Most of these studies find an unfavorable clinical effect in patients with high cyclin A protein expression in the tumor tissue. In two materials of mainly colon cancers and to a lesser extent rectal cancers regarded as a whole, cyclin A protein overexpression was associated with impaired overall survival [ 51 , 52 ].
However, it is hard to decipher exactly how large proportion of one of these materials [ 52 ] was colon cancers. Another problem may be that overall survival may not reflect the cancer specific survival. In another material of colorectal patients the conclusion was the same [ 53 ]. These three reports were on colorectal patients, that is, a mixture of colon and rectal cancers. If the clinical effects of high cyclin A differ between colon and rectal cancers, the interpretation of these three studies might be somewhat difficult.
The expression of c-Myc was also analyzed in this study and compared to the expression of the same protein in colon adenocarcinomas. Control of the cell cycle is usually lost if the expression of c-Myc is deregulated [ 55 ]. Higher c-Myc was associated with reduced cancer specific survival in rectal cancer patients, while in colon cancer patients without adjuvant chemotherapy, high c-Myc expression was associated with better prognosis.
To evaluate whether overexpression of cyclins detected in the present study was a result of amplification at the DNA level, gene amplification analyses were performed for all cyclins included in the study. Gene amplification analyses on the rectal cancers revealed a significant but fairly low correlation between gene amplification and protein expression only for the cyclins B1, D3, and E.
No correlation between gene amplification and protein expression was observed for cyclin A2. Earlier studies have showed that protein overexpression of cyclins can occur without gene amplification [ 20 , 56 — 58 ]. Our results indicate that gene amplification contributes to the variation seen in protein expression of cyclins in rectal cancer. But it does not offer a major explanation to this. Therefore, protein expression of cyclins in rectal cancer has to be regulated mainly by other mechanisms.
It is of importance, especially regarding cyclin A2, to explore the mechanism behind overexpression. It has been shown that overexpression of cyclin A in the S-phase of the cell cycle is associated with poor prognosis, while overexpression of cyclin A in the M-phase of the cell cycle is associated with better prognosis.
It is reason to believe that overexpression caused by reduced degradation of a protein may result in accumulation of this protein also in the M-phase, while overexpression caused by high production, but intact degradation process may act mostly at the S-phase of the cell cycle. It is possible to speculate that overexpression of cyclin A2 caused by gene amplification may act mainly in the S-phase of the cell cycle.
Thus, in rectal cancer, we believe overexpression of cyclin A2 protein is caused mainly by impaired degradation of the protein. This causes a high cyclin A2 concentration in M-phase in addition to in S-phase, leading to better clinical outcome. Most colon cancers, especially those distal to the splenic flexure, evolve by the cromosomal instability CIN pathway.
Fifteen percent of colon cancers evolve by the microsatellite instability MSI pathway. The MSI cancers are typically located proximal to the splenic flexure. In sporadic cancers, MSI is mainly caused by epigenetic silencing. Other investigations only partially support these results [ 61 , 62 ].
However, although their approaches differ from ours, except on -catenin [ 62 ], individual results in these investigations indicate differences between rectal and colon cancers. This is in accordance with our findings. In conclusion, only a few surveys exist on the biological differences between colon and rectal adenocarcinomas, despite the fact that colon and rectal cancer patients may have different clinical prognosis.
The present study is one of the first studies where proteins important for cell cycle regulation are examined separately in colon and rectal adenocarcinomas. The results show biological differences between rectal and colon adenocarcinomas. The study demonstrates the necessity for examining these two disease entities separately. These biological differences may have significant impact when planning therapy for colorectal cancer patients. This is an open access article distributed under the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Article of the Year Award: Outstanding research contributions of , as selected by our Chief Editors. Read the winning articles. Journal overview. Special Issues. Received 22 Jun Accepted 23 Sep Published 15 Dec Abstract Adenocarcinomas of rectum and colon may be different with regard to the cellular biological basis for cancer development.
Introduction Despite the fact that adenocarcinomas of rectum and colon have the same appearance both macroscopically and microscopically, they may be different with regard to the cellular biological basis for cancer development. Materials and Methods 2. Patient Materials All available tumor samples from a consecutive series of paraffin-embedded rectal adenocarcinomas removed surgically at Akershus University Hospital in the years — were scrutinized for inclusion into the survey.
Immunohistochemistry Serial sections micrometers from formalin fixed, paraffin wax embedded archive tumor tissue were applied to coated slides before immunohistochemical staining. Table 1. Figure 1. Representative example of immunopositivity grade 3 for cyclin A original magnification. Figure 2. Representative example of immunopositivity grade 3 for cyclin D1 original magnification.
Figure 3. Representative example of immunopositivity grade 3 for cyclin E original magnification. Figure 4. Table 2. Primer and probe sequences for cyclins used in real time quantitative polymerase chain reaction. Table 3.
Table 4. Protein expression. Variables that showed a significant difference between rectal cancers and colon cancers results of binary logistic regression analysis on patients. Table 5. Gene amplification. Amplification was measured by real-time quantitative polymerase chain reaction, and levels were determined by the comparative method method. Table 6. Cyclin Pearson correlation coefficient squared -value Number of rectal cancers examined Cyclin A2 0.
Table 7. Correlation between protein expression and gene amplification of cyclins in rectal cancers. Table 8. Table 9. Kaplan-Meier Log Rank Test. References R. Aamodt, J. Bondi, S. Andersen, G. Bukholm, and I. View at: Google Scholar C. Assoian and X. Ohtsubo, A.
Theodoras, J. Schumacher, J. Roberts, and M. View at: Google Scholar F. Girard, U. Strausfeld, A. Fernandez, and N. Current chemotherapy regimens provide only minimal survival benefit, predominantly when used in combination with surgery or radiation.
Recently clinical trial ToGA in Asian and European countries showed that anti-HER2 monoclonal antibody trastuzumab treatment significantly improved the survival of patients with gastric adenocarcinoma and HER2 overexpression and amplification. The clinical trial of trastuzumab to treat esophageal adenocarcinoma patients are approved in United States and European countries.
Here is a comprehensive review of HER2 overexpression and amplification in esophageal adenocarcinoma. IHC studies on HER2 overexpression: In esophageal adenocarcinoma, HER2 overexpression and amplification recently has been reported at frequencies similar to those observed in breast cancer.
It is difficult to compare their criteria since there are no pictures in their reports. Reichelt et al. Similarly, Brien et al.
They considered that the tumor cell nuclei were truncated due to standardized thin tissue sectioning. Therefore, three dimension FISH need to be further evaluated to help better understand any prognostic significance. Actually the similar phenomenon was reported in esophageal adenocarcinoma cases Higher HER2 amplification from Radu may be caused by thicker section. HER2 amplification or overexpression correlating with patient survival and clinicopathological factors: In esophageal adenocarcinoma, the relationship between HER2 amplification and prognosis is limited and controversial [ 66 , 67 ].
Brien et al. In contrast, Reichelt et al. In addition, Rauser et al. Our results 68 indicate no association of HER2 amplification with patient survival in a large cohort studies total patients by both CISH and high density DNA microarrays methods although HER2 amplification group shows better prognosis 23 months vs 25 months. The association between HER2 amplification and these clinicopathological factors were controversial. First, Brien [ 66 ] reported that HER2 amplification was not significantly associated with any clinicopathological features such as depth of tumor invasion, lymph node metastasis, differentiation and pathological stage.
Nineteen were male, and 2 female M:F ratio, , with a mean age of 63 years range, 51 to 74 years. The remaining patients 85 males and 10 females [M:F ratio, ]; mean age, 65 years [34 to 85 years] had no amplification. Yoon [ 69 ] study supported our finding that HER2 amplification cases were significantly associated with better differentiation, but HER2 amplification cases were not associated with age and gender.
However, they also showed that HER2 amplification was associated with lower depth of tumor invasion T stage , fewer malignant nodes, and absence of signet ring cells.
In summary, the association of HER2 amplification with survival and clinicopathological features is not very clear. At least HER2 amplification was not associated with worse prognosis in most large cohort studies. In addition, the HER2 amplification may be associated better differentiation, but not associated with age and sex. The large, multi-institute study is needed to confirm current studies. Trastuzumab or other HER2 related medication on treatment of HER2 amplification esophageal adenocarcinoma: Safran et al [ 70 , 71 ] , first reported clinical trial with trastuzumab, paclitaxel, cisplatin and radiation for locally advanced esophageal adenocarcinoma patients with HER2 overexpression.
The median survival for all 19 patients is 24 months, which is similar to prior studies. Esophagitis, nausea, dehydration, and neutropenia were the most common toxicity.
Therefore, trastuzumab does not increase toxicities when added to chemoradiation for patients with esophageal cancer. ToGA clinical trials in patients with gastric adenocarcinoma trial vs control: vs patients and gastroesophageal junction adenocarcinoma trial vs control: 58 vs 48 patients have shown a significant survival benefit for patients treated with a combination of trastuzumab and standard chemotherapy. Their primary goal is to determine whether trastuzumab increases disease-free survival when combined with radiotherapy, paclitaxel, and carboplatin followed by surgery in patients with HER2-overexpressing esophageal adenocarcinoma.
It is interesting to follow up their results. This alteration results in amplification of an amplicon on chromosome 17 that contains the HER2 proto-oncogene[ 73 , 74 ]. Gene amplification is the primary mechanism that drives HER2 receptor protein over-expression in this important subset of breast cancers.
HER2 over-expression resulting from gene amplification dramatically increases the likelihood of receptor activation and signaling, contributing to a more aggressive tumor biology and is associated with worse clinical outcome including higher rates of early, predominantly visceral and central nervous system recurrence and mortality. HER2 over-expression in breast cancer was recognized early on as being an ideal target for therapy, given the location of the receptor on the surface of tumor cells and its role in driving the clinical course of disease for the subset of patients with the HER2 alteration [ 78 ], [ 79 ].
The drug Trastuzumab was developed as a targeted biologic therapeutic against the HER2 receptor protein.
Trastuzumab is a humanized monoclonal antibody that combines the mouse recognition sequence of a monoclonal antibody clone 4D5 against an extracellular epitope of the receptors with a human IgG1[ 74 ]. Trastuzumab demonstrates a high affinity and specificity for the HER2 receptor and in preclinical studies was shown to be effective at inhibiting the growth of HER2 over-expressing breast cancer cells.
In numerous clinical trials, targeting HER2 has been shown to be remarkably effective against HER2 positive breast cancer in both the metastatic and the adjuvant settings, particularly in combination with cytotoxic chemotherapy.
Treatment with the drug Trastuzumab has been shown to improve response rates, time to progression, and even survival when used alone[ 18 ] or added to chemotherapy in metastatic setting. FISH evaluates the status of the HER2 gene in the nucleus and is a surrogate for protein expression, while IHC directly evaluates over-expression of the receptor protein at the surface of the cell. However, unusual HER2 genotypes such as polysomy for chromosome 17 and genomic heterogeneity can lead to discrepant non-correlating cases that may be clinically important.
Despite the remarkable clinical efficacy of HER2 targeted therapy, not all patients respond and de novo as well as acquired resistance remains an important clinical issue.
Currently there are no clinically validated factors that can be used to predict resistance to HER2 targeted therapy in breast cancer.
HER2 amplification, overexpression and score criteria in esophageal adenocarcinoma. Mod Pathol ; Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution 3.
Help us write another book on this subject and reach those readers. Login to your personal dashboard for more detailed statistics on your publications. Edited by Yahwardiah Siregar. E2F3 expression showed the best correlation with the microsatellite marker D6S located most closely to the gene Figure 4C.
However, this apparent correlation was mostly due to the strongly increased copy number of D6S in the cell line; if this data point is removed, the relationship is essentially random. Relationship of 6p22 gene expression changes to copy number changes of adjacent microsatellites in bladder cancer cell lines. To determine whether the results from the cell lines can be extended to bladder cancer tissues, the expression of the three genes was determined in 28 tumor tissue samples and 6 morphological normal samples from cystectomy specimens by real-time RT-PCR Figure 5 , Table 1.
In contrast, ID4 expression essentially did not differ between normal and cancer tissues. Instead, individual cancer specimens showed strongly increased expression beyond the range of normal tissues. Expression of genes at 6p Note the different scales in the three figure parts. Taken together with previous analyses of 6p Specifically, the findings raise interesting aspects with regard to ID4. Our findings indicate that 6p The telomeric region around DEK had not been investigated as well yet [ 10 ].
Our study confirms that this region is also subject to copy number gains and amplifications. Specifically, our findings are in good accord with ref. The three markers investigated in that study were located within 0. Thus, upon closer analysis, this region of amplification appears also heterogeneous in itself.
The intermediate region harboring ID4 had been more or less disregarded in previous studies, but our data indicate that it is clearly gained or even amplified in a certain number of cases, sometimes concomitantly with, and sometimes independent of the other two regions.
In summary, therefore, one might discern three main segments of amplification, which split up into further subregions in individual cancers. The 6p In this regard, it is interesting to compare the cell line data, where ID4 emerged as the most frequently over-expressed gene with the tissue data which showed generalized increases in expression of E2F3 and of DEK Figure 1 vs.
Figure 5. This apparent discrepancy can be relatively simply resolved by two plausible assumptions. Normal bladder tissue is largely quiescent, albeit proliferation increases strongly in response to tissue damage [ 20 ]. Thus, urothelial cancers are distinguished from normal tissue not only by expression of cancer-specific genes, but also by generalized over-expression of genes associated with cell proliferation. The generally increased expression of E2F3 and DEK in the cancer tissues may reflect the latter effect, with further increases in individual cases due to deregulation and copy number gains of these genes.
In contrast, early passage cultured urothelial cells proliferate as rapidly as cancer cell lines [ 21 — 23 ]. In contrast, ID4 expression has probably to be considered as ectopic in bladder cancer, since it is normally restricted to other tissues including testes and brain [ 19 ]. Thus, overexpression may more strictly depend on amplification of the gene, particularly in tumor tissues.
It is commonly assumed that regions in the genome that are amplified in cancers harbor proto-oncogenes that are activated by overexpression as a consequence of increased gene dosage. Indeed, several bona fide oncogenes have been found in amplified regions and some have even been identified by cloning from amplicons. In such cases, amplicons consistently contain one particular gene, alone or together with a limited number of others, e. Interestingly, the structure of such amplicons can be quite simple [ 24 — 26 ].
The mechanism underlying such amplifications is not understood in detail, but appears to involve the re-replication of a single chromosome fragment, most likely via a circular double-minute intermediate [ 26 ]. Clearly, the 6p22 amplicon in bladder cancer belongs to a different class of amplicons which are characterized by great heterogeneity and instability.
Such amplicons often contain different segments and accordingly different genes from one region and even sequences from different chromosomes [ 27 — 30 ]. The mechanism causing these amplifications is considered to be most likely breakage-fusion-bridge cycles initiated e. Considering this background, the question which is the oncogene targeted by 6p22 amplifications in bladder cancer and the specific issue of the role of ID4 have to be approached with due caution, since in each individual case the amplicon may be influenced by random factors such as the location of an initiating double-strand break and structural factors such as preferred sites of breakage of dicentric chromosomes arising during breakage-fusion-bridge cycles.
Nevertheless, the relatively high prevalence of 6p22 amplifications in bladder cancer and the relative specificity of this amplification for this cancer type argue for a functional selection as well. For several 6p22 genes subject to amplification, it is plausible to assume that their overexpression may confer a more aggressive phenotype to bladder cancer cells. SOX factors determine cell fate and cell differentiation [ 33 ], so SOX4 overexpression might lead to further dedifferentiation.
DEK is part of a oncogenic fusion protein resulting from t 6;9 p23;q34 translocations in acute myeloid leukemia [ 35 ] and is implicated in regulation of chromatin structure, which is evidently aberrant in invasive bladder cancers. However, specific functional studies on the role of these proteins in urothelial cells are lacking. ID4 belongs to a protein family whose members have been shown to interfere with cell differentiation by blocking the effects of HLH transcription factors and pocket proteins, including RB1.
Several members have been reported to be over-expressed in human cancers [ 15 — 18 ]. ID4 in particular has been shown to be overexpressed in rat mammary carcinomas. Accordingly, overexpression of ID4 blocked the differentiation of HC11 mammary epithelial cells and stimulated their proliferation [ 36 ]. It is also the target of a specific chromosomal translocation in some cases of B-cell acute lymphoblastic leukemia [ 37 ].
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C , C , and C You can also search for this author in PubMed Google Scholar. Correspondence to Akishi Ooi. Reprints and Permissions. Ooi, A. Protein overexpression and gene amplification of HER-2 and EGFR in colorectal cancers: an immunohistochemical and fluorescent in situ hybridization study. Mod Pathol 17, — Download citation.
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Skip to main content Thank you for visiting nature. Download PDF. Abstract Overexpression of HER-2 and the epidermal growth factor receptor EGFR has been observed in many cancers, sometimes accompanied by gene amplification. Main The HER-2 gene is located on chromosomal region 17q Materials and methods Tissue Samples We examined primary colorectal carcinomas and concurrently excised nodal metastases obtained from consecutive surgeries performed at the Department of Surgery, Yamanashi Medical University between and
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