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Molecular Biology and Genetics |
Department of Cytogenetics and Molecular Genetics, Women’s and Children’s Hospital, Adelaide, South Australia 5006, Australia [M. M., K. R., E. W., S. D., H. E., M. F., L. H., J. N., E. B., R. I. R.]; Peter MacCallum Cancer Institute, East Melbourne, Victoria, Australia [D. V.]; and Department of Genetics, The University of Adelaide, South Australia 5000, Australia [R. I. R.]
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ABSTRACT |
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INTRODUCTION |
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Recent detailed molecular analysis of the common fragile site FRA3B region revealed a predisposition to localized deletion that is frequently observed in certain forms of cancer (7 , 10) . The cancer-associated FRA3B deletions can result in inactivation of the FHIT gene, an event that is thought to have a role in tumor growth (11) . Although the DNA sequence of the region containing FRA3B has been determined, neither the molecular basis for the cytogenetic expression of the fragile site nor the cancer-associated instability has been clearly resolved as yet (12) . There has been considerable controversy and conflicting data regarding the role of FHIT in cancer (13, 14, 15) . In one study using neoplastic cells that had FRA3B deletions and that therefore were deficient in FHIT protein, "replacement" with stable, overexpressed FHIT protein did not alter in vitro or in vivo properties of these cells (16) . In another study (11) , replacement of FHIT protein in cancer cells suppressed their tumorigenicity. It remains to be assessed whether dysregulation of the FHIT gene, and therefore, the inappropriate "cell cycle" appearance or cellular compartmentalization of FHIT protein is the mechanism for its contribution to neoplasia.
Another common fragile site, FRA7G, has also been shown to
be located within a 
1-Mb region of frequent deletion in breast and
prostate cancer (17
, 18)
, as well as squamous cell
carcinomas of the head and neck, renal cell carcinomas, ovarian
adenocarcinomas, and colon carcinomas (19)
. The human
caveolin-1 and -2 genes are located within the same commonly deleted
region as FRA7G. Caveolin-1 has been shown to have a role in
the anchorage dependant inhibition of growth in NIH 3T3 cells
(20)
. The caveolins are therefore candidates for the tumor
suppressor gene that is presumed to be located in the FRA7G
region (19)
.
Fragile sites have been found to act as amplification boundaries (21 , 22) in selection experiments; however, a role in cancer-associated amplification is yet to be demonstrated. It is not yet clear whether the reported instances of association are due to a predisposition conferred by the fragile site locus or, alternatively, the selection of an associated gain and/or loss of gene function.
The long arm of chromosome 16 is of particular interest in cancer genetics because it exhibits frequent loss in tumor cells (23 , 24) . It is also the location of the rare chromosomal fragile site FRA16B at 16q22.1 (25) and the common, aphidicolin-inducible fragile sites FRA16C at 16q22.1 and FRA16D at 16q23.2. FRA16D has been localized within a large overlapping region of chromosomal instability in breast and prostate cancer as defined by LOH (23 , 24) . In addition, a gene for Wilms’ tumor has been mapped to 16q (26) , and a gene for familial leukemia has been mapped to 16q21–23.2 (27) .
We have therefore physically mapped the FRA16D region in detail to provide markers for identifying any possible relationship between this fragile site and DNA instability in neoplasia. This analysis reveals the existence of an intimate relationship between the location of FRA16D and homozygous deletions in various tumors (this report and Ref. 28 ), culminating in the coincidence of two tumor cell DNA breakpoints with the most likely position of the fragile site.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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subclone libraries in GEM11 or GEM12 vectors
(Promega) according to the supplier’s protocol. My801B6 and 325M3
appeared to have intact human DNA inserts, based on comparative pulsed
field gel mapping of the YACs and BACs across the region (data not
shown).
FISH.
FRA16D-expressing metaphases were obtained from peripheral
blood lymphocytes by standard methods. Briefly, cultures were grown for
72 h in Eagle’s minimal essential medium, minus folic
acid, supplemented with 5% FCS. Induction of FRA16D was
with 0.5 µM aphidicolin (dissolved in 70%
ethanol) added 24 h before harvest (31)
.
DNA clones were nick translated with biotin-14-dATP, preassociated with 6 µg/µl total human DNA, hybridized at 20 ng/µl to metaphase preparations, and detected with one or two amplification steps using biotinylated antiavidin and avidin-FITC as described previously (32) . Hybridization signal was visualized using an Olympus AX70 microscope fitted with single pass filters for 4',6-diamindino-2-phenylindole (for chromosome identification), propidium iodide (as counterstain), and FITC.
FRA16D-expressing chromosomes were scored for signal only
when the width of the fragile site gap was greater than the width of
one chromatid, so that signal was unambiguously proximal or distal to
the gap (Fig. 3)
. Only fluorescent dots that touched chromatin were scored as signal;
the few fluorescent dots that lay within the fragile site gap but did
not touch proximal or distal segments were therefore not scored as
signal, because there was a possibility that they comprised nonspecific
background. clones that gave very poor FISH results (high
nonspecific hybridization to other chromosomes) were not able to be
scored with respect to the fragile site. This is likely to be due to
the large amount of repetitive DNA within these particular clones, as
determined by their DNA
sequence.5
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PCR Detection of Homozygous Deletion in Tumor Cell DNAs.
PCRs for the detection of individual STSs from across the
FRA16D region were duplexed (33)
with control
PCRs from the dystrophin gene on the X chromosome (DMD Pm or DMD49,
Ref. 34
) or the APRT gene on chromosome 16
(35)
. This allowed verification that the PCR was working
in the absence of a FRA16D region PCR product (Fig. 4
). PCR primers for Alu29, 17Sp6, Alu20, 178poly, 5.1A6,
RD69, and IM7 were as described by Paige et al.
(28)
. For 504CA, the forward primer was
5'-AACACAGCTCTTATCACATCC-3', and the reverse primer was
5'-TGGCTGTATTTGTCAGAACTG-3'. Other primers and their GenBank [or
Genome Data Base (GDB)] accession numbers were as follows:
D16S518, Z24645; Afma336yg9 (GDB
1222843); WI2755, G03520; STSG-10102, Z23147;
D16S3029 (GDB 605884); WI-17074, G22903;
IM9, R05832; D16S3096, Z53592, and D16S516(GDB 200080). PCRs for GenBank accession number AA368108 (forward,
5'-TAATCCTCAGCCTCTAGAATGCCT-3'; reverse
5'-GTATGATGATTTTCAGGGAG-AAAC-3') and GenBank
accession number AA398024 (forward,
5'-TGTCCTCAACTGATTCTTACAAAC-3; reverse, 5'-TCAATGGGTTAGGCACAGACC-3')
were derived from partial sequence analysis of BAC353B15.5
Control PCRs for FRA3B deletions were D3S1234
(GenBank accession number 186387), D3S1300 (188420), and
D3S1841 (254090).
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. The individual YACs from this contig were also
used as hybridization probes to further localize the fragile site.
These experiments identified the YAC 801B6 as spanning
FRA16D, and therefore, this YAC was used as a source of DNA
for subcloning the region to provide shorter DNA fragments for further
refinement of the fragile site position. In addition, BAC clones were
identified from the region to provide redundancy of cloned human DNA in
an effort to avoid potential problems of instability of human DNA in
YACs, as has been noted previously for other fragile site regions,
including FRAXA (36)
, FRA10B
(37)
,6
and a Chinese hamster aphidicolin-inducible fragile site region
(38)
.
A pulsed-field gel restriction map of YAC 801B6 was constructed by
using HincII restriction fragment subclones of the YAC for
use as hybridization probes (H13m, H22s, H23m, H29m, and H40m; Fig. 2A
). The position of the BACs (379C2, 325M3, and 353B15)
with respect to the YAC restriction map was determined by both the
restriction mapping of the BACs and the positioning of common markers
by PCR or hybridization (Fig. 2A)
. The STS (D16S518,
Afma336yg9, WI2755, STSG-10102, and D16S3029) content
of the YACs and BACs was also determined to assist in map construction.
Subclone libraries of DNA from YAC 801B6 and BAC 325M3 were generated
using the vectors GEM12 and GEM11 (Promega), respectively,
and assembled into a contig by end-fragment hybridization and
restriction mapping. The integrity of the YAC restriction map was
verified by comparison with that of the BACs 325M3 and 353B15. For the
region between the BACs, the integrity was verified by the use of
long-range PCR using human chromosomal DNA as template (data not
shown).
Localization of FRA16D by FISH.
There have been difficulties in determining the precise localization of
common chromosomal fragile sites using FISH [FRA3B
(12
, 39, 40, 41)
, FRA7G (17
, 18)
, and
FRA7H (42)
]. The FISH data have been
interpreted as due to the fragile sites being spread out over long DNA
sequences (e.g., hundreds of kilobases) or that there
are multiple fragile sites at a single locus. An alternative
explanation is that the DNA in the immediate vicinity of the fragile
site is not tightly "packaged" into chromatin. We therefore chose
to score only those chromosomes in which the width of the gap or break
at the FRA16D fragile site was greater than that of one
chromatid (Fig. 3)
. This approach was intended to reduce the
possibility that the "unpackaged fragile site DNA" might be
looping back over the distant side of the fragile site and therefore
give a false "spanning" signal, particularly for probes that are
very close to or within the fragile site region. In addition, although
the use of pre-reassociation in the hybridization process dramatically
improved the signal to noise ratio, it did cause repeat-rich regions to
be poor hybridization probes. This was particularly evident in
the FRA16D region, where there is an abundance of DNA repeat
sequences of various kinds.5
The results of the FISH experiments are plotted in Fig. 4
. The closest
clearly proximal probe to FRA16D is 1–44, whereas the
closest unequivocally distal probe is 433. These probes map at a
distance of 200 kb apart. However, this 200-kb region includes
consistent scatter of distal signal around 1–38 and 1–27 and
the poor hybridization between 181 and 511 (due to repetitive DNA
content). Therefore, this 200-kb region defined by FISH analysis is
likely to be the maximum sequence required to define FRA16D,
rather than provide any evidence that the fragile site is spread
over such a distance.
Detection of Homozygous Deletion in Tumor Cell Lines.
The FRA3B fragile site FHIT gene intron 4 region
is a frequent site of deletion in various types of cancer
(7)
. Homozygous FRA3B deletions have been
detected in various human adenocarcinoma cell lines, including
(gastric) AGS and Kato III; (breast) MDA-MB436; and
(colon) LoVo, HT29, SW480, and LS180 (7)
. Because these
deletions are somatic events that presumably occur as a result of
exposure of these cells to certain environmental factors
(10)
, we chose to analyze tumor cell lines that exhibit
FRA3B deletions for the presence of homozygous deletion at
the FRA16D locus.
STSs that were either mapped to the FRA16D region
(Fig. 1)
7
or generated from partial sequence analysis through the region (data
not shown) were used to screen for homozygous deletion in various tumor
cell line DNAs. The STSs were duplexed with a PCR from the dystrophin
locus as an internal control. The results for the analysis of one of
the FRA16D region markers, STSG-10102, is shown in Fig. 5
.
Of the seven tumor cell lines tested, the stomach tumor cell line AGS
was found to be homozygously deleted at STSG-10102 and a series of
contiguous markers through the region (Table 1)
, thus suggesting the presence of minimal deletions spanning the
FRA16D region in each chromosome 16 present in the AGS cell
line.
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falls within the same interval (Alu20–178poly) as that
of the HCT116 colon adenocarcinoma cell line homozygous deletion
proximal boundary described by Paige et al.
(28)
. This is also the most likely location of
FRA16D (Fig. 2)
. The distal boundary of the AGS homozygous
deletion is within the same interval (IM7–IM9) of the PEO4 ovarian
adenocarcinoma cell line distal boundary (28)
. This
coincidence of breakpoint boundaries suggests the likelihood of a
common mechanism of deletion.
Detection of Heterozygous Deletion in AGS Tumor Cell Line DNA.
The maximal extent of heterozygous deletion in the AGS tumor cell line
in the FRA16D region was determined by genotyping
polymorphic markers. The markers D16S518 and
D16S3029 both gave two alleles indicating proximal and
distal outer limits to the deletion of either chromosome 16 in AGS
cells (Fig. 2A)
. The markers Afma336yg9 and 504CA
were uninformative and therefore did not aid in delineating the limits
of heterozygous deletion.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). The dysregulated
expression results in elevated c-MAF mRNA levels, which is
thought to contribute to neoplasia. These translocations were not
identified by conventional cytogenetic analysis. Their detected
frequency in multiple myeloma cell lines suggests an incidence of
25%.
Using representational difference analysis to identify differences
between the genomes of normal and tumor cells, the FRA16D
region has also been shown to be the site of homozygous deletion in
three different types (lung, ovary, and colon) of adenocarcinoma
(28)
. The commonly deleted region includes
FRA16D, with the minimal deletion in colon tumor cell line
corresponding almost exactly to the 200-kb region shown by our FISH
studies to span the FRA16D fragile site. If common
aphidicolin fragile sites confer susceptibility to mutagen induced DNA
instability in cancer, then tumor cell lines that have been shown to
have such instability at one fragile site are likely to exhibit
instability at another fragile site. By analyzing tumor cell lines with
known FRA3B deletions, we have found that the AGS cell line
derived from a stomach cancer exhibits homozygous deletion spanning
FRA16D. Heterozygosity of the flanking markers
D16S518 and D16S3029 indicates that the
chromosome 16 deletions are confined to the immediate vicinity of
FRA16D.
Taken together, these deletion data confirm the hypothesis that FRA16D is associated with specific chromosomal instability in cancer. Each of the common aphidicolin chromosomal fragile sites that have been analyzed in detail (FRA3B, FRA7G, and FRA16D) has been found to exhibit this association, supporting the hypothesis that this is a general property of this class of fragile site. There are an additional 75 such fragile sites in the human genome (31) , and presumably, these are also targets for DNA instability in cancer cells. Although found in all individuals, the different common fragile site loci are found at different frequencies in metaphase cells, with FRA3B being the most frequently observed, followed by FRA16D. The molecular basis for this variation is not yet known. It may be that cytogenetic expression is an indicator of the relative susceptibility of the region to DNA instability. Different individuals do exhibit variation in the level of common fragile site expression, and it will be intriguing to determine whether the level of cytogenetic expression in an individual correlates with the likelihood of that individual having DNA instability (such as deletion, amplification, or rearrangement) at a given common fragile site.
The mouse Fhit gene exhibits instability in mouse tumor cell lines (44) , similar to its human homologue, and it also spans a region known to contain a common, aphidicolin-inducible fragile site (45) . This apparent conservation of the relationship between the FHIT gene and a common fragile site during evolution suggests that there may be a functional association between regions of late DNA replication (defined by this class of fragile site) and a particular type of gene, the product of which has a role in coupling DNA replication and cell division (as has been proposed for FHIT; Refs. 46 and 47 ). FRA16D is of the same (common, aphidicolin-inducible) classification as FRA3B and FRA7G, and therefore, if the DNA instability at FRA3B and FRA7G really is a consequence of the sequences that cause this class of fragile site, then one would expect FRA16D to behave in a similar manner.
What, then, are the possible biological consequences of FRA16D deletion? Given that the observed deletions are homozygous, they are therefore likely to represent the loss of a negative function (e.g., tumor suppressor) rather than the gain of a tumor promoting function. If the analogy with the FRA3B locus holds, then a gene either spanning or at least partially within the FRA16D commonly deleted region may contribute to neoplasia as a consequence of quantitative and/or qualitative effects of the deletion. Alternatively, the proximity of the FRA16D deletions to the c-MAF gene suggests that they have the potential to affect c-MAF expression. The FRA3B fragile site is associated with a region of "late" replication (48) , as are the rare fragile sites FRAXA and FRAXE (49 , 50) . Assuming that replication timing is affected by proximity to fragile site loci and given the coupling of replication with transcription, the deletion of the FRA16D region may lead to an alteration in the timing, with respect to the cell cycle, of the expression of genes in the area, including c-MAF.
The present study adds further evidence to the proposal that DNA instability is a common property of common fragile site loci, and therefore, the issue of whether fragile sites have an active or passive role in the mutation process requires further investigation. For example, it is not clear whether cytogenetic manifestation of fragile sites in vivo is necessary to render the DNA in the region sensitive to either somatic or germ-line mutagenesis. The differential sensitivity of different tissues to FRA3B-associated deletion led Sozzi et al. (10) to suggest that sensitive tissues may be those at greatest exposure to environmental mutagens. Germ-line DNA breakage has been found to occur at the FRA11B-rare, folate-sensitive fragile site (51) . Because rare and common fragile sites appear to be due to different DNA sequences, this breakage would suggest that chromosome fragility does have a role to play in DNA instability rather than the instability being simply due to particular DNA sequences that different classes of fragile sites might have had in common. The identification of DNA sequences that are necessary and sufficient for common fragile site expression and the molecular mechanism(s) involved in their cytogenetic appearance will, we hope, lead to a greater understanding of the mutation process associated with fragile sites and the role of this process in neoplasia.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 This work was supported by grants from the
Anti-Cancer Foundation of the Universities of South Australia, the
Women’s and Children’s Hospital Research Foundation, and the National
Health and Medical Research Council of Australia. K. R. was supported
by a postdoctoral fellowship from Deutscher Akademischer Austausch
Dienst (Germany). 
2 These authors contributed equally to this work
and are listed alphabetically.
3 To whom requests for reprints should be
addressed. Phone: 618-8204-7111; Fax: 618-8204-7342; E-mail: rrichard{at}medicine.adelaide.edu.au
4 The abbreviations used are: LOH, loss of
heterozygosity; BAC, bacterial artificial chromosome; FISH,
fluorescence in situ hybridization; FHIT, fragile
histidine triad; STS, sequenced-tagged site; YAC, yeast
artificial chromosome.
5 K. Ried et al., manuscript
in preparation.
6 O. Handt, personal communication.
7 V. Watson, personal communication.
Received 8/ 2/99. Accepted 1/19/00.
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