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Molecular Biology and Genetics |
Instituto Multidisciplinario de Biología Celular, La Plata, Argentina [S. M. R., G. B., G. L. P., M. S. B., N. O. B.], and Division of Human Cancer Genetics, Ohio State University, Columbus, Ohio [P. P.]
We analyzed 40 pairs of breast normal/cancer tissues for the presence of
mitochondrial (mt) genome instability and nuclear MSI in tumor cells.
As mt, markers we used a (CA)n mt microsatellite (MS)
starting at the 514-bp position of the D loop region and 4 informative
MnlI sites located between the 16,108- and 16,420-bp
positions of the D loop region. Nuclear microsatallite instability
(MSI) was tested with 8 (CA)n MS, syntenic for the 13q
chromosome arm. Moreover, we tested the spontaneous frequency of mtMSI
and mt-MnlI mutations in 459 mother/descendant events.
Mutations of mt-MnlI sites were found in 19 of 40
(47.5%) breast tumors, representing a 216-fold increase over the
spontaneous rate in the female germline. Instability of the mtMS
occurred in 17 of 40 (42.5%) breast cancers, which implies a 16-fold
increase over the rate of spontaneous mutations. Nuclear MSI was found
in 20 of 40 (50%) cases. In 15 of these cases the MSI was restricted
to one locus, whereas in 5 instances the change of alleles was detected
in 2 or 3 loci. Analysis of the correlation between mt and nuclear
mutations showed no significant associations, suggesting that different
systems are responsible for mt and nuclear genome instability in tumor
cells. We propose that the two main mechanisms producing mtRFLP and
mtMSI are damage by free radicals and error repair by the polymerase
, the first mechanism being a major cause of
MnlI mutations and a secondary cause of mtMSI.
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