic variant. We previously tested DNA from 11 tumors from women who come from families carrying BRCA1 or BRCA2 pathogenic variants, but who do not carry the variant themselves as defined by blood testing [28]. Although genetic alterations in any of the 11 tumor samples have not been demonstrated, several potential driver mutations were observed through testing with the Agilent 572 oncogene panel.…”

“…Additional samples would further confirm the lack of familial pathogenic variants as well as any commonalities in family variants or in the somatic variants of the phenocopies. Interestingly, the one patient with non-HBOC phenotype (endometrial carcinoma) had a complex family history of maternal HBOC history (breast and ovarian cancers) with pathogenic 6794 insA variant in BRCA2 and paternal Lynch syndrome history (colon, lung and bone cancers) without any familial variant reported [28]. The possibility exists, therefore, that this patient is a phenocopy of a paternally inherited variant.…”

“…However, a study by Azzollini et al [4] did not find the familial variants in tumor samples, blood leukocytes, buccal mucosa nor urine of BRCA phenocopies. We previously explored natural chimerism as an alternative explanation for BRCA phenocopies [28]. We hypothesized that breast and ovarian cancer can still be caused by familial BRCA variants, but transmitted in an alternative, non-mendelian fashion (e.g., through maternal-fetal or tetragametic chimerism) so that the altered genes are present in chimeric tissues rather than in blood.…”

“…Since BRCA mutant cells are much more likely to give rise to cancer than non-mutants cells, in a chimeric organism, the tumor would be BRCA -mutant. We analyzed tumor tissue in BRCA phenocopies for the known familial variant using targeted PCR and qPCR methods [28]. In our cohort of 11 cases, we did not find the familial alteration in the tumor tissues.…”