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Howard Hughes Medical Institute [B. V.], Johns Hopkins Oncology Center [I-M. S., W. Z., S. N. G., C. L., K. W. K., B. V.], and Department of Pathology [I-M. S.], Johns Hopkins Medical Institutions, Baltimore, Maryland 21231
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ABSTRACT |
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Introduction |
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13% of CRCs, mismatch repair deficiency leads to MIN,
characterized by widespread insertions and deletions in microsatellite
repeats and associated with numerous nucleotide substitutions (4
, 5)
. In the remaining 87% of CRCs, CIN appears to result in a
large number of gross chromosomal changes. Although the biochemical
mechanisms underlying MIN are well known, the mechanisms underlying CIN
are only beginning to emerge (3
, 6)
. If genetic instability is essential to human neoplasia, one might expect it to begin early during the tumorigenic process and thereby accelerate the acquisition of growth-promoting mutations. Evidence has been presented that MIN often occurs very early, prior to the occurrence of the APC gene mutations that initiate the abnormal growth phase (7) . On the other hand, the timing of CIN is uncertain. Although most CRCs are aneuploid (suggesting CIN), the prevalence of aneuploidy in benign colorectal tumors is less than in cancers and appears to increase as the tumors enlarge in size (8, 9, 10, 11, 12) . Virtually all adenomas that have been studied through karyotypic or flow cytometric methods have been rather large, containing billions of cells, and there have been few karyotypic or molecular studies focused on very small benign tumors. The choice of tumors studied previously has been dictated by the fact that small benign tumors have relatively few neoplastic cells and a higher fraction of stromal cells, presenting significant experimental obstacles.
To address the question posed above, we have studied a series of colorectal adenomas averaging 2 mm in diameter. AI, reflecting gains or losses of particular chromosomal regions, was used as a marker for CIN. To overcome the obstacles associated with the molecular genetic analysis of these small tumors, we used a recently developed PCR-based approach called digital SNP analysis, in which the alleles within a tumor sample are individually counted, one by one (13 , 14) . Using this method, we found a remarkably high degree of AI in small tumors, strongly suggesting that CIN occurs early during colorectal tumorigenesis.
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Materials and Methods |
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Digital PCR Analysis.
SNP markers on chromosomes 1p, 8p, 15q, and 18q were retrieved from the
Whitehead human SNP
database4
and National Cancer Institute SNP
map.5
The SNP markers within the APC gene on chromosome 5q were
based on common polymorphisms reported previously (15)
.
Forward and reverse primers were designed for each SNP, allowing the
amplification of 100-bp PCR products (Table 1)
. Molecular Beacons (16
, 17)
were designed for each of
these 24 polymorphisms. For each case, DNA from normal mucosa was first
tested for heterozygosity for SNP markers on all five chromosomes. For
each chromosome, one SNP that exhibited heterozygosity in the normal
sample was then used to assess AI in DNA from the corresponding tumor.
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. Microdissection is therefore mandatory to derive a population that is
enriched in the neoplastic cell component. But analysis of the
microdissected samples with genetic markers is associated with its own
set of problems. To overcome such problems, we have used a technique
called digital SNP, in which alleles are directly counted, one by one
(14)
. Because SNPs rather than microsatellite markers are
used with this method, DNA degradation of the larger microsatellite
alleles does not pose a problem (19)
. However, because
only limited amounts of DNA are purified from microdissected lesions,
sampling errors can produce artifactual enrichments for one allele when
conventional AI assays are used, even with SNPs. For example, if only a
few template molecules are successfully amplified in the PCR, one
allele may be overrepresented by chance alone. Digital SNP minimizes
such sampling errors, because the exact number of alleles evaluated in
each assay is determined. Rigorous statistical methods are then used to
conclude whether AI is present.
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. DNA from normal and microdissected tumor samples was diluted in a
384-well PCR plate so that there was <1 DNA template/well. PCR was
performed using a SNP for which the patient was heterozygous. The
resultant PCR products were analyzed using Molecular Beacon probes to
determine allelic representation. In the DNA sample from normal colonic
mucosae of the patient depicted in Fig. 2
A, there were 29
"A" alleles (red; detected with a Hex-labeled Molecular
Beacon) and 34 "G" alleles (green; detected with a
fluorescein-labeled Molecular Beacon). In the sample from the small
adenoma of this patient, there were 33 "A" alleles and
11 "G" alleles (Fig. 2A)
.
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. For example, if only 50% of the DNA from the
microdissected samples originated from neoplastic cells and the other
50% originated from nonneoplastic cells, the observed allelic
proportion would be 66.7%, not 100%. SPRT curves were therefore
constructed to choose between the hypotheses P = 50% and P = 66.7%, using the
conservative assumption that at least 50% of the DNA in the sample was
derived from neoplastic cells. The two curves representing these two
assumptions are depicted in Fig. 2B
. The number of alleles
studied in each sample is plotted on the abscissa, and the observed
ratio of the two alleles is plotted on the ordinate. The
ratio is defined as the number of wells containing the allele that
appeared to be in excess to the total number of wells containing either
allele. Samples represented by points above curve 1 were interpreted to
have AI. It is important to note that the confidence interval of each
point above curve 1 excludes allelic proportion values that are
expected to occur in normal cells (14
, 18)
. Points below
the bottom curve were categorized as being in allelic balance. In
the example shown in Fig. 2
B, the allelic
proportion of DNA from the normal colonic mucosae was below curve 2 and
was therefore interpreted as being in allelic balance. In contrast, the
allelic proportion in the DNA from the adenoma was above curve 1, and
this tumor was interpreted to have AI.
AI in Small Adenomas.
We selected 32 adenomas with an average diameter of 2 mm (range, 1–3
mm) for this study (Fig. 1)
. Neoplastic cells from these adenomas were
carefully microdissected with the contamination from nonneoplastic
cells estimated at 30–60% by histological examination. DNA was
purified from the microdissected tissue and used as template for
digital SNP analysis. Five different chromosomal arms were evaluated
for AI. For each chromosomal arm, we developed Molecular Beacon pairs
that reliably distinguished paternal from maternal alleles. The
sequences of the relevant primers and Molecular Beacons for the 24
different SNPs studied are detailed in Table 1
. Using these 24 markers,
we were able to find at least one heterozygous SNP for each chromosomal
arm in the great majority of patients studied.
All of the normal mucosa samples analyzed were found to be in allelic
balance, because their allelic proportions were below curve 2 (data not
shown). Scatterplots of the data from the tumors are shown in Fig. 3
and summarized in Fig. 4
. Among the informative cases, the percentages of samples exhibiting AI
of chromosomes 1p, 5q, 8p, 15q, and 18q were 10, 55, 19, 28, and 28%,
respectively. There was no significant correlation between AI and the
site of adenomas or the age and sex of patients. Over 90% of the
adenomas exhibited AI of at least one chromosomal arm. When chromosome
5q was excluded from analysis, 66% of the adenomas exhibited AI of at
least one of the other chromosomal arms. There was no obvious
clustering of the AI in the tumors (Fig. 4)
.
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Although the above represents our preferred interpretation, several alternative interpretations should be pointed out:
(a) We have studied tumors at a single time point. Although our data are consistent with the existence of a true instability (which can only be measured through a time course, not through a single determination), other scenarios are conceivable. For example, it is possible that one abnormal division occurred during the tumorigenic process, leading to AI at multiple loci, and that there was no persistent chromosomal instability in these lesions. We cannot infer from our static observations any quantitative estimate of the rate of chromosomal loss and can only state that the AI we observed is consistent with a chromosomal instability such as that formally demonstrated in CRC cell lines in vitro (21) .
(b) A second proviso concerns the term "early." The
selected adenomas were the smallest tumors generally noted during
pathological examination of surgically excised tissues and were also
the smallest from which we could reproducibly obtain a sufficient
number of alleles for analysis with several probes. However, these
2-mm adenomas contain 1 x 106 neoplastic cells, and the term "early" is
a relative one. On the basis of clinical studies, it would likely take
10–30 years for these tiny adenomas to progress to malignancy
(22)
, and it therefore is legitimate to label them
"early."
How do our results compare with previous molecular studies of AI? Although allelic imbalances of chromosome 5q were expected (15 , 23 , 24) , the other AIs were surprising. For example, loss of heterozygosity of chromosomes 1p, 8p, 15q, and 18q have previously been observed rarely in adenomas, even in large ones (23 , 25, 26, 27, 28) . There are two factors that might reconcile these observations: (a) the digital SNP method we used is more sensitive than previous methods to detect allelic loss. Some of the AIs we observed might have been present in only 50% of the neoplastic cells, for example, and standard techniques would not have detected them. Digital SNP reliably discerns AI but cannot distinguish (for example) whether this AI is attributable to allelic loss in 100% of the neoplastic cells in a specimen composed of 50% nonneoplastic cells versus allelic loss in 60% of the neoplastic cells in a specimen composed of 80% neoplastic cells. We therefore might be observing losses in major subpopulations of neoplastic cells that only become completely clonal at later stages of tumorigenesis. Such progression has been observed previously in colon and other tumors (24 , 29 , 30) . Additionally, our analysis does not distinguish between chromosome gains and chromosome losses as the cause of the AI. Previous studies that concentrated on loss of heterozygosity might not have detected chromosome gains. From a CIN (rather than functional) point of view, chromosome gains and losses are equally important and indicative of instability (3) . It is also noteworthy that the chromosomes we analyzed harbor tumor suppressor genes, and losses of such chromosomes may result in a selective growth advantage. Whether such losses confer a selective advantage, or are simply random, does not affect the data or conclusions of this study.
Previous cytogenetic and flow cytometric studies of colorectal
neoplasms are in general consistence with our observations, although
there have been very few examinations of colorectal tumors as small as
those studied here. There have been several reports of aneuploidy in
larger adenomas, with the suggestion that aneuploidy increases with
tumor progression (8, 9, 10, 11, 12)
. Accordingly, our study showed
that AI in adenomas (Fig. 4)
is much less common than that in cancers
studied previously. Indeed, it is not uncommon to observe AI in over
one-third of the total chromosomes in primary tumors (30)
,
and chromosomes 1p, 8p, and 18q exhibit allelic losses in a much higher
proportion of cancers (14
, 23 , 31
, 32)
than in small
adenomas (Fig. 4)
. If CIN began early, one would expect to see
increasing degrees of aneuploidy as tumors enlarged, because of
repeated rounds of clonal selection.
Our observations and conclusions are also consistent with those made on the early stages of other tumor types. For example, AI has been found in metaplastic lesions associated with gastric carcinoma (33) , in intraepithelial neoplasia of the vulva (34) , in dysplastic esophageal epithelium in Barrett’s esophagus (35) , and in fibrocystic changes of breast (36) . Although the temporal relationship between such lesions and cancer is less well defined than in colorectal tumorigenesis, such studies support the idea that CIN is an early component of human neoplasia in general.
It is interesting to speculate whether CIN precedes the advent of APC gene mutations. Studies in mice, as well as in humans, have shown that APC inactivation occurs very early during the neoplastic process (reviewed in Ref. 37 ). In many cases, this inactivation involves mutation of one allele and loss of the other. Such inactivations could occur in two ways. A mutation in one APC allele could occur first, followed by a loss of the second allele, or vice versa. In either case, the allelic loss event could be precipitated by CIN, although occasional allelic losses also occur in normal cells that are chromosomally stable (38, 39, 40) . As a working hypothesis, we propose that CIN drives the allelic loss of chromosome 5 in some cases and that CIN may already be present in a proportion of the tiny neoplastic lesions containing APC mutations. This hypothesis can only be convincingly refuted or confirmed once the mechanism(s) underlying CIN is identified.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 This work was supported by the Clayton Fund, the
V Foundation, and NIH Grants CA43460, CA 57345, and CA62924. 
2 To whom requests for reprints should be
addressed, at Johns Hopkins Oncology Center, 1650 Orleans Street,
Baltimore, MD 21231. E-mail: vogelbe{at}welch.jhu.edu
3 The abbreviations used are: CRC, colorectal
cancer; MIN, microsatellite instability; CIN, chromosomal instability;
SNP, single-nucleotide polymorphism; AI, allelic imbalance; APC,
adenomatous polyposis coli; SPRT, sequential probability ratio test.
4 Internet address:
http://www.genome.wi.mit.edu/SNP/human/index.html.
5 Internet address:
http://lpg.nci.nih.gov/html-snp/imagemaps.html.
4 W. Zhou, G. Galizia, S. Goodman, K. Romans, E. Lieto, K. W. Kinzler, B. Vogelstein, M. Choti, and E. Montgomery, unpublished observations.
Received 10/12/00. Accepted 12/13/00.
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L. Luo, B. Li, and T. P. Pretlow DNA Alterations in Human Aberrant Crypt Foci and Colon Cancers by Random Primed Polymerase Chain Reaction Cancer Res., October 1, 2003; 63(19): 6166 - 6169. [Abstract] [Full Text] [PDF]
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R. A. Gatenby and T. L. Vincent An Evolutionary Model Of Carcinogenesis Cancer Res., October 1, 2003; 63(19): 6212 - 6220. [Abstract] [Full Text] [PDF]
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C. A. French, E. K. Alexander, E. S. Cibas, V. Nose, J. Laguette, W. Faquin, J. Garber, F. Moore Jr, J. A. Fletcher, P. R. Larsen, et al. Genetic and Biological Subgroups of Low-Stage Follicular Thyroid Cancer Am. J. Pathol., April 1, 2003; 162(4): 1053 - 1060. [Abstract] [Full Text] [PDF]
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O. M. Sieber, K. Heinimann, P. Gorman, H. Lamlum, M. Crabtree, C. A. Simpson, D. Davies, K. Neale, S. V. Hodgson, R. R. Roylance, et al. Analysis of chromosomal instability in human colorectal adenomas with two mutational hits at APC PNAS, December 24, 2002; 99(26): 16910 - 16915. [Abstract] [Full Text] [PDF]
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M. A. Nowak, N. L. Komarova, A. Sengupta, P. V. Jallepalli, I.-M. Shih, B. Vogelstein, and C. Lengauer The role of chromosomal instability in tumor initiation PNAS, December 10, 2002; 99(25): 16226 - 16231. [Abstract] [Full Text] [PDF]
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 H.-W. Chang, S. M. Lee, S. N. Goodman, G. Singer, S. K. R. Cho, L. J. Sokoll, F. J. Montz, R. Roden, Z. Zhang, D. W. Chan, et al. Assessment of Plasma DNA Levels, Allelic Imbalance, and CA 125 as Diagnostic Tests for Cancer J Natl Cancer Inst, November 20, 2002; 94(22): 1697 - 1703. [Abstract] [Full Text] [PDF]
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A. K. Meeker, J. L. Hicks, E. A. Platz, G. E. March, C. J. Bennett, M. J. Delannoy, and A. M. De Marzo Telomere Shortening Is an Early Somatic DNA Alteration in Human Prostate Tumorigenesis Cancer Res., November 15, 2002; 62(22): 6405 - 6409. [Abstract] [Full Text] [PDF]
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E. G. Luebeck and S. H. Moolgavkar Multistage carcinogenesis and the incidence of colorectal cancer PNAS, November 12, 2002; 99(23): 15095 - 15100. [Abstract] [Full Text] [PDF]
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H. Rubin and G. R. Anderson Correspondence re: G. Anderson et al., Intrachromosomal Genomic Instability in Human Sporadic Colorectal Cancer Measured by Genome-Wide Allelotyping and Inter-(Simple Sequence Repeat) PCR. Cancer Res., 61: 8274-8283, 2001. Cancer Res., November 1, 2002; 62(21): 6350 - 6351. [Full Text] [PDF]
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N. T. van Heek, A. K. Meeker, S. E. Kern, C. J. Yeo, K. D. Lillemoe, J. L. Cameron, G. J. A. Offerhaus, J. L. Hicks, R. E. Wilentz, M. G. Goggins, et al. Telomere Shortening Is Nearly Universal in Pancreatic Intraepithelial Neoplasia Am. J. Pathol., November 1, 2002; 161(5): 1541 - 1547. [Abstract] [Full Text] [PDF]
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H.-W. Chang, C.-Y. Yen, S.-Y. Liu, G. Singer, and I.-M. Shih Genotype Analysis Using Human Hair Shaft Cancer Epidemiol. Biomarkers Prev., September 1, 2002; 11(9): 925 - 929. [Abstract] [Full Text] [PDF]
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R. J. Oldt III, R. J. Kurman, and I.-M. Shih Molecular Genetic Analysis of Placental Site Trophoblastic Tumors and Epithelioid Trophoblastic Tumors Confirms Their Trophoblastic Origin Am. J. Pathol., September 1, 2002; 161(3): 1033 - 1037. [Abstract] [Full Text] [PDF]
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 B. W. Kirk, M. Feinsod, R. Favis, R. M. Kliman, and F. Barany Single nucleotide polymorphism seeking long term association with complex disease Nucleic Acids Res., August 1, 2002; 30(15): 3295 - 3311. [Abstract] [Full Text] [PDF]
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H.-W. Chang, S. Z. Ali, S. K. R. Cho, R. J. Kurman, and I.-M. Shih Detection of Allelic Imbalance in Ascitic Supernatant by Digital Single Nucleotide Polymorphism Analysis Clin. Cancer Res., August 1, 2002; 8(8): 2580 - 2585. [Abstract] [Full Text] [PDF]
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K. M. Haigis, J. G. Caya, M. Reichelderfer, and W. F. Dove Intestinal adenomas can develop with a stable karyotype and stable microsatellites PNAS, June 25, 2002; 99(13): 8927 - 8931. [Abstract] [Full Text] [PDF]
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A. Fabarius, A. Willer, G. Yerganian, R. Hehlmann, and P. Duesberg Specific aneusomies in Chinese hamster cells at different stages of neoplastic transformation, initiated by nitrosomethylurea PNAS, May 14, 2002; 99(10): 6778 - 6783. [Abstract] [Full Text] [PDF]
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G. Singer, R. J. Kurman, H.-W. Chang, S. K.R. Cho, and I.-M. Shih Diverse Tumorigenic Pathways in Ovarian Serous Carcinoma Am. J. Pathol., April 1, 2002; 160(4): 1223 - 1228. [Abstract] [Full Text] [PDF]
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M. M. Huycke, V. Abrams, and D. R. Moore Enterococcus faecalis produces extracellular superoxide and hydrogen peroxide that damages colonic epithelial cell DNA Carcinogenesis, March 1, 2002; 23(3): 529 - 536. [Abstract] [Full Text] [PDF]
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W.-Q. Ding, S. M. Kuntz, and L. J. Miller A Misspliced Form of the Cholecystokinin-B/Gastrin Receptor in Pancreatic Carcinoma: Role of Reduced Cellular U2AF35 and a Suboptimal 3'-Splicing Site Leading to Retention of the Fourth Intron Cancer Res., February 1, 2002; 62(3): 947 - 952. [Abstract] [Full Text] [PDF]
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F. Bunz, C. Fauth, M. R. Speicher, A. Dutriaux, J. M. Sedivy, K. W. Kinzler, B. Vogelstein, and C. Lengauer Targeted Inactivation of p53 in Human Cells Does Not Result in Aneuploidy Cancer Res., February 1, 2002; 62(4): 1129 - 1133. [Abstract] [Full Text] [PDF]
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C. Lengauer How do tumors make ends meet? PNAS, October 23, 2001; 98(22): 12331 - 12333. [Full Text] [PDF]
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 M. Chicurel Dangerous Liaisons Sci. Aging Knowl. Environ., October 3, 2001; 2001(1): oa3 - 3. [Abstract] [Full Text] [PDF]
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I.-M. Shih, T.-L. Wang, G. Traverso, K. Romans, S. R. Hamilton, S. Ben-Sasson, K. W. Kinzler, and B. Vogelstein Top-down morphogenesis of colorectal tumors PNAS, February 15, 2001; (2001) 51629398. [Abstract] [Full Text]
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I.-M. Shih, T.-L. Wang, G. Traverso, K. Romans, S. R. Hamilton, S. Ben-Sasson, K. W. Kinzler, and B. Vogelstein Top-down morphogenesis of colorectal tumors PNAS, February 27, 2001; 98(5): 2640 - 2645. [Abstract] [Full Text] [PDF]
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, chromosome arms in
which AI was identified through digital SNP; 
, chromosome arms in
which both alleles were in balance; 
, chromosome arms that could not
be evaluated because all SNP markers tested were uninformative in the
normal mucosae or because the allelic ratio in SPRT analysis did not
fall above curve 1 or below curve 2.