X inactive-specific transcript RNA coating and genetic instability of the X chromosome in BRCA1 breast tumors.
Identification among breast tumors of those arising in a hereditary BRCA1 context remains a medical challenge. Abnormalities in X chromosome copy number and in the epigenetic stability of the inactive X chromosome (Xi) have been proposed to characterize BRCA1 breast tumors. In particular, it has been proposed that loss of BRCA1 function can lead to loss of X inactive-specific transcript (XIST) RNA association with the Xi. However, few studies have addressed this issue in a sufficiently large series of BRCA1 primary tumors. Here we assess X-chromosome status using single-cell (RNA and DNA fluorescence in situ hybridization) and global genomic (array-comparative genomic hybridization and allelotyping) approaches on a series of 11 well-defined BRCA1 tumors. We show that many or most cells of the tumors contain one or more XIST RNA domains. Furthermore, the number of XIST RNA domains per cell varied considerably even within a single tumor. Frequent X-chromosome allelic and copy number aberrations were found, in agreement with aberrant XIST RNA domain numbers. In summary, by combining multiple approaches to assess the genetics and epigenetics of a large series of BRCA1 primary tumors, we can conclude definitively that BRCA1 is not required for XIST RNA coating of the X chromosome. The intratumoral and intertumoral variability in XIST RNA domain number in BRCA1 tumors correlates with chromosomal genetic abnormalities, including gains, losses, reduplications, and rearrangements of the X-chromosome. Finally, we also show the necessity for combined global and single-cell approaches in the assessment of tumors with such a high degree of heterogeneity.
Vincent-Salomon
Anne
A
Institut Curie, Centre de Recherche, Paris, France.
Ganem-Elbaz
Carine
C
Manié
Elodie
E
Raynal
Virginie
V
Sastre-Garau
Xavier
X
Stoppa-Lyonnet
Dominique
D
Stern
Marc-Henri
MH
Heard
Edith
E
D000328:Adult; D000368:Aged; D019313:BRCA1 Protein / Q000172:deficiency / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics*; D041321:Chromosomes, Human, X / Q000235:genetics*; D005260:Female; D019398:Genes, BRCA1; D050172:Genes, X-Linked; D018095:Germ-Line Mutation; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008875:Middle Aged; D009693:Nucleic Acid Hybridization; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated / Q000235:genetics*; D049951:X Chromosome Inactivation
D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; C077885:XIST non-coding RNA