TY  - JOUR
A1  - Galetzka, Danuta
A1  - Hansmann, Tamara
A1  - El Hajj, Nady
A1  - Weis, Eva
A1  - Irmscher, Benjamin
A1  - Ludwig, Marco
A1  - Schneider-Rätzke, Brigitte
A1  - Kohlschmidt, Nicolai
A1  - Beyer, Vera
A1  - Bartsch, Oliver
A1  - Zechner, Ulrich
A1  - Spix, Claudia
A1  - Haaf, Thomas
T1  - Monozygotic twins discordant for constitutive BRCA1 promoter methylation, childhood cancer and secondary cancer
JF  - Epigenetics
N2  - We describe monozygotic twins discordant for childhood leukemia and secondary thyroid carcinoma. We used bisulfite pyrosequencing to compare the constitutive promoter methylation of BRCA1 and several other tumor suppressor genes in primary fibroblasts. The affected twin displayed an increased BRCA1 methylation (12%), compared with her sister (3%). Subsequent bisulfite plasmid sequencing demonstrated that 13% (6 of 47) BRCA1 alleles were fully methylated in the affected twin, whereas her sister displayed only single CpG errors without functional implications. This between-twin methylation difference was also found in irradiated fibroblasts and untreated saliva cells. The BRCA1 epimutation may have originated by an early somatic event in the affected twin: approximately 25% of her body cells derived from different embryonic cell lineages carry one epigenetically inactivated BRCA1 allele. This epimutation was associated with reduced basal protein levels and a higher induction of BRCA1 after DNA damage. In addition, we performed a genome-wide microarray analysis of both sisters and found several copy number variations, i.e., heterozygous deletion and reduced expression of the RSPO3 gene in the affected twin. This monozygotic twin pair represents an impressive example of epigenetic somatic mosaicism, suggesting a role for constitutive epimutations, maybe along with de novo genetic alterations in recurrent tumor development.
KW  - BRCA1
KW  - childhood cancer
KW  - DNA Methylation
KW  - epimutation
KW  - monozygotic twins
KW  - secondary cancer
KW  - somatic mosaicism
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-125386
VL  - 7
IS  - 1
ER  -