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Figure 1.
Array-based comparative genomic hybridization of colorectal, papillary thyroid, and anaplastic thyroid carcinomas. Comparative genomic hybridization did not reveal gains or losses in indolent papillary thyroid carcinomas, while aggressive colorectal cancers and anaplastic cancer exhibited significant copy number aberrations. Chromosome position is shown on the x-axis; the vertical line indicates the position of the centromere. Representative results for chromosomes 7 (chr7) and 8 (chr8) are shown.

Array-based comparative genomic hybridization of colorectal, papillary thyroid, and anaplastic thyroid carcinomas. Comparative genomic hybridization did not reveal gains or losses in indolent papillary thyroid carcinomas, while aggressive colorectal cancers and anaplastic cancer exhibited significant copy number aberrations. Chromosome position is shown on the x-axis; the vertical line indicates the position of the centromere. Representative results for chromosomes 7 (chr7) and 8 (chr8) are shown.

Figure 2.
Spectral karyotypes of papillary and colorectal carcinomas. A, Papillary carcinoma: a representative karyotype of a papillary thyroid carcinoma cell. No changes in chromosome number or structure were detected in the metaphases examined from 7 tumors. B, Colorectal carcinoma: translocations detected in several metaphases from a single colon carcinoma. Each block shows a translocation(s) from an individual cell and demonstrates the extensive large-scale genomic instability and substantial intratumoral heterogeneity that typifies these tumors.

Spectral karyotypes of papillary and colorectal carcinomas. A, Papillary carcinoma: a representative karyotype of a papillary thyroid carcinoma cell. No changes in chromosome number or structure were detected in the metaphases examined from 7 tumors. B, Colorectal carcinoma: translocations detected in several metaphases from a single colon carcinoma. Each block shows a translocation(s) from an individual cell and demonstrates the extensive large-scale genomic instability and substantial intratumoral heterogeneity that typifies these tumors.

Figure 3.
Evolution of aggressive tumors is aided by multiple forms of genomic instability. Multiple forms of genomic instability arise sequentially during tumor progression. Early events, detected by inter–simple sequence repeat polymerase chain reaction, are copious but small. Many mutations remain silent and evolution to relatively “benign” neoplasms is enabled. Later events, detected by allelotyping, array-based comparative genomic hybridization, or spectral karyotyping, are larger and unmask previously silent mutations. Selection for aggressive disease occurs.

Evolution of aggressive tumors is aided by multiple forms of genomic instability. Multiple forms of genomic instability arise sequentially during tumor progression. Early events, detected by inter–simple sequence repeat polymerase chain reaction, are copious but small. Many mutations remain silent and evolution to relatively “benign” neoplasms is enabled. Later events, detected by allelotyping, array-based comparative genomic hybridization, or spectral karyotyping, are larger and unmask previously silent mutations. Selection for aggressive disease occurs.

Table 1. 
Loss of Heterozygosity by Marker andTumor in Papillary Thyroid Cancer
Loss of Heterozygosity by Marker andTumor in Papillary Thyroid Cancer
Table 2. 
Genomic Instability Profiles of Thyroid and Colorectal Neoplasms
Genomic Instability Profiles of Thyroid and Colorectal Neoplasms
1.
Anderson  GRBrenner  BMSwede  H Intrachromosomal genomic instability in human sporadic colorectal cancer measured by genome-wide allelotyping and inter-(simple sequence repeat) PCR. Cancer Res 2001;618274- 8283
PubMed
2.
Bartos  JDStoler  DLMatsui  S Genomic heterogeneity and instability in colorectal cancer: spectral karyotyping, glutathione transferase-Ml and ras. Mutat Res 2004;568283- 292
PubMedArticle
3.
Swede  HBartos  JDChen  N Genomic profiles of colorectal cancers differ based on patient smoking status. Cancer Genet Cytogenet 2006;16898- 104
PubMedArticle
4.
American Cancer Society Cancer Facts & Figures 2006.  Atlanta, Ga: American Cancer Society; 2006. http://www.cancer.org/downloads/STT/CAFF2006PWSecured.pdf. Accessed July 6, 2006
5.
Are  CShaha  AR Anaplastic thyroid carcinoma: biology, pathogenesis, prognostic factors, and treatment approaches. Ann Surg Oncol 2006;13453- 464
PubMedArticle
6.
Wiseman  SMLoree  TRHicks  WL  Jr Anaplastic thyroid cancer evolved from papillary carcinoma: demonstration of anaplastic transformation utilizing the inter-simple sequence repeat polymerase chain reaction. Arch Otolaryngol Head Neck Surg 2003;12996- 100
PubMedArticle
7.
Basik  MStoler  DLKontzoglou  KCRodriguez-Bigas  MAPetrelli  NJAnderson  GR Genomic instability in sporadic colorectal cancer quantitated by inter-(simple sequence repeat) PCR analysis. Genes Chromosomes Cancer 1997;1819- 29
PubMedArticle
8.
Stoler  DLChen  NBasik  M The onset and extent of genomic instability in sporadic colorectal tumor progression. Proc Natl Acad Sci U S A 1999;9615121- 15126
PubMedArticle
9.
Stoler  DLDatta  RVCharles  MA  et al.  Genomic instability measurement in the diagnosis of thyroid neoplasms. Head Neck 2002;24290- 295
PubMedArticle
10.
Wiseman  SMLoree  TRRigual  NR Papillary thyroid cancer: high inter-(simple sequence repeat) genomic instability in a typically indolent cancer. Head Neck 2003;25825- 832
PubMedArticle
11.
Cowell  JKNowak  NJ High resolution analysis of genetic events in cancer cells using BAC array and comparative genomic hybridization. Adv Cancer Res 2003;9091- 125
PubMed
12.
Matsui  SFaitar  SLRossi  MRCowell  JK Application of spectral karyotyping to the analysis of the human chromosome complement of interspecies somatic cell hybrids. Cancer Genet Cytogenet 2003;14230- 35
PubMedArticle
13.
Hundahl  SAFleming  IDFremgen  AM A National Cancer Data Base report on 53,856 cases of thyroid carcinoma treated in the US, 1985-1995. Cancer 1998;832638- 2648
PubMedArticle
14.
Alrawi  SJCarroll  REHill  HC Genomic instability of human aberrant crypt foci: inter-SSR PCR and aCGH. Mutat Res 2006;60130- 38
PubMedArticle
15.
Chen  NStoler  DLJahreis  JPAnderson  GR Analysis of inter-(simple sequence repeat) PCR products from human colorectal cancers. Oncol Res 2005;15233- 238
16.
Kitamura  YShimizu  KTanaka  SIto  KEmi  M Allelotyping of anaplastic thyroid carcinoma: frequent allelic losses on 1q, 9p, 11, 17, 19p, and 22q. Genes Chromosomes Cancer 2000;27244- 251
PubMedArticle
17.
Ward  LSBrenta  GMedvedovic  MFagin  JA Studies of allelic loss in thyroid tumors reveal major differences in chromosomal instability between papillary and follicular carcinomas. J Clin Endocrinol Metab 1998;83525- 530
PubMed
18.
Vogelstein  BFearon  ERKern  SE Allelotype of colorectal carcinomas. Science 1989;244207- 211
PubMedArticle
19.
Califano  JAJohns  MM  IIIWestra  WH An allelotype of papillary thyroid cancer. Int J Cancer 1996;69442- 444
PubMedArticle
20.
Bauer  AJCavalli  LRRone  JD Evaluation of adult papillary thyroid carcinomas by comparative genomic hybridization and microsatellite instability analysis. Cancer Genet Cytogenet 2002;135182- 186
PubMedArticle
21.
Wreesmann  VBGhossein  RAPatel  SG Genome-wide appraisal of thyroid cancer progression. Am J Pathol 2002;1611549- 1556
PubMedArticle
22.
Wreesmann  VBGhossein  RAHezel  M Follicular variant of papillary thyroid carcinoma: genome-wide appraisal of a controversial entity. Genes Chromosomes Cancer 2004;40355- 364
PubMedArticle
23.
Miura  DWada  NChin  K Anaplastic thyroid cancer: cytogenetic patterns by comparative genomic hybridization. Thyroid 2003;13283- 290
PubMedArticle
24.
Wilkens  LBenten  DTchinda  J Aberrations of chromosomes 5 and 8 as recurrent cytogenetic events in anaplastic carcinoma of the thyroid as detected by fluorescence in situ hybridisation and comparative genomic hybridization. Virchows Arch 2000;436312- 318
PubMedArticle
25.
Foukakis  TThoppe  SRLagercrantz  S Molecular cytogenetic characterization of primary cultures and established cell lines from non-medullary thyroid tumors. Int J Oncol 2005;26141- 149
PubMed
Original Article
May 2007

Comparative Genomic Instabilities of Thyroid and Colon Cancers

Author Affiliations

Author Affiliations: Departments of Head and Neck Surgery (Drs Stoler, Loree, Rigual, and Hicks), Pathology (Dr Stoler), Cancer Prevention (Dr Nowak), Cancer Genetics (Dr Matsui), Cancer Biology (Drs Dutt and Anderson), Clinical Cytogenetics (Dr Sait), and Surgical Oncology (Dr Anderson), Roswell Park Cancer Institute, Buffalo, NY; Department of Surgery, St Paul's Hospital, Vancouver, British Columbia (Dr Wiseman); Department of Dermatology, Stanford University School of Medicine, Stanford, Calif (Dr Chen); and Department of Biochemistry and Biophysics, University of Rochester School of Medicine and Dentistry, Rochester, NY (Dr Bartos).

Arch Otolaryngol Head Neck Surg. 2007;133(5):457-463. doi:10.1001/archotol.133.5.457
Abstract

Objectives  To assess the forms and extent of genomic instability in thyroid cancers and colorectal neoplasms and to determine if such measurements could explain the generally excellent prognosis of thyroid malignant neoplasms compared with colon carcinoma.

Design  Tumor genome analyses. Genomic instability was measured by the following 4 methods, listed in ascending order based on the size of events detected: inter–simple sequence repeat polymerase chain reaction (ISSR-PCR), fractional allelic loss (FAL) analysis, array-based comparative genomic hybridization (aCGH), and spectral karyotyping (SKY).

Results  The genomic instability index of 32 thyroid carcinomas, 59 colon carcinomas, and 11 colon polyps was determined by ISSR-PCR; no difference was seen among the 3 groups by this method. Fractional allelic loss rates were comparable in thyroid cancers and colon polyps and lower than FAL rates in colorectal cancers. Indolent papillary thyroid carcinomas were essentially diploid with no large-scale alterations in chromosome number or structure when evaluated by aCGH or SKY. In anaplastic thyroid cancers, aCGH revealed abundant chromosome alterations. Colorectal carcinomas showed extensive copy number changes and chromosomal rearrangements when analyzed by aCGH and SKY.

Conclusions  Genomic alterations in papillary thyroid carcinoma, such as in benign colon polyps, are principally smaller events detected by ISSR-PCR. With the more aggressive tumor types (ie, anaplastic thyroid and colorectal carcinomas), larger events detected by FAL analysis, aCGH, and SKY were revealed. We hypothesize that mutations caused by smaller genomic alterations enable thyroid cells to achieve a minimal malignant phenotype. Mutations for aggressive biological behavior appear with larger genomic events.

Cancer represents the consequence of somatic evolution, with natural selection of advantageous genomic alterations. This rapid evolution may result from an increased rate of mutation (genomic instability) or from epigenetic events. In either case, tightly controlled cellular processes are dysregulated to bring about the malignant phenotype. Genomic instability has emerged as a key underlying process in the evolution of normal cells to malignant masses, enabling both tumorigenesis and tumor heterogeneity. Previous analyses of colorectal tumors using varied methods have revealed that several independent forms of genomic instability are detectable in these tumors.13 The genomic damage detected by these different techniques range in size from the whole chromosomal, through subchromosomal events, to single base-pair alterations.

The American Cancer Society estimates that the incidence of thyroid cancer in 2006 will be about 30 000 new cases, with an estimated mortality of only 1500 individuals.4 Thyroid cancer encompasses a broad spectrum of histologic types, ranging from well-differentiated papillary and follicular carcinomas to undifferentiated anaplastic tumors. While papillary thyroid tumors, representing the majority of these endocrine cancers, tend to be indolent and associated with excellent long-term patient survival, very rare anaplastic tumors are highly aggressive and patient survival is generally less than a year after diagnosis.5 It has been hypothesized that anaplastic thyroid tumors are the product of continued evolution of well-differentiated carcinomas based on the coexistence of anaplastic and well-differentiated tissues within a single tumor.5,6

In contrast to thyroid cancer, colorectal carcinoma is a far more prevalent and far more aggressive disease. Cancer of the colon or rectum is the fourth most common cancer in the United States, with an estimated 148 000 new cases and 55 000 deaths in 2006.4 The majority of these colorectal cancers will have progressed through a benign polyp stage before achieving malignancy.

In an effort to determine the molecular basis for their very different biological behavior, we compared the patterns of genomic instability previously reported for colorectal carcinoma2,7,8 with those of thyroid cancers. Genomic instability was detected by bacterial artifical chromosome (BAC) array-based comparative genomic hybridization (aCGH), spectral karyotyping (SKY), loss of heterozygosity (LOH), and inter–simple sequence repeat polymerase chain reaction (ISSR-PCR) analyses. Genomic instability as measured by ISSR-PCR has been previously reported.9,10

METHODS
PATIENTS, TUMOR SPECIMENS, AND DNA PREPARATION

The 2 study populations, 59 patients with colorectal cancer and 33 patients with thyroid cancer, are described in detail elsewhere.7,10 Specimens were procured under the supervision of the institutional review board of the Roswell Park Cancer Institute, Buffalo, NY, and informed consent for participation in this study was obtained from all patients preoperatively. Histologically normal and tumor tissue from the same patient were procured immediately after surgery. Hematoxylin-eosin–stained sections of paraffin-embedded, neutral-buffered, formalin-fixed (10% formalin by volume in water; pH 7.4) specimens were reviewed by a pathologist to confirm the histologic features of the procured tissue. The tumor and normal tissue were either cultured, as described in the “Spectral Karyotyping” subsection, or stored at −70oC for subsequent DNA extraction for all other genomic assays. DNA extraction from the frozen tumor and normal tissue specimens was carried out as previously described.7

INTER–SIMPLE SEQUENCE REPEAT PCR

The ISSR-PCR analyses were performed as previously described.7,9 Genomic instability index is the percentage of altered PCR products amplified from an individual's tumor DNA compared with the PCR products of that individual's normal DNA. This method detects alterations that have occurred in normal sequences between 2 microsatellites and is totally distinct from microsatellite instability.1,7

LOH ASSAYS

The LOH assays were performed on 26 papillary thyroid cancers as previously described.1 Primers for all 22 autosomes are listed in Table 1. Fractional allelic loss (FAL) was calculated by determining the total fraction of all informative markers for a tumor DNA that showed LOH.1

BAC ARRAY-BASED CGH

The details of BAC aCGH were as previously described by Cowell and Nowak.11 Briefly, DNA isolated from tumor tissues and a sex-mismatched pool of 15 normal DNA samples were separately labeled with either Cy3 or Cy5 fluorescent tags, mixed, and competitively hybridized to an array of over 6500 immobilized BAC clone targets. The ratio of red (Cy5) to green (Cy3) signal was quantified and plotted graphically to reveal amplifications and deletions within the tumor genome. Array-based CGH was performed on 16 papillary thyroid carcinomas and 4 anaplastic thyroid carcinomas.

SPECTRAL KARYOTYPING

Short-term primary cultures of 7 papillary thyroid carcinomas were established according to the method of Matsui et al.12 Metaphase chromosome preparations were prepared using standard hypotonic treatment and air-drying methods. Chromosomes were sequentially digested with ribonuclease (RNase) and pepsin, as recommended by Applied Spectral Imaging, Carlsbad, Calif, and then denatured in 70% formamide. Human SKY probes representing a mixture of individual chromosome DNA samples were hybridized to the metaphase preparations. Following in situ hybridization and developing chromosome-specific fluorescence spectra with rhodamine, Texas red, Cy5, Cy5.5, and fluorescence isothiocyanate, SKY images were captured using interferometer-based spectral imaging, and karyotypes were prepared using the SKYView software (version 1.62). At least 10 metaphases were examined for each tumor specimen.

RESULTS

Papillary thyroid cancer exhibits moderate clinical behavior compared with other malignant neoplasms such as colorectal carcinoma or anaplastic thyroid cancer; 10-year survival occurs in greater than 90% of patients with a diagnosis of having cancer.13 We investigated if the basis of this difference in clinical behavior might be attributed to the types or degree of genomic instability detected in these tumors. In several previous studies, we have used the genome sampling technique of ISSR-PCR to quantify one form of genomic instability in benign and malignant thyroid lesions and colorectal cancers and polyps.7,8 In addition, we have examined other forms of genomic instability in colorectal neoplasms using allelotyping, BAC aCGH, and/or SKY.13 We have applied the latter 3 techniques to thyroid cancers and compared the types of genomic instabilities detected in indolent papillary thyroid cancer with the more aggressive anaplastic thyroid cancer and colon cancer and with benign polyps.

Genomic instability as measured by ISSR-PCR has been found to be an early event in colorectal carcinogenesis.8,14 Sequence analysis of altered ISSR-PCR products generated from tumor DNA has revealed that this technique preferentially detects small alterations in the genome.15 The mean genomic instability index estimate of genomic damage for 59 colorectal carcinomas was nearly identical to that measured in 7 adenomatous polyps (3.9% vs 4.1%).8 Our 2 subsequent analyses of papillary, follicular, and anaplastic thyroid cancers using ISSR-PCR revealed mean genomic instability index values of 2.9% and 3.1%.9,10 These levels of genomic damage were not statistically different from those seen in colorectal carcinomas or polyps. Furthermore, the genomic instability index of the 1 anaplastic carcinoma available for study was 3.0%, suggesting that a large increase in this form of genomic instability is not responsible for the evolution to the more aggressive tumor type. These data are summarized in Table 2.

Our published study of allelic loss in colorectal cancers and polyps demonstrated a greater than 3-fold higher fraction of markers in carcinomas compared with adenomas; FAL rates were 0.095 in malignant neoplasms vs 0.03 in the benign lesions.1 Allelotyping generally detects allelic loss events of moderate size ranging from less than a megabase to entire chromosomes. The lower frequency of LOH in polyps indicates that these are events more closely associated with the later stages of tumor progression. Using a panel of 21 markers that map to 18 of the autosomal chromosomes, we interrogated the LOH incidence in 26 papillary thyroid cancers (Table 1). Fewer than half of the markers tested demonstrated 1 or more allelic losses. Loss of heterozygosity was detectable in 52% of the tumors, ranging from 0 to 0.154, with a mean FAL of 0.035 (range for colorectal cancers, 0 to 0.450). The mean level of FAL in papillary thyroid cancer was comparable to that observed in benign colon adenomas, far below levels seen in colorectal malignancies.

Bacterial artifical chromosome aCGH is a high-resolution screening technique that assesses DNA copy number aberrations in tumors. An analysis of 33 colorectal carcinomas revealed numerous gains and losses on nearly all chromosomes.3 As might be expected, polyps had significantly fewer chromosomal copy number aberrations, indicating that this form of instability generally occurs later in colon tumor progression.14 Interestingly, papillary carcinomas analyzed by aCGH were again found to be more similar to colon polyps than to carcinomas. The aCGH profiles for these cancers showed no significant deviation from normal diploid DNA (Figure 1). Occasional spikes were observed in one tumor or another, but no consistent alterations in copy number were observed. However, with the evolution to the more aggressive anaplastic thyroid tumor, aCGH detected amplifications and deletions on several chromosomes. Most alterations were only found in a single tumor's DNA and may represent random DNA damage. The deletions and amplifications on the p and q arms, respectively, of chromosome 8 in Figure 1 were detected in 2 of the 4 anaplastic tumors.

To assess levels of genomic instability at the chromosomal level, 7 papillary thyroid cancer primary cultures were subjected to SKY. At least 10 metaphases were scored per tumor. All cells observed in all 7 tumors were scored as diploid with no detectable structural changes. A representative thyroid tumor cell is depicted in Figure 2A. Colon tumors cells were aneuploid, frequently pseudotetraploid, and contained numerous translocations (Figure 2B). Each panel in Figure 2B contains 1 or more altered chromosomes obtained from 7 different cells from the same colon tumor, indicating that colorectal tumors are highly heterogeneous. Anaplastic thyroid tumors were not available for primary cell culture.

The data summarizing all 4 measurements of genomic instability in papillary thyroid, anaplastic thyroid, and colorectal carcinomas, as well as colon adenomas, are given in Table 2. While all of these tumors possess ISSR-PCR–detected instability, those tumors that are associated with better prognoses (ie, papillary thyroid cancer and polyps) lack high-level genomic instability as measured by the remaining methods in Table 2.

COMMENT

Genomic instability, generally accepted as a facilitator of solid tumor progression, occurs in 3 general forms, microsatellite instability, aneuploidy, and intrachromosomal instability. While much has been learned about the underlying mechanisms of microsatellite instability and aneuploidy, less is known of the molecular basis of intrachromosomal instability. Indeed, it now appears that intrachromosomal instability can be subdivided into several independent forms, each presumably with its own molecular origin, that are apparent when different assay methods are used.

In this study, we have compared the genomic instabilities detected in thyroid carcinomas with those observed in colorectal cancers and adenomas to determine if differences in their instability profiles were related to the distinct clinical behavior of the 2 cancers. Four methods were used to measure diverse genomic instabilities that result in genome alterations ranging in size from a few base pairs to whole chromosomes.

Our results demonstrate that thyroid cancers possess levels of genomic instability as measured by ISSR-PCR that are equivalent to those detected in both malignant and benign lesions of the colon or rectum. In addition, ISSR instability in anaplastic carcinoma was no greater than in papillary cancer. Therefore, this form of instability is not likely to be responsible for the evolution of aggressive behavior observed in the anaplastic carcinoma.

A meta-analysis of published studies of LOH in thyroid cancer performed by Ward et al17(p525) revealed that “papillary carcinomas had exceedingly low rates of LOH.” In 2 separate genome-wide allelotyping studies, Vogelstein et al18 and Califano et al19 confirm that FAL levels (defined in both studies as the fraction of chromosomal arms lost) in papillary thyroid cancers are far lower than those of colorectal cancer. In addition, anaplastic thyroid cancer has been shown to exhibit numerous LOH events on several different chromosomes.16

We were unable to find any reports of aCGH analysis of thyroid malignant neoplasms for comparison with our data. Our aCGH analysis detected few gains or losses in papillary thyroid carcinoma relative to the anaplastic form of the disease or to colon cancer. In addition, we did not detect any consistent changes. Several investigators have used metaphase-based CGH to analyze thyroid cancers. Bauer et al20 reported that only 4 of 15 papillary thyroid cancers exhibited less than 4 aberrations per tumor, with the remaining 11 having normal diploid karyotypes. Wreesmann et al21 found few gains or losses in 15 well-differentiated papillary thyroid cancers and numerous alterations in 27 poorly differentiated or anaplastic carcinomas. In a subsequent report from this group, higher numbers of gains and losses were reported in follicular variant of papillary carcinoma, but very few alterations were detected in classic papillary cancers.22 Miura et al23 demonstrated several copy number aberrations in anaplastic tumors and an anaplastic cell line, but only 2 copy number aberrations in the papillary cell line they evaluated. Gains of chromosome 8q were reported as a recurrent event in anaplastic thyroid cancers and cell lines by Wilkens et al.24 The low level of aCGH-detected genomic instability in papillary thyroid cancer indicates that the events measured by ISSR-PCR in this disease are smaller than the 150 000–base pair average size of BAC clones. Furthermore, our data coupled with the many published reports, suggest that large-scale alterations of the genome are typical of progression to anaplastic carcinoma.

To our knowledge, this study is only the second report of SKY of nonradiation-induced human thyroid malignant neoplasms. Our analyses did not detect any numerical or structural aberrations at the chromosomal level. In the report by Foukakis et al,25 only 1 translocation in 1 of 10 papillary thyroid cancers assessed was detected. Together, our data suggest that large-scale chromosomal events are rare in papillary thyroid cancers. Also, these tumors did not exhibit the type of heterogeneity we observed using SKY in colon cancers. Foukakis et al25 also reported karyotype data from a single anaplastic thyroid cancer cell line. Abundant chromosomal aberrations were observed using SKY coupled with standard G-banding, including a high-level amplification of chromosome 8q23-qter. Whether these chromosomal abnormalities and tumor heterogeneity exist in anaplastic carcinomas remains to be determined.

Our measurements of genomic instability and those from the literature have led us to the model of genomic instabilities in tumor progression presented in Figure 3. Several forms of genomic instability can occur within a tumor cell, some arising earlier than others.

The earlier wave of genomic damage consists of thousands of small genome alterations that are readily detected by ISSR-PCR,8,10 not as readily detected by allelotyping, and rarely detected by assays such as aCGH or SKY (Figure 3A).

Because these events are small, the probability of hitting both copies of a particular sequence is low and the effects of some mutations remain masked. Those tumors in which this type of instability predominates tend to be relatively benign (ie, adenomas and papillary thyroid carcinomas). Subsequent waves of genomic instability tend to cause larger damage to the genome in forms such as deletions, amplifications, and uniparental conversion of some chromosomes, which can be revealed by allelotyping, SKY, and aCGH.

With the onset of large event–causing instabilities, the probability of revealing a previously silent mutation increases. Unmasked mutations are now able to contribute to the evolution of the tumor to more aggressive disease.

The tumors that exhibit multiple forms of genomic instability are clinically more aggressive tumors such as colorectal cancer and anaplastic thyroid cancer. The combination of these multiple forms of instability enable normal cells to evolve through benign neoplasms to highly aggressive malignant neoplasms.

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Article Information

Correspondence: Garth R. Anderson, PhD, Department of Cancer Biology, Roswell Park Cancer Institute, Buffalo, NY 14263 (garth.anderson@roswellpark.org).

Submitted for Publication: July 31, 2006; accepted November 7, 2006.

Author Contributions: Drs Stoler and Anderson had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Stoler, Nowak, Loree, and Anderson. Acquisition of data: Stoler, Nowak, Matsui, Wiseman, Chen, Dutt, Bartos, Loree, Rigual, Hicks, and Sait. Analysis and interpretation of data: Stoler, Nowak, Wiseman, Bartos, Loree, Rigual, and Anderson. Drafting of the manuscript: Stoler and Hicks. Critical revision of the manuscript for important intellectual content: Nowak, Matsui, Wiseman, Chen, Dutt, Bartos, Loree, Rigual, Sait, and Anderson. Statistical analysis: Bartos. Obtained funding: Loree and Anderson. Administrative, technical, and material support: Stoler, Nowak, Matsui, Wiseman, Chen, Dutt, Bartos, Loree, Rigual, Hicks, Sait, and Anderson. Study supervision: Anderson.

Financial Disclosure: None reported.

Funding/Support: This work was supported by grants RO1 CA 74127 (Dr Anderson) and P30 CA16056 from the National Institutes of Health.

Previous Presentation: This work was presented at the American Head and Neck Society 2006 Annual Meeting and Research Workshop on the Biology, Prevention, and Treatment of Head and Neck Cancer; August 17-20, 2006; Chicago, Ill.

Acknowledgment: We acknowledge Ann Marie Bauer, RN, MSN, for invaluable assistance in the Head and Neck Surgery clinic at Roswell Park Cancer Institute, Buffalo, NY.

References
1.
Anderson  GRBrenner  BMSwede  H Intrachromosomal genomic instability in human sporadic colorectal cancer measured by genome-wide allelotyping and inter-(simple sequence repeat) PCR. Cancer Res 2001;618274- 8283
PubMed
2.
Bartos  JDStoler  DLMatsui  S Genomic heterogeneity and instability in colorectal cancer: spectral karyotyping, glutathione transferase-Ml and ras. Mutat Res 2004;568283- 292
PubMedArticle
3.
Swede  HBartos  JDChen  N Genomic profiles of colorectal cancers differ based on patient smoking status. Cancer Genet Cytogenet 2006;16898- 104
PubMedArticle
4.
American Cancer Society Cancer Facts & Figures 2006.  Atlanta, Ga: American Cancer Society; 2006. http://www.cancer.org/downloads/STT/CAFF2006PWSecured.pdf. Accessed July 6, 2006
5.
Are  CShaha  AR Anaplastic thyroid carcinoma: biology, pathogenesis, prognostic factors, and treatment approaches. Ann Surg Oncol 2006;13453- 464
PubMedArticle
6.
Wiseman  SMLoree  TRHicks  WL  Jr Anaplastic thyroid cancer evolved from papillary carcinoma: demonstration of anaplastic transformation utilizing the inter-simple sequence repeat polymerase chain reaction. Arch Otolaryngol Head Neck Surg 2003;12996- 100
PubMedArticle
7.
Basik  MStoler  DLKontzoglou  KCRodriguez-Bigas  MAPetrelli  NJAnderson  GR Genomic instability in sporadic colorectal cancer quantitated by inter-(simple sequence repeat) PCR analysis. Genes Chromosomes Cancer 1997;1819- 29
PubMedArticle
8.
Stoler  DLChen  NBasik  M The onset and extent of genomic instability in sporadic colorectal tumor progression. Proc Natl Acad Sci U S A 1999;9615121- 15126
PubMedArticle
9.
Stoler  DLDatta  RVCharles  MA  et al.  Genomic instability measurement in the diagnosis of thyroid neoplasms. Head Neck 2002;24290- 295
PubMedArticle
10.
Wiseman  SMLoree  TRRigual  NR Papillary thyroid cancer: high inter-(simple sequence repeat) genomic instability in a typically indolent cancer. Head Neck 2003;25825- 832
PubMedArticle
11.
Cowell  JKNowak  NJ High resolution analysis of genetic events in cancer cells using BAC array and comparative genomic hybridization. Adv Cancer Res 2003;9091- 125
PubMed
12.
Matsui  SFaitar  SLRossi  MRCowell  JK Application of spectral karyotyping to the analysis of the human chromosome complement of interspecies somatic cell hybrids. Cancer Genet Cytogenet 2003;14230- 35
PubMedArticle
13.
Hundahl  SAFleming  IDFremgen  AM A National Cancer Data Base report on 53,856 cases of thyroid carcinoma treated in the US, 1985-1995. Cancer 1998;832638- 2648
PubMedArticle
14.
Alrawi  SJCarroll  REHill  HC Genomic instability of human aberrant crypt foci: inter-SSR PCR and aCGH. Mutat Res 2006;60130- 38
PubMedArticle
15.
Chen  NStoler  DLJahreis  JPAnderson  GR Analysis of inter-(simple sequence repeat) PCR products from human colorectal cancers. Oncol Res 2005;15233- 238
16.
Kitamura  YShimizu  KTanaka  SIto  KEmi  M Allelotyping of anaplastic thyroid carcinoma: frequent allelic losses on 1q, 9p, 11, 17, 19p, and 22q. Genes Chromosomes Cancer 2000;27244- 251
PubMedArticle
17.
Ward  LSBrenta  GMedvedovic  MFagin  JA Studies of allelic loss in thyroid tumors reveal major differences in chromosomal instability between papillary and follicular carcinomas. J Clin Endocrinol Metab 1998;83525- 530
PubMed
18.
Vogelstein  BFearon  ERKern  SE Allelotype of colorectal carcinomas. Science 1989;244207- 211
PubMedArticle
19.
Califano  JAJohns  MM  IIIWestra  WH An allelotype of papillary thyroid cancer. Int J Cancer 1996;69442- 444
PubMedArticle
20.
Bauer  AJCavalli  LRRone  JD Evaluation of adult papillary thyroid carcinomas by comparative genomic hybridization and microsatellite instability analysis. Cancer Genet Cytogenet 2002;135182- 186
PubMedArticle
21.
Wreesmann  VBGhossein  RAPatel  SG Genome-wide appraisal of thyroid cancer progression. Am J Pathol 2002;1611549- 1556
PubMedArticle
22.
Wreesmann  VBGhossein  RAHezel  M Follicular variant of papillary thyroid carcinoma: genome-wide appraisal of a controversial entity. Genes Chromosomes Cancer 2004;40355- 364
PubMedArticle
23.
Miura  DWada  NChin  K Anaplastic thyroid cancer: cytogenetic patterns by comparative genomic hybridization. Thyroid 2003;13283- 290
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