Article Figures & Data
Figures
- Figure 1.
Genetic reversion of BRCA1 mutation in three recurrent BRCA1-mutated ovarian cancer cases. A, DNA sequences of BRCA1 in peripheral blood lymphocytes and the primary and recurrent tumors from a patient (UW80) with BRCA1-mutated ovarian cancer. In the lymphocytes, a heterozygous SNP of the BRCA1 locus (4956A/G) was detected, in addition to a heterozygous mutation (185delAG). In the primary tumor, a hemizygous mutation (185delAG) was detected and loss of heterozygosity (LOH) of the SNP was confirmed. In the microdissected recurrent tumor, LOH of the SNP was confirmed, but wild-type sequence was 80% to 90% of the sequences identified at the site of 185delAG. Importantly, the SNP in the recurrent tumor (4956G) is identical to that in the primary tumor (4956G). This indicates that the recurrent tumor had acquired wild-type BRCA1 by genetic reversion (back mutation to wild-type). Residual 185delAG sequence could represent heterogeneity in the tumor. A speculative model of BRCA1 alleles in samples from this patient is also depicted. B, DNA sequences of BRCA1 in peripheral blood lymphocytes; the primary and recurrent tumors from two patients (UW91 and UWF27) with BRCA1-mutated ovarian cancer. In the lymphocytes, a heterozygous mutation (185delAG) was detected. In the primary tumors, a hemizygous mutation (185delAG) was detected. In the microdissected recurrent tumor specimens, wild-type sequence was detected, suggesting that the recurrent tumors had acquired wild-type BRCA1 by back mutation. Analyses of intragenic SNPs of these cases are shown in Supplementary Fig. S1.
- Figure 2.
BRCA1 protein expression is restored in recurrent ovarian tumors with genetic reversion of BRCA1 mutation. A, schematic presentation of BRCA1 proteins encoded by 185delAG and wild-type BRCA1. Functional domains of BRCA1 protein [RING finger, nuclear localization signals (NLS), and BRCT domains] are depicted. The region that the BRCA1 antibody (MS110) for immunohistochemical staining recognizes (amino acids 89–222; ref. 16) is also depicted. B, immunohistochemical staining of BRCA1 in a primary tumor with BRCA1.185delAG mutation and a recurrent tumor with genetic reversion of the BRCA1 mutation (UW91 patient). The primary tumors are negative for BRCA1 immunostaining, whereas the recurrent tumors are positive for nuclear BRCA1 immunostaining. Bar, 10 μm.
- Figure 3.
Genetic reversion of BRCA1 mutation in a primary ovarian tumor with platinum resistance and another secondary BRCA1 mutation in a recurrent tumor of the same patient. A, DNA sequences of BRCA1 in peripheral blood lymphocytes and the primary and recurrent tumors from a patient (UW40) with BRCA1-mutated ovarian cancer. In the lymphocytes, heterozygous SNPs of the BRCA1 locus (2201C/T and 2430T/C) were detected, in addition to a heterozygous mutation (2594delC). In the primary tumor, LOH of the SNPs was confirmed, but the primary tumor specimen shows heterozygous sequence of wild-type BRCA1 and a BRCA1 mutation (2594delC). In the recurrent tumor specimen, LOH of the SNPs was confirmed and mixed sequences of 2594delC and 2594delC;2606_2628del23 were detected. B, a speculative model of BRCA1 alleles in samples from this patient. The lymphocytes have both the wild-type and mutant (2594delC) alleles. The primary tumor has lost the wild-type BRCA1 allele with SNPs 2201T and 2430C, but has retained the allele with the inherited mutation (2594delC) and SNPs 2201C and 2430T. This mutant allele has presumably been duplicated, and one of the mutated alleles is reverted to wild-type by genetic reversion (back mutation to wild-type). In the recurrent tumor, the allele with wild-type BRCA1 sequence is lost, and the allele with the inherited mutation (2594delC) was again duplicated. One of them obtained a different second mutation (2606_2628del23), which cancels the frameshift caused by the inherited mutation (2594delC). This model explains why we see mixed sequences of BRCA1 in the primary and recurrent tumors. C, schematic presentation of BRCA1 proteins encoded by 2594delC and 2594delC;2606_2628del23.
Tables
- Table 1.
Secondary genetic changes of BRCA1 in BRCA1-mutated ovarian cancer treated with platinum
Patient Inherited mutation Specimen Clinical platinum sensitivity Secondary genetic change Paired specimens CS1 185delAG Pre-platinum Sensitive Post-platinum Sensitive No CS4 185delAG Pre-platinum Sensitive Post-platinum Sensitive No UW91 185delAG Pre-platinum Sensitive Post-platinum Resistant Yes (back mutation) CS14 185delAG Pre-platinum Sensitive Post-platinum Resistant No UW40 2594delC Pre-platinum Resistant Yes (back mutation) Post-platinum Resistant Yes (2606_2628del23) UW80 185delAG Pre-platinum Sensitive Post-platinum Resistant Yes (back mutation) UWF27 185delAG Pre-platinum Sensitive Post-platinum Resistant Yes (back mutation) Nonpaired posttreatment specimens UW208 3867G>T (E1250X) Post-platinum Sensitive No UW317 3171insTGAGA Post-platinum Resistant No
Supplementary Data, Swisher, et al.
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Volume 68, Issue 8
