Molecular patterns of nuclear and mitochondrial microsatellite alterations in breast tumors.
The widespread distribution of microsatellite sequences within the human genome has allowed researchers to identify alternative patterns of microsatellite alterations in cancer cells. Among them, aneuploid patterns of nuclear microsatellites, pseudo-diploid microsatellite instability patterns, and also patterns of microsatellite instability within the mitochondrial genome. In this context, while aneuploid patterns of multiple genomic gains and losses had already been described in breast tumors, data on nuclear microsatellite instability still remain controversial and limited data on mitochondrial instability are available. In order to clarify this, we undertook an extensive analysis of nuclear and mitochondrial microsatellite alterations in breast ductal adenocarcinomas, stratified by grades. No instability was detected in any of the 40 dinucleotide microsatellites analysed nor in bat26 and APDelta3 mononucleotide repeats, clearly concluding that microsatellite instability is not a feature of ductal breast tumorigenesis. Instead, microsatellites defined a clear pattern of aneuploid genomic gains and losses among which, losses of BRCA1 at D17S855 and gains of plakoglobin at D17S846 significantly associated to grade III tumors and poor prognosis. On the other hand, mitochondrial instability at the transcription control region was also detected in 10.8% of cases. None of the new mitochondrial variants was found in the normal tissue counterparts, confirming that these new variants arise as sporadic somatic mutations in the tumor cells. Also, no association was found between heteroplasmy in the normal tissue and mitochondrial instability in the tumors. We therefore suggest that these new variants arise in tumors as a consequence of the progressive accumulation of slippage somatic mutations and the intrinsic instability of these microsatellite sequences. Finally, our results also confirm that mitochondrial instability does not associate with nuclear MSI.
Alazzouzi
Hafid
H
Molecular Pathology Program, Centre d'Investigacions en Bioquímica i Biologia Molecular (CIBBIM), Hospital Universitari Vall d'Hebron, Barcelona, Spain.
Farriol
Mireya
M
Espín
Eloi
E
Armengol
Manel
M
Pena
Manel
M
Zeh
Karin
K
Schwartz
Simó
S
Schwartz
Simó
S
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000782:Aneuploidy; D001943:Breast Neoplasms / Q000235:genetics*; D002467:Cell Nucleus / Q000378:metabolism*; D003001:Cloning, Molecular; D004272:DNA, Mitochondrial / Q000235:genetics*; D005260:Female; D006801:Humans; D019656:Loss of Heterozygosity; D018895:Microsatellite Repeats; D008875:Middle Aged; D017422:Sequence Analysis, DNA
D004272:DNA, Mitochondrial