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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.]
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ABSTRACT |
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, the first mechanism being a major cause of
MnlI mutations and a secondary cause of mtMSI. |
INTRODUCTION |
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mtDNA is transmitted from the mother to all children, but only the female descendants pass it on to the next generation. Accordingly, mtDNA molecules are haploid due to the lack of homologous molecules of paternal origin. The number of mt genomes per cell varies from a few (resting lymphocytes) to several thousands (oocytes), giving rise to mtDNA polyhaploidy in all cells. A significant amount of ROS is generated during mt OXPHOS. This increase in ROS concentration in the mt microenvironment, combined with the lack of the protective action of histones and a deficiency in mtDNA repair, gives rise to a rate of mt genome mutations 10- to 100-fold higher than the nuclear DNA mutation rate (2, 3, 4, 5) . The association of nonmutated and mutated mt subpopulations in the cells of an individual is identified as heteroplasmy; several degenerative diseases, apoptosis, and senescence are assumed to occur when mt mutations are disadvantageous and the number of defective mt genomes in the heteroplasmic cell population exceeds a certain threshold (6 , 7) .
Extensive mt genome deletions and base changes mainly involving purine transitions are the two types of mt mutations assumed to occur after the action of ROS; thus far, renal (8 , 9) , breast (10) , and colon cancer cells (11 , 12) have been reported to show a variable spectrum of ROS-induced mt mutations.
There is a variety of tumors exhibiting an abnormally high rate of spontaneous mutations that result from malfunction of DNA MMR genes and that is identified as nuclear genome instability. The most common form of nuclear genome instability is the appearance of novel, noninherited microsatellite alleles in tumor cells with persistence of inherited alleles in the normal cell counterpart. The first descriptions of MSI were reported in hereditary non-polyposis colorectal carcinomas (13, 14, 15, 16) . Ever since, MSI has been found in several types of hereditary and sporadic tumors, including breast cancer (17, 18, 19) .
In normal individuals, starting at 514 bp of the mtDNA control region, there is a (CA)n microsatellite showing 5 haploid alleles differing in size by the number of dinucleotide repeats (Ref. 20 ; data in this report). Heerdt et al. (11) tested 24 pairs of normal/colorectal cancer tissues and found no allelic change in the mtMS.
Extending from 16,184 bp to 16,193 bp of the mtDNA control region,
there is a poly(C) tract interrupted by a T at the 16,189 bp position
(21)
. One of the mt variants that usually occur in normal
individuals is the appearance of an uninterrupted poly(C) tract due to
a T
C transition at 16,189 bp; these cases, in addition to the
TC transition, also show by length heteroplasmies of the poly(C)
tract that are matrilineally transmitted from the female ancestor to
her descendants (22)
. Some colorectal cancers carry
the TC transition and the poly(C) tract heteroplasmy in tumor but
not in normal cells (23)
, the TC transition being the
primary event and the poly(C) tract instability the secondary effect.
In this report, we analyze 40 pairs of breast normal/cancer cells. The
rate of allele changes in the mt(CA)n MS of tumor
cells determines the frequency of mtMSI. Moreover, we used 4
informative MnlI sites located between 16,108 bp and 16,420
bp of the mt control region (21)
to detect RFLP between
normal and tumor cells; the TC transition at 16,189 bp is detected
by the loss of one of the above sites. We also tested 8 MS loci to
assess the rate of nuclear MSI in tumor cells. Furthermore, we analyzed
the frequency of appearance of mtRFLPs and (CA)n
mtMS allele changes in 459 mother/descendant events to estimate the
spontaneous rate of mtMSI and mt-MnlI mutations in the
female germline and to compare these rates with the rate of mt
mutations in breast tumor tissues.
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MATERIALS AND METHODS |
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MtDNA Analysis.
The (CA)n microsatellite starting at 514 bp
(21)
was amplified with the primers and PCR conditions
reported by Szibor et al. (20)
. Microsatellite
allele identification was performed by electrophoresis in 15% neutral
polyacrylamide and Sybr-Green fluorescence. Allele nomenclature in the
text and tables was based on the number of repeats (20)
.
RFLP for MnlI sites [CCTC(N)7] was
detected in a mtDNA fragment of 312 bp extending from the 16,108 bp
position to the 16,420 bp position. Primers used were mtL16,108
5'-CAGCCACCATGAATATTGTAC-3' (forward) and mtH16,420
5'-TGATTTCACGGATGGTG-3' (backward). PCR conditions were 30 cycles with
56°C annealing temperature. According to the reference sequence of
Anderson et al. (21)
, the 312-bp fragment
comprises five MnlI sites producing fragments of 118, 89,
39, 35, 28, and 3 bp (Fig. 1
,
a). With the exception of the 3-bp fragment, which could not
be identified due to its small size, all of the other fragments and
their corresponding RFLPs (Fig. 1
, a–l) were detected
by electrophoresis in 10% neutral polyacrylamide and Sybr-Green
fluorescence staining. In the text, tables, and figures, the position
of MnlI sites is identified by the position of the
restriction site located 7 bp downstream of the end of the recognition
site.
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Autosomal MS.
A set of eight (CA)n MS syntenic for the 13q
chromosome arm were amplified with the primers reported by Deka
et al. (25)
. We used four duplex PCR reactions
combining the primers for FLT1 and D13S197
(55°C annealing), D13S118 and D13S193 (55°C
annealing), D13S121 and D13S71 (55°C
annealing), and D13S122 and D13S124 (49°C
annealing). Alleles were detected by electrophoresis in 15% neutral
polyacrylamide and Sybr-Green fluorescence. Alleles are identified in
the text by the number of repeats. Allele diversities reported in
literature for each one of the MS are: FLT1, 19 alleles
(156–200 bp); D13S118, 12 alleles (176–200 bp);
D13S121, 15 alleles (150–180 bp); D13S71, 11
alleles (67–81 bp); D13S122, 28 alleles (75–113 bp);
D13S197, 31 alleles (87–145 bp); D13S193, 18
alleles (119–151 bp); and D13S124, 10 alleles (177–195 bp)
(25)
. Cases showing allele changes between normal and
tumor cells were tested twice to confirm the results.
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RESULTS |
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. Allele changes between the ancestor and descendant(s) were observed in
three families (Fig. 2
). In family 35, six of the eight F1 descendants
showed allele changes. One case was homoplasmic, two other cases were
heteroplasmic for two mtDNA subpopulations, and three were
heteroplasmic for three subpopulations, one of which corresponded to
the maternal ancestor allele (Fig. 2
). In F2 of
family 1408 (Fig. 2
), the ancestral allele 7 changed into a homoplasmic
allele 8 in one male descendant and into a 7/8 heteroplasmy in a female
descendant. Finally, in family 1413, we observed one homoplasmic change
that does not fit the pattern of maternal transmission (Fig. 2
).
Because the CEPH family repository is stored as Epstein-Barr
immortalized lymphoblastoid cell lines (26)
, we assume
that the allele shifting in family 1413 was due to the process of
immortalization. Allelic changes caused by lymphocyte immortalization
have been reported by Weber and Wong (27)
and Bianchi
et al. (28)
. Thus, if in heteroplasmies we
count as mutations only those alleles differing from the maternal
allele, we have a total of 12 novel MS alleles representing a
spontaneous mutation rate of 2.6% (12 of 459) and a mutation rate due
to lymphoblastoid transformation of 0.2% (1 of 459).
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; Table 2
). Accordingly, the spontaneous rate of MnlI mutations in
female germline cells is 1 of 459 or 0.22%. We sequenced three
randomly selected samples showing the TC transition at 16,189 bp,
and in all of them we found the poly(C) length heteroplasmy reported by
Bendall and Sykes (22)
. We conclude that in our series of
normal/cancer pairs poly(C) instability is a constant event
accompanying all cases with a TC transition at 16,189 bp.
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A
transversion (29)
. In case of equivalent coamplification
of mt-like nuclear and genuine mt sequences, all samples having the
MnlI 16,189 mt site would be heteroplasmic due to the
coexistence of 89-bp + 35-bp fragments (presence of the site
in the mt fragment) with a 124-bp fragment (lack of the site in the
mt-like nuclear fragment). Because this is not the case, we conclude
that due to the differential amount of targets (thousands of mtDNA
targets per cell versus only two chromosome 11 targets per
cell) the PCR fragment amplified is predominantly of mt and not of
nuclear origin, a conclusion valid not only for CEPH families but also
for normal/cancer breast tissue pairs.
(CA)n mtMSI and MnlI RFLPs in
Normal/Cancer Breast Tissues.
Over a total of 40 normal breast tissues analyzed for
(CA)n MS, we detected one heteroplasmic sample
(case 4, alleles 5/6; Table 3
). Accordingly, the total number of alleles detected in the 40 samples
of normal breast tissues was 41. Table 1
depicts the allele frequency
in normal tissues. The analysis of tumor sample counterparts showed
allele changes in 17 of 40 cases (42.5%; Table 3
). Eight of these
cases exhibited a shifting from allele 5 in the normal tissue to allele
4 in the tumor tissue; 7 cases showed a 4- to 5-allele changes; one
case had allele 5 in normal tissue and a 6/8 heteroplasmy in cancer
cells (case 11; Table 3
), whereas the remaining case was heteroplasmic
for alleles 5/6 in normal tissue and homoplasmic for allele 5 in tumor
cells (case 4; Table 3
).
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). Nine cases gained 1 and
10 cases lost 1 MnlI site with regard to normal tissues. If
we combine MS and MnlI data, the mtGI observed in cancer
tissues was 27 of 40 (65%).
Nuclear MSI.
To define MSI, we followed the recommendations and guidelines
reported for colorectal cancers (30)
. Thus, we identified
as MSI any change in length produced by the insertion or deletion of
one or more repeat units in tumor tissues MS as compared with MS
alleles in normal counterpart tissues. MSI-L and MSI-H were
characterized, respectively, by allelic changes in one locus (MSI-L) or
in two or more loci (MSI-H) of the eight loci used. Cases in which the
normal tissues showed two different alleles and tumor tissues showed
only one of the alleles in normal cells (i.e., cases 1, 2,
20, and 23; Table 3
) were not counted as MSI because we considered it
difficult to clearly discern between loss of heterozygosity or MSI
(30)
. Using these criteria, we found 15 of 40 (37.5%)
cases of MSI-L (cases 5, 6, 8, 11, 14, 15, 16,18, 20, and 23–28; Table 3
) and 5 cases (12.5%) of MSI-H (cases 17, 19, 21, 22, and 30; Table 3
). Approximately one-half of the mutated alleles showed length
contraction and half-length expansion.
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DISCUSSION |
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We had no special reason to select the eight MS markers used in this
report except that they are routinely used by our and other groups for
population studies. One of the main peculiarities of this set of
markers is that they do not follow the predictions of the single-step
mutation model (25)
. Thus, length contractions and
expansions comprising more than one repeat are frequent (Table 3)
.
We found MSI in 20 of 40 (50%) of tumor cases. Liu et al. (41) have defined three different groups of cancer with MSI: group 1, cancers with a family history of malignancy, which usually show two or more loci exhibiting MSI (MSI-H); group b, tumors with MSI-H but with no family history of cancer; and group c, tumors with no family history of cancer and with a lower prevalence of MSI (MSI-L). According to these criteria, 15 of our cases correspond to the third group and 5 to the second group.
Malfunction of the two alleles in at least one locus of the MMR genes loci (hMSH2, hMLH1, hPMS2, or hPMS1) has been documented in colorectal cancers of groups a and b (15 , 41) , and also, although at lower frequency, in endometrial and gastric cancers with MSI-H (42, 43, 44) . Therefore, by extrapolation it has been assumed that breast cancers showing MSI-H have also defective MMR genes (18) . On the other hand, no defective MMR genes have been detected in colorectal, endometrial, and gastric cancers with MSI-L (42 , 44 , 45) . MSI-L in these tumors has been explained by endogenous damage by ROS, exogenous factors including smoking and diet, and deficiencies in repair mechanisms not controlled by the major cohort of MMR genes (30) .
mt GI.
The presence of mtDNA mutations in tumor cells has been investigated in
gastric (46)
, breast (10)
, and colorectal
cancers (11
, 12 , 23)
. A deletion of 50 bp extending from
298 to 348 bp was detected in 12.5% of gastric adenocarcinomas of the
gastroesophageal junction (4 of 32 cases tested) but in none of the 45
cases having more distal gastric cancers (46)
.
Furthermore, of a total of seven cases of breast cancer in which the
whole mt genome was tested for RFLP with the use of nine different
restriction enzymes, five cases exhibited mutations in tumor but not in
normal cells (10)
. Heerdt et al.
(11)
sequenced a fragment of the mt-D loop (371–570 bp)
and analyzed the appearance of allele changes in the
(CA)n mtMS in 24 pairs of normal/tumor tissues of
colorectal cancers, finding no tumor mutations. Polyak et
al. (12)
amplified by PCR and sequenced the entire mt
genome in seven cell lines derived from colorectal tumors. Of the 88
mutations detected (4–31 per tumor cell line), 8 were present in
protein coding genes and 4 in tRNA genes. To confirm whether these
variants were specific of cancer cells or the result of the in
vitro conditions, the authors tested the primary cancer cells from
which the cell lines were derived and also the normal colon tissue
counterparts. They found that 12 of the 88 mutations were specific of
tumor cells. Eleven of these mutations were TC or GA transitions
and one was a base insertion; 10 mutations were homoplasmic, and 2 were
heteroplasmic for 2 mt genome subpopulations. Habano et al.
(23)
analyzed the (CA)n mtMS and the
D loop poly(C) tract in 45 pairs of normal/tumor tissues from sporadic
colorectal cancers. No mtMSI was detected in tumor tissues, whereas 20
cases (44%) of tumor cells showed instability of the poly(C) tract
very likely produced by TC transitions at the 16,189 bp position.
In the series reported here, we found 17 of 40 (42.5%) tumors showing mtMSI. Because the spontaneous rate mutation rate for this MS in female gametes was 2.6%, we conclude that breast tumor tissues had a 16-fold increase in the rate of mtMSI. Mutations of MnlI sites appeared in 47.5% (19 of 40) of cancer breast tissues and 0.22% of CEPH pedigrees; this represents a 216-fold increase in the mutation rate of cancer cells with regard to the spontaneous rate detected in female gametes.
Table 4
shows the lack of significance between the observed and the expected
frequencies of nuclear MSI, mtMSI, and mtRFLP associations. Data in
this table indicate that nuclear GI and the two forms of mtGI analyzed
in this report are independent phenomena caused by abnormalities at
different stages of the pathway leading to cell transformation.
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The mtDNA fragment tested for MnlI RFLPS is part of the D
loop segment. This region has a triple-stranded DNA conformation and is
the point of attachment of the mtDNA to the mt membrane (47)
. All cases
of breast cancers included in our series correspond to postmenopausal
women whose normal breast cells were in a metabolic resting state due
to the lack of hormonal stimulus. Breast cancer cells, on the other
hand, exhibit an active OXPHOS pathway producing a marked increase of
ROS (10)
. These DNA breakdown products (lipid peroxides,
alkoxyl radicals, peroxyl radicals, and aldehydes) mainly occur at the
mt membrane level and preferentially damage the single chain of the
triple-stranded DNA structure of the D loop (48)
. The base
repair process used to correct the damage in the mtDNA molecule is
mediated by polymerase (Pol ), an enzyme with decreased proof
reading efficiency (49
, 50) . Thus, the combination of
increased DNA damage by free radicals and deficient base repair by Pol
are the causes explaining the 216-fold increase of MnlI
mutations detected in the D loop region of breast cancer cells.
Slipped strand mispairing followed by deficient repair are the
mechanisms accounting for the origin of MS repeat variants
(51)
. Accordingly, in breast tumors, the nuclear and mtDNA
replication resulting from the continuous cell cycling of transformed
cells gives the basis for the appearance of slipped strand mispairing.
In nuclear MSI-H, the homozygous malfunction in one locus of the cohort
of MMR genes seems to play a fundamental role in the appearance of
facultative MS allele changes. On the other hand, besides ROS damage,
dietary components and smoking have been assumed to enhance MSI-L
(30)
, although the role played by these factors in the
induction of slippage mispairing is not clear. The moderate increase of
mtMSI in breast cancer cells with regard to the spontaneous rate
observed in germline cells (16-fold versus the 216-fold
detected in MnlI mtRFLPs) emphasizes that mtMS allele
changes in breast cancer are mainly due to Pol errors and, to a
lesser extent, to ROS-induced DNA damage.
Homoplasmy of mt Mutations.
In human ovary carcinoma, the average of mitochondria per cell
was 4.6, with 10 being the average of DNA molecules per mitochondria
(52)
. Although we do not have equivalent estimations for
breast cancer cells, it seems reasonable to assume that the number of
mtDNA molecules per cell probably ranges from a few hundreds to a few
thousands. Damage to mtDNA by ROS and error repair by Pol should
occur at random, giving rise to cell heteroplasmies comprising multiple
subpopulations of mutated mtDNA molecules. Yet, in our series, most
tumor cells exhibiting mt MnlI variants or MSI were
homoplasmic for the mutated DNA. Polyak et al.
(12)
also found that 10 of 12 cases of colorectal cancers
showed mtDNA homoplasmic mutations. Two opposite hypotheses have been
formulated to explain the predominance of homoplasmic versus
heteroplasmic mutated mtDNA in cancer cells. According to the report of
Shay and Werbin (1)
, under particular environmental
conditions, some of the mt mutations may result in selective advantage,
enabling the cell(s) harboring the mutation to outgrow other cells in
the population and also allowing the mtDNA with the advantageous
mutation to outgrow other mt genomes in the cell. Conversely, Polyak
et al. (12)
proposed that mt genomes with
mutations affecting their functional efficiency overreplicate to
maintain a normal OXPHOS pathway by an increase in number. Over the
thousands of generations required for the tumor to progress and expand,
the most overreplicated mtDNA molecule(s) easily replace other mt
subpopulations, giving rise to homoplasmy. Because all mt genes and
markers are in linkage disequilibrium, the overreplicated mtDNA gives
rise to homoplasmy, not only for the advantageous or disadvantageous
mutations but also for all other mt markers associated with it.
Final Remarks.
By using eight autosomal MS, one mtMS, and four polymorphic mt
MnlI sites, we were able to detect nuclear and/or mtGI in 35
of 40 (87.5%) breast cancers; a figure high enough to have importance
for the diagnosis of malignancy. Damage by ROS and lipid peroxides
combined with Pol error repair seem to be the mechanisms subjacent
for MnlI mtRFLPs. On the other hand, mtMSI seems to depend
more on the Pol mismatch repair than on damage by ROS. Although we
did not find any correlation between the type of nuclear or mt damage
detected and the pathology of the tumor cases analyzed (Table 3)
, in
the future it would be advisable to extend these studies to explore
whether the distinct types of mt and nuclear GI found in breast cancer
cells may be correlated with different clinical forms or with different
therapeutic responses and survival.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by grants from Consejo Nacional de
Investigaciones Científicas y Técnicas, Comision de
Investigaciones Científicas de la Provincia de Buenos Aires,
Agencia Nacional de Promoción Científica y
Técnólogica, and Liga Argentina de Lucha Contra el
Cáncer of Argentina and NIH Grant CA82282. 
2 To whom requests for reprints should be
addressed, at IMBICE, Calle 526 e/10 y 11, 1900 La Plata,
Argentina. Phone/Fax: (54 221) 425 3320; E-mail: bianchi{at}satlink.com/imbice@satlink.com
3 The abbreviations used are: mtDNA, mitochondrial
DNA; mt, mitochondrial; ROS, reactive oxygen species; OXPHOS, oxidative
phosphorylation; MMR, mismatch repair; MS, microsatellite; MSI,
microsatellite instability; CEPH, Centre d’étude du
Polymorphisme Humain; MSI-L, MSI characterized by allelic changes in
one locus of the eight loci used; MSI-H, MSI characterized by allelic
changes in two or more loci of the eight loci used; GI, genome
instability; Pol , polymerase .
Received 11/19/99. Accepted 6/ 1/00.
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REFERENCES |
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at sites of base loss or oxidative damage. J. Biol. Chem., 270: 9202-9206, 1995.This article has been cited by other articles:
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