Fig 1 - available via license: CC BY
Content may be subject to copyright.
BRCA phenocopy hypothesis. A. Maternal-fetal microchimerism. B. Tetragametic chimerism. C. A woman with BRCA-mutant chimeric cells. https://doi.org/10.1371/journal.pone.0195497.g001
Source publication
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 thi...
Contexts in source publication
Context 1
... further hypothesized that it is these BRCA-mutant cells that give rise to breast and ovarian cancers in chimeric individuals as these cells are known to be susceptible to malignant transformation. See Fig 1A. Therefore, the progeny of these cells (the majority of cells in the tumor) would be BRCA-mutant as well. ...
Similar publications
Hereditary breast and ovarian cancer syndrome (HBOC) represents 5–10% of all patients with breast cancer and is associated with high-risk pathogenic alleles in BRCA1/2 genes, but only for 25% of cases. We aimed to find new pathogenic alleles in a panel of 143 cancer-predisposing genes in 300 Mexican cancer patients with suspicion of HBOC and 27 hig...
Background: Deleterious variants in the tumour suppressor BRCA1 are known to cause hereditary breast and
ovarian cancer syndrome (HBOC). Missense variants in BRCA1 pose a challenge in clinical care, as their effect on
protein functionality often remains unknown. Many of the pathogenic missense variants found in BRCA1 are located
in the BRCA1 C-term...
Citations
... 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. ...
... 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. ...
Background:
BRCA phenocopies are individuals with the same phenotype (i.e. cancer consistent with Hereditary Breast and Ovarian Cancer syndrome = HBOC) as their affected relatives, but not the same genotype as assessed by blood germline testing (i.e. they do not carry a germline BRCA1 or BRCA2 mutation). There is some evidence of increased risk for HBOC-related cancers in relatives of germline variant carriers even though they themselves test negative for the familial variant (BRCA non-carriers). At this time, BRCA phenocopies are recommended to undergo the same cancer surveillance as individuals in the general population. This raises the question of whether the increased cancer risk in BRCA non-carriers is due to alterations (germline, somatic or epigenetic) in other cancer-associated genes which were not analyzed during BRCA analysis.
Methods:
To assess the nature and potential clinical significance of somatic variants in BRCA phenocopy tumors, DNA from BRCA non-carrier tumor tissue was analyzed using next generation sequencing of 572 cancer genes. Tumor diagnoses of the 11 subjects included breast, ovarian, endometrial and primary peritoneal carcinoma. Variants were called using FreeBayes genetic variant detector. Variants were annotated for effect on protein sequence, predicted function, and frequency in different populations from the 1000 genomes project, and presence in variant databases COSMIC and ClinVar using Annovar.
Results:
None of the familial BRCA1/2 mutations were found in the tumor samples tested. The most frequently occurring somatic gene variants were ROS1(6/11 cases) and NUP98 (5/11 cases). BRCA2 somatic variants were found in 2/6 BRCA1 phenocopies, but 0/5 BRCA2 phenocopies. Variants of uncertain significance were found in other DNA repair genes (ERCC1, ERCC3, ERCC4, FANCD2, PALB2), one mismatch repair gene (PMS2), a DNA demethylation enzyme (TET2), and two histone modifiers (EZH2, SUZ12).
Conclusions:
Although limited by a small sample size, these results support a role of selected somatic variants and epigenetic mechanisms in the development of tumors in BRCA phenocopies.
We report the first case of blood chimerism involving a pathogenic RB1 variant in naturally conceived monochorionic-dizygotic twins (MC/DZ) with the twin-twin-transfusion syndrome (TTTS), presumably caused by the exchange of stem-cells. Twin A developed bilateral retinoblastoma at 7 months of age. Initial genetic testing identified a de novo RB1 pathogenic variant, with a 20% allelic ratio in both twins' blood. Subsequent genotyping of blood and skin confirmed dizygosity, with the affected twin harboring the RB1 pathogenic variant in skin and blood, and the unaffected twin carrying the variant only in blood.
