Human papillomavirus and tobacco use in tongue base cancers.

Human papillomavirus 16 (HPV-16) infection and tobacco use are associated with human oropharyngeal cancers. We conducted a study of the role of HPV and tobacco use in base of the tongue (BOT) cancers. DNA from 34 such cancers was subjected to HPV-16 and HPV-18-specific polymerase chain reaction analysis. Demographic and clinicopathologic data were obtained from each patient's medical record. HPV-16 was detected in 68% of tumors. Tobacco use was the only factor found to be significantly associated with HPV status. Tumors from 100% of patients who had never used tobacco tested positive for HPV, compared with only 56% of those who had ever used tobacco (Fisher exact test, p = 0.024). All tumors were associated with either tobacco use or HPV infection. These findings are consistent with the hypothesis that either tobacco use or HPV infection is necessary to the etiology of BOT tumors, and they suggest that tongue base carcinoma may be prevented by combining HPV vaccination with tobacco avoidance.

Genomic instability measured by inter-(simple sequence repeat) PCR and high-resolution microsatellite instability are prognostic of colorectal carcinoma survival after surgical resection.

BACKGROUND: During the multiyear progression to colorectal cancer, numerous genomic alterations arise in events ranging from single base mutations to gains or losses of entire chromosomes. A single genetic change might not stand out as an independent predictor of outcome. The goal of this study was to determine if more comprehensive measurements of genomic instability provide clinically relevant prognostic information. METHODS: Our study included 65 sporadic colorectal cancer patients diagnosed from 1987 to 1991 with last follow-up ascertained in 2006. We estimated an overall tally of alterations using the genome-wide sampling technique of inter-(simple sequence repeat [SSR]) polymerase chain reaction (PCR), and evaluated its relationship with all-cause survival. We also extended and sensitized the Bethesda criteria for microsatellite instability (MSI), by analyzing 348 microsatellite markers instead of the normal five. We expanded the MSI categories into four levels: MSI stable (MSS), very low-level MSI, moderately low-level MSI, and classical high-level MSI. RESULTS: Tumors with genomic instability above the median value of 2.6% as measured by inter-SSR PCR, were associated with far greater risk of death compared to tumors with lower levels of genomic instability. Adverse outcome was most pronounced for patients presenting with stage 3 disease. A gradient of increased survival was observed across increasing MSI levels but did not reach statistical significance. CONCLUSION: Our findings suggest genomic instabilities quantified by inter-SSR PCR and increased precision in MSI values may be clinically useful tools for estimating prognosis in colorectal cancer.

Uniparentalism in sporadic colorectal cancer is independent of imprint status, and coordinate for chromosomes 14 and 18.

Our previous allelotyping studies of 59 sporadic colorectal cancers revealed that loss of heterozygosity is most frequent for regions of chromosomes 14 and 18. Yet subsequent BAC microarray comparative genomic hybridization studies of the same tumor DNAs showed no corresponding pattern of copy number alteration for chromosome 14. To clarify this apparent discrepancy, we utilized hybridization to SNP microarrays; this revealed frequent uniparentalism for chromosome 14 and for chromosome 18. Based on the BAC array results combined with fluorescent in situ hybridization data, it was evident that uniparental disomy was occurring in many colorectal cancers as well as in additional chromosomes, and often coordinately involved chromosomes 14 and 18. Further studies examined the possibility that uniparentalism was directed towards the selection for imprinted genes, but no association with imprinting was observed.

Family cancer syndromes: inherited deficiencies in systems for the maintenance of genomic integrity.

Familial cancer syndromes have revealed important fundamental features regarding how all cancers arise through destabilization of the genome, such that somatic evolution can select for the disruption of critical cellular coordinating and regulatory features. The authors examine those cellular genes and systems whose normal role is to preserve genomic integrity and relate them to the genetic foundations of heritable cancers. By examining how these cellular systems normally function, how family cancer genes are able to affect the process of tumor progression can be learned. In so doing, a clearer picture of how sporadic cancers arise is additionally gained.

Colorectal cancers in patients with the (9A/6A) polymorphism of TGFBR1 exhibit lesser inter-(simple sequence repeat) PCR genomic instability and present clinically at greater age.

TGFbeta is involved in the response to DNA damage and signaling the cell cycle checkpoint response, in large part achieved by modulating the activity of the ATM kinase. We have investigated if the presence of a common polymorphism in the TGFbeta receptor TGFBR1 might impact genomic instability in human colorectal cancer. In order to obtain statistically significant numbers of patients with the lesser polymorphism, 177 colorectal cancer patients were genotyped for either the major form of the TGFBR1 receptor gene, homozygous for an internal segment of 9 alanines (9A/9A), or the lesser form, heterozygous for the polymorphism containing 6 alanines (9A/6A). Intrachromosomal genomic instability in the tumors was then quantified by the robust inter-(simple sequence repeat) PCR method. Tumors from all 26 patients heterozygous with the (9A/6A) polymorphism in TGFBR1 exhibited significantly lower genomic instability than from a randomly selected set [the first identified] of 37 patients with the (9A/9A) polymorphism (p=0.0002, Mann-Whitney). The median age of onset for the (9A/6A) patients was 70 years, compared with a median age of onset of 63 years for the patients carrying the (9A/9A) form (p=0.031, Mann-Whitney). These results are consistent with the model wherein genomic instability facilitates tumor progression, with lesser instability associated with later disease presentation. Clinically, our findings may be developed into improved screening guidelines with respect to the age at which colonoscopy is initiated in carriers of the TGFBR1*6A allele.

Comparative genomic instabilities of thyroid and colon cancers.

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.

Allelic losses at genomic instability-associated loci in villous adenomas and adjacent colorectal cancers.

Allelic imbalances in premalignant villous adenomas were compared with those in adjacent microdissected colorectal carcinoma that had arisen directly from the adenomas. Carcinoma-adenoma pairs were examined from 17 patients who underwent resections for colorectal cancer. In all, 28 microsatellite markers were examined, from regions of the genome where individual allelic losses have been associated with overall genomic instability in colorectal carcinomas. Microsatellite instability (MSI) was also evaluated for each marker in each tissue type. Loss of heterozygosity for multiple markers was found in 35% of adenomas and 65% of carcinomas; the average fractional allelic loss rate was 2.5 times higher in carcinomas than in adenomas. Of the 17 patients, 4 had MSI for >30% of markers in both adenoma and carcinoma, with no significant differences between the two tissues. Markers with particularly high imbalance rates in adenomas were seen on chromosomes 11, 14, and 15. These findings provide further evidence that genomic instability is an ongoing process during carcinogenesis, with a markedly increased frequency of allelic losses seen in carcinomas, compared with adjacent adenomas. Markers on chromosomes 11, 14, and 15 may become valuable tools in the identification of patients destined to progress to colorectal carcinomas.

aCGH local copy number aberrations associated with overall copy number genomic instability in colorectal cancer: coordinate involvement of the regions including BCR and ABL.

In order to identify small regions of the genome whose specific copy number alteration is associated with high genomic instability in the form of overall genome-wide copy number aberrations, we have analyzed array-based comparative genomic hybridization (aCGH) data from 33 sporadic colorectal carcinomas. Copy number changes of a small number of specific regions were significantly correlated with elevated overall amplifications and deletions scattered throughout the entire genome. One significant region at 9q34 includes the c-ABL gene. Another region spanning 22q11-q13 includes the breakpoint cluster region (BCR) of the Philadelphia chromosome. Coordinate 22q11-q13 alterations were observed in 9 of 11 tumors with the 9q34 alteration. Additional regions on 1q and 14q were associated with overall genome-wide copy number changes, while copy number aberrations on chromosome 7p, 7q, and 13q21.1-q31.3 were found associated with this instability only in tumors from patients with a smoking history. Our analysis demonstrates there are a small number of regions of the genome where gain or loss is commonly associated with a tumor's overall level of copy number aberrations. Our finding BCR and ABL located within two of the instability-associated regions, and the involvement of these two regions occurring coordinately, suggests a system akin to the BCR-ABL translocation of CML may be involved in genomic instability in about one-third of human colorectal carcinomas.

Genomic profiles of colorectal cancers differ based on patient smoking status.

Human sporadic colorectal cancer is the result of a lengthy somatic evolutionary process facilitated by various forms of genomic instability. Such instability arises endogenously from mutations in genes whose role is to preserve genomic integrity, and exogenously from environmental agents that generate genomic damage. We have found that cigarette smoking shifts the genomic profiles and genomic instability patterns of colorectal carcinomas. The genomic profiles of 57 consecutive cancers were examined; 31 cases were current or former smokers and 26 were nonsmokers. Genome-wide allelotypes of 348 markers were examined, along with comparative genomic hybridization (CGH) on ordered BAC microarrays, microsatellite instability, and inter-(simple sequence repeat) polymerase chain reaction instability. Tumors from nonsmokers exhibited losses of heterozygosity, particularly on chromosomes 14 and 18, whereas tumors from smokers exhibited a more diffuse pattern of allelic losses. Tumors from smokers exhibited higher overall rates of loss of heterozygosity, but showed lower rates of background microsatellite instability (MSI-L). On BAC array CGH, higher levels of generalized amplifications and deletions were observed in tumors from smokers, differentially affecting male smokers. In the transforming growth factor-beta signaling pathway, MADH4 mutations were more common in tumors from smokers, whereas transforming growth factor-beta RII mutations were more common among nonsmokers.

Genomic instability of human aberrant crypt foci measured by inter-(simple sequence repeat) PCR and array-CGH.

Aberrant crypt foci (ACF) are the earliest identifiable neoplastic lesions in the colon. Thirty-two ACFs were examined for genomic instability in forms detectable either by inter-(simple sequence repeat) PCR or by array comparative genomic hybridization [array-CGH]. One-fourth of ACFs revealed moderate instability by inter-(simple sequence repeat) PCR; none showed amplifications or deletions on array-CGH. The absence of genomic events detectible by BAC array-CGH indicates early events in colorectal tumor progression are typically smaller than the approximate 150 kb size of a BAC clone insert.

Aberrant crypt foci.

Colon cancer evolves through epithelial cell deregulation and inappropriate proliferation. These histopathological characteristics are exemplified in the biochemical, immunohistochemical, genetic and epigenetic elements detected within colonic mucosa. Early detection is paramount for the prevention of colon cancer deaths. Aberrant crypt foci (ACF) are thought to be the earliest identifiable neoplastic lesions in the colon carcinogenetic model. The progression of ACF to polyp and, subsequently, to cancer parallels the accumulation of several biochemical alterations and mutations whereby a small fraction of ACF evolve to colon cancer. Recent data indicate that, not uncommonly, some ACF bypass the polyp stage in their carcinogenesis thus reinforcing the importance of their early detection and our understanding of their pathogenesis. Since ACF were first detected in carcinogen-treated mice, research efforts have focused on these microscopically visible lesions both in animal and human models. ACF show variable histological features, characterized by Kudo (20) and, therefore, can be grouped into differing categories by in vivo examination with high-magnification-chromoscopic-colonoscopy (HMCC). As expected, ACF are more frequently detected in distal animal and human colons coinciding with the geographic distribution of colorectal cancer (CRC). Various proteomic (Prot) markers may be altered within ACF suggesting possible prospective pathological changes. These markers include Calreticulin, Transgelin, Serotransferrin, Triphosphate isomerase and Carbonic anhydrase II. Other markers of importance include carcinoembryonic antigen (CEA), B-catenin, placental cadherin (P-cadherin), epithelial cadherin (E-cadherin), inducible nitric oxide synthase (iNOS), cyclooxygenase (COX-2) and P16INK4a. Genetic mutations of K-ras, B-Raf APC and p53 have been demonstrated in ACF as well as the epigenetic alterations of CpG island methylation. Genomic instabilities (GI), illustrated by a higher GI Index (GII), microsatellite instability (MSI), loss of heterozygosity (LOH) and defects in mismatch repair (MMR) systems, are also expressed. These transformations may lead to the identification of the earliest pathological features initiating colon tumorigenesis. In this review, the advances in ACF research as precursors of CRCs are highlighted.

Genomic instability in invasive breast carcinoma measured by inter-Simple Sequence Repeat PCR.

We have measured genomic instability in invasive breast carcinomas and assessed the relationship of genomic instability to known tumor prognostic factors. DNAs from tumors and adjacent normal tissue of 18 breast cancer patients were subjected to inter-Simple Sequence Repeat (inter-SSR) PCR for quantitation of tumor genomic instability. Associations between genomic instability level and known breast cancer prognostic factors were evaluated using the Pearson Product Moment Correlation, the Kruskal-Wallis test of independent samples and the Mann-Whitney non-parametric test. Genomic instability was detected by inter-SSR PCR in over 90% of the breast tumors. The mean instability index was 3.08% (0-7.59%), approximately the same mean value observed in studies of colorectal and thyroid carcinomas. Significantly higher levels of instability were associated with tumors exhibiting necrosis. Genomic instability as measured is detected in the majority of breast cancers at levels comparable to other tumor types. Hypoxia, such as that observed in necrotic regions of tumors, has been associated with elevated genomic damage. We hypothesize that the higher levels of genomic instability detected in necrotic tumors is a consequence of hypoxia-associated DNA damage.

Tissue eosinophilic infiltration: a useful marker for assessing stromal invasion, survival and locoregional recurrence in head and neck squamous neoplasia.

UNLABELLED: The assessment of stromal invasion in aerodigestive neoplastic squamous proliferation often poses diagnostic and therapeutic challenges. Eosinophilic infiltration is thought to be an adjunctive histologic criterion in determining tumor aggressiveness and invasion. We investigated whether an eosinophilic infiltration in head and neck squamous cell carcinoma measured in biopsies would aid in predicting tumor invasion, response to treatment, locoregional recurrence, and survival. METHODS: Eighty-seven patients with in situ and invasive squamous cell carcinoma of the head and neck region were evaluated and treated according to their staging. The number of eosinophils per high-power field (eosinophil/HPF), and per 10 high-power fields (eosinophil/10 HPF) at the tumor interface and in tumor tissue, was counted and classified as focally or diffusely present. Each sample was assigned an eosinophilic index of 1-4 based on the number of eosinophils/HPF or 10 HPF. Of 87 patients, 20 patients were followed up after appropriate treatment for locoregional recurrence, distant metastasis, and disease-free survival. RESULTS: Eosinophilic counts were elevated focally and/or diffusely more frequently in invasive squamous cell carcinoma than in noninvasive tumors. The increased eosinophilic counts, specifically > 10/HPF and > 20/10 HPF, were both significantly associated with stromal invasion. Greater than 10 eosinophils/HPF and/or > 20 eosinophils/10 HPF had the highest predictive power for invasion, with sensitivity, specificity, and positive predictive values of 66%, 94%, 96% and 61%, 100%, and 100%, respectively. Eosinophilic counts greater than 20 eosinophils/10 HPF and eosinophilic indices > 2 were virtually diagnostic for tumor invasion. Patients' biopsies with eosinophilic indices < 2 had a better survival (P = 0.0156). Using Cox regression analysis, we found that most patients' biopsies that had eosinophilic indices > 2 recurred locally or regionally. CONCLUSIONS: The elevated eosinophilic counts in biopsies and eosinophilic indices in specimens of squamous cell carcinoma of the aerodigestive tract are a histopathologic marker associated with tumor invasion and a clinical predictor for aggressive tumor biology. Similarly, the presence of eosinophils meeting these thresholds in an excisional specimen should indicate the need for additional therapeutic measures and close surveillance to detect earlier locoregional recurrence and possible distant metastasis.

Molecular prognosticators and genomic instability in papillary thyroid cancer.

OBJECTIVES/HYPOTHESIS: Tumor progression has been attributed to the accumulation of DNA damage concurrent with selection of advantageous mutations; this DNA damage may result from failure to maintain genomic integrity or from susceptibility to carcinogens. Glutathione S-transferases (GSTs), enzymes that metabolize many carcinogens, may play a role in preserving genome integrity. The objectives of this study are to assess the relationship of GST genotypes with prognosis, clinicopathologic parameters, and genomic instability in papillary thyroid cancer. STUDY DESIGN: Prospective analysis. METHODS: GSTM1 and GSTT1 genotypes of 35 matched normal and papillary thyroid cancer specimens were determined by polymerase chain reaction (PCR) using primers specific for the coding sequences of each gene. Genomic instability was measured by intersimple sequence repeat PCR for each tumor/normal pair and compared with the GAMES prognostic scoring system and clinicopathologic parameters including age, extrathyroidal extension, tumor grade, size, stage metastasis, sex, and smoking history. RESULTS: GSTM1 and GSTT1 null genotypes were found in the normal tissues of 46% and 45%, respectively. No gene losses were detected in the tumor specimens. A significant association between the GSTM1 null genotype and increased risk of recurrence and death was observed. Elevated GII correlated with smoking and tumor stage but not with GST genotype. CONCLUSION: The association of GSTM1 null genotype with intermediate and high risk GAMES categories suggests that GSTM1 provides some protection against disease progression. However, this protection does not confer resistance to disease onset. GST genotyping may be a useful adjunct prognosticator with GAMES.

Analysis of inter-(simple sequence repeat) PCR products from human colorectal cancers.

Genomic instability is a fundamental characteristic of solid tumors, and understanding genomic instability should significantly clarify the process of tumorigenesis. We adapted the sampling technique of inter-(simple sequence repeat) PCR [inter-(SSR) PCR] to measure genetic alterations between simple sequence repeats in colorectal tumors. It becomes important to precisely define both normal and altered inter-(SSR) PCR products. BLAT searches of 131 cloned inter-(SSR) PCR sequences reveal that inter-(SSR) PCR products are located on almost all the chromosomes except chromosome Y, indicating that inter-(SSR) PCR samples a representative diverse range of the genome. We confirm that a change in the pattern of the inter-(SSR) PCR products as seen on gel electrophoresis reflects a true alteration within the genome.

Genomic heterogeneity and instability in colorectal cancer: spectral karyotyping, glutathione transferase-Ml and ras.

Genomic instability in cancer is frequently described as being either chromosomal instability or microsatellite instability, although when events within chromosomes are monitored, extensive intrachromosomal instability is also found. Spectral karyotyping was used to visualize how extensively genomic instability gives rise to intratumor genomic heterogeneity in sporadic colorectal carcinomas. Two factors were then examined which might relate to intrachromosomal instability in colorectal cancers: the presence of the glutathione transferase-Ml gene to detoxify potential carcinogens, and the presence of activated ras which has been associated with chromosomal instability when first expressed. Intrachromosomal genomic instability was previously determined by inter-(simple sequence repeat) PCR (inter-SSR PCR) and by fractional allelic loss rate for 348 markers. GSTM1 status was determined for each of 49 tumors through use of specific PCR, and 28 of the tumors showed the GSTM1 null genotype. A significant association was found between GSTMl-null status and elevated inter-(simple sequence repeat) PCR instability. In contrast, no association was found with fractional allelic loss rate. The first exons of the K-ras and H-ras oncogenes were sequenced in 72 colorectal cancers; 19 of the tumors had a mutation in codon 12 of the K-ras gene (24.5%), but no H-ras mutations were found. A weak correlation (p=0.10) was observed between mutant K-ras and inter-(simple sequence repeat) PCR genomic instability, and no association existed with fractional allelic loss rate.

The role of genomic instability in the pathogenesis of squamous cell carcinoma of the head and neck.

Measurements of genomic instability, or identification of genes responsible for instability, may potentially be used as molecular markers to predict disease course and response to therapy. Other possible applications include use of genomic instability measurements, or genes, as tools to screen for primary or recurrent disease. Methodologies for detection of genetic mutations in saliva, blood, and sputum have already been described[61,62]. Brennan et al [63] have described a molecular technique for analyzing histopathologically negative margins and lymph nodes for the presence of p53 gene mutation. This study showed that a positive molecular margin significantly predicted disease recurrence. The recognition that HNSCC is a genetically heterogeneous disease represents a major step toward developing an understanding of its underlying genetic basis. To develop an insight into this genetically heterogeneous disease, investigators must not only focus their efforts on specific head and neck disease sites. Laser-capture microdissection represents a powerful tool for isolating very specific cell populations from tumors [64]. Leethanakul et al[65] performed laser-capture microdissection on oral cavity SCC to construct stage-specific cDNA libraries. Sequencing of 96 clones from each of the six libraries constructed suggested the existence of 132 novel genes, which may play a role in the pathogenesis of HNSCC. The current literature suggests that many individuals diagnosed withHNSCC are genetically predisposed to developing malignancy because of some inherent deficiency of their capacity to maintain their genome in the presence of environmental stressors. Head and neck cancers are highly heterogeneous tumors and exhibit a wide variety of forms of genomic instability. Thus, genomic instability may be viewed as a fundamental force driving head and neck tumorigenesis and evolution. Future study of the specific genetic mechanisms that underlie genomic instability in the HNSCCpatient population is needed. It is only through study of this fundamental force that drives the development of these tumors that clinicians may gain the insight required to develop new diagnostic and therapeutic modalities to benefit the HNSCC patient population as a whole.

Papillary thyroid cancer: high inter-(simple sequence repeat) genomic instability in a typically indolent cancer.

OBJECTIVES: The object of this study is to measure genomic instability in papillary thyroid cancer and correlate these measurements with known clinical prognosticators such as patient age, tumor size, histologic subtype, and three commonly used thyroid risk assessment indices. A secondary objective of this study was to use the measurements of genomic instability to estimate the number of mutational events present in the papillary thyroid cancer genome. METHODS: Inter-simple sequence repeat polymerase chain reaction (ISSR-PCR) is a rapid and reproducible technique for quantitation of genomic instability, or the degree of genome alteration, in solid tumors. This includes quantitation of amplifications, deletions, translocations, and insertions. Twenty-eight papillary carcinomas were evaluated by ISSR-PCR. RESULTS: Evaluation of 28 papillary carcinomas by ISSR-PCR demonstrated a wide range of genomic instability. Of the panel of clinicopathologic factors examined, only patient age was significantly associated with genomic instability. The mean genomic instability index value was greatest in the youngest age group, which was significantly different from the median value measured in the oldest age group (3.7, 2.5, respectively, p =.05). The mean value in the intermediate age group fell between the younger and older groups (3.1). By use of ISSR-PCR, we have calculated 15,000 individual genomic events as having occurred in each papillary tumor cell. CONCLUSIONS: Despite its generally indolent biologic behavior, papillary thyroid cancer exhibits a high degree of genomic instability comparable to that seen in colorectal cancer. These results suggest that elevated genomic instability, as measured by ISSR-PCR, may not be sufficient to enable thyroid tumor progression to less indolent disease and that this process is severely constrained by some additional essential factor such as the differentiated state of the tissue or the need to bring into play an additional form of genomic destabilization.

Anaplastic transformation of thyroid cancer: review of clinical, pathologic, and molecular evidence provides new insights into disease biology and future therapy.

BACKGROUND: Anaplastic thyroid cancer ranks among the most lethal of all human malignancies. Its rarity and rapidly fatal course have made it a difficult cancer to both study and treat. Unfortunately, there has been little progress in the management and control of this malignancy. Anaplastic transformation, or the intratumoral evolution of anaplastic carcinoma from pre-existing differentiated thyroid cancer, has become a well-accepted process, despite a limited understanding of its underlying mechanisms. METHODS: It is through review of the literature that an understanding of the aggressive disease biology can be developed. The aim of this review is to evaluate the relevant clinical, pathologic, and molecular studies to develop an insight into the mechanisms that underlie the intratumoral molecular evolution of anaplastic thyroid carcinoma. RESULTS/CONCLUSION: It is based on an understanding of this process that effective treatments for this aggressive malignancy are currently being developed.