|Year : 2014 | Volume
| Issue : 2 | Page : 317-323
Analysis of the chromosomal aneuploidy by interphase fluorescence in situ hybridization (FISH) in Squamous cell carcinoma of the cervix in Jammu region of J and K state
Roopali Fotra1, Shashi Gupta2, Sumit Koul1, Subash Gupta3
1 Institute of Human Genetics, University of Jammu, Jammu and Kashmir, India
2 Department of Gynecology and Obstetrics, SMGS Hospital/Govt. Medical College, Jammu, India
3 Human Genetic Research Cum Counseling Centre, Govt. Medical College/University of Jammu, Jammu, India
|Date of Web Publication||14-Jul-2014|
Centre Coordinator, HGRCC, GMC/JU, Jammu
Source of Support: None, Conflict of Interest: None
Aim: The present study was aimed to analyze the chromosomal changes obtained by using FISH. Fluorescence in situ hybridization (FISH) is a powerful technique used in the detection of chromosomal abnormalities.
Materials and Methods: During the present study, FISH technique was carried out in 26 cases of Squamous cell carcinoma of the cervix using Centromere Enumeration Probes, CEP for chromosome 3 and 17. Statistical tests including ANOVA and Chi square tests were used to analyze the numerical chromosome aberration data obtained by FISH analysis. FISH technique was also carried out in 10 healthy samples (control) by using both CEP 3 and CEP 17 probe.
Results and Discussion: FISH results of CEP 3 in the present study showed the frequent gains of chromosome 3 in Squamous cell carcinoma over the chromosome 17. ANOVA results were found to be significant for both CEP 3 and CEP-17 in Squamous cell carcinoma of the cervix. Chi square test (disease v/s control) was also used to study the significant difference between the patients and the controls and it was found to be significant for both chromosomes 3 and 17.
结果与讨论：在目前的研究FISH结果表明FISH结果在鳞状细胞癌中3号染色体的检测频度于17号染色体。方差分析结果表明在宫颈鳞癌中CEP 3和CEP 17都有重要意义。卡方检验（病人与对照）也表明患者和对照组之间差异显著，无论是染色体3号还是17号。
Keywords: Carcinoma, cervix, chromosomes, fluorescence in situ hybridization
|How to cite this article:|
Fotra R, Gupta S, Koul S, Gupta S. Analysis of the chromosomal aneuploidy by interphase fluorescence in situ hybridization (FISH) in Squamous cell carcinoma of the cervix in Jammu region of J and K state. J Can Res Ther 2014;10:317-23
|How to cite this URL:|
Fotra R, Gupta S, Koul S, Gupta S. Analysis of the chromosomal aneuploidy by interphase fluorescence in situ hybridization (FISH) in Squamous cell carcinoma of the cervix in Jammu region of J and K state. J Can Res Ther [serial online] 2014 [cited 2020 Jan 17];10:317-23. Available from: http://www.cancerjournal.net/text.asp?2014/10/2/317/136612
| > Introduction|| |
Cancer in its various forms is a genetic disease, characterized by deviations of the normal genetic mechanisms that regulate cell growth. These manifest themselves in a number of different ways, including chromosomal changes that can be detected microscopically.  Tumorigenesis is a multistep process that involves a series of genetic and epigenetic alterations.  It has been suggested that cancer cells are genetically unstable and that acquisition of genetic instability may represent an early step in the process of carcinogenesis. 
Carcinoma cervix worldwide accounts for 15% of all cancers diagnosed in women.  It is the second most common cancer in women globally and 80% of these occur in developing countries. The incidence is highest in Africa, India and Central/South America (approximately 29 per 100,000 person/years) and lowest in Oceania, North America and most Muslim counties (approximately 7.5 per 100,000 PY).  India has a high incidence of cervical cancers with roughly 87,500 newly diagnosed patients each year, 16% of the world's total cases. 
SCC usually starts in the area of the squamocolumnar junction (transformation zone). Occasionally, however, it arises in the endocervix, sometimes deep to the lining. SCC of the cervix is seen in the microinvasive and invasive forms. Some invasive cancers of the cervix are hypertrophic or exophytic, producing a cauliflower-like mass, whereas others are mainly eroding and ulcerative or infiltrative. Histologically, these SCCs are large cell keratinizing, non-keratinizing and small cell types.
Refinements in the cytogenetic techniques over the past 30 years have allowed the increasingly sensitive detection of chromosomal abnormalities in hematological malignancies, with the advent of fluorescence in situ hybridization (FISH) techniques providing significant advances in both diagnosis and research of hematological malignancies and solid tumors. Molecular biology has led to the development of many new techniques for the study of genetic alterations in human genetic diseases. One such method, fluorescence in situ hybridization (FISH), is uniquely suited to the definition of DNA alterations in single cells, permitting correlations with morphology and with other marker studies applied to the same cells.
| > Materials and methods|| |
FISH is essentially based upon the same principle as a Southern blot analysis, a cytogenetic equivalent that exploits the ability of single-stranded DNA to anneal to complementary DNA. In the case of FISH, the target is the nuclear DNA of either interphase cells or of metaphase chromosomes affixed to a microscope slide, although FISH can also be performed using bone marrow or peripheral blood smears, or fixed and sectioned tissue. 
During the present study, FISH technique was carried out in 26 cases of Squamous cell carcinoma of the cervix by using Vysis made Alphoid DNA probes (Centromere Enumeration Probes, CEP) and the site of the hybridization of probes with cellular DNA was observed under fluorescence microscope Olympus BX 61 for fluorescent signals. The probes used were namely:
- CEP 3 (D3Z1) 3p11.1- q11.1 Alpha satellite DNA Spectrum orange probe
- CEP 17 (D17Z1) 17p11.1- q11.1 Alpha satellite DNA Spectrum orange probe
The protocol for FISH was followed according  with slight modifications. In brief, slides were denatured by incubation with formamide (70% in 2X SSC) at 73°C for 5 mins in a water bath. Then the slides were dehydrated through a graded ethanol system (70%, 80%, 90%1 min for each slide) hybridization solution (5 μl) was applied to each slide which was covered with a coverslip and sealed with rubber cement. After incubation for 16 hrs at 37°C in a humidified chamber, slides were washed with 2X SSC for 5 mins at 73°C. Then DAPI (2 μl) was applied to each spot and again covered with a coverslip. Apart from diseased samples, 10 samples of healthy subjects (controls) were also used for FISH were also both CEP 3 and CEP 17 probes were used.
Statistical tests including ANOVA and Chi square tests were used to analyze the numerical chromosome aberration data obtained by FISH analysis.
| > Results|| |
Classical Cytogenetic analysis of solid tumors often remained incomplete, because chromosome regions that appeared abnormal did not always have a characteristic band that could be accurately identified. Therefore, molecular cytogenetic technique like Fluorescent in situ hybridization (FISH) is mostly used as a confirmatory technique which provides brief knowledge about cytogenetic abnormalities.
Fluorescent in situ hybridization (FISH) is a technology where the fluorescent labeled DNA probes are used to detect or confirm the changes both at gene or at chromosome level that are generally beyond the resolution of conventional cytogenetics. , when the mitotic index is low, or the cytogenetics preparation is suboptimal, an accurate chromosomal profile cannot be achieved using standard banding techniques. 
FISH results of CEP 3 in the present study showed the frequent gains of chromosome 3 in squamous cell carcinoma over the chromosome 17 [Table 1] and [Table 2] [Figure 1] and [Figure 2]. The average percentage frequencies of different types of the cells (Normal, Nullisomic, Monosomic, Trisomic and Polysomic) by using CEP 3 in SCC was found to be the highest in Trisomic cells (25.32%) followed by Polysomic cells (21.66%).
|Figure 1: Representative FISH analysis: A case in which in most of the cells carry three copies for the centromeric signal of chromosome 3|
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|Figure 2: Interphase FISH using centromeric enumeration probe (CEP- 3) probe in Squamous cell carcinoma of the cervix showing multiple copies of the signals for chromosome 3|
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During the current study, it was noted that there was a preferential loss of chromosome 17 in Squamous cell carcinoma. The average percentage frequencies of different types of the cells (Normal, Nullisomic, Monosomic, Trisomic and Polysomic) by using CEP 3 and CEP 17 in Squamous cell carcinoma of the cervix was found to be 28.7% in monosomic cells [Figure 3] and [Figure 4].
|Figure 3: Interphase FISH using centromeric enumeration probe (CEP- 17) probe in Squamous cell carcinoma of the cervix|
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|Figure 4: Red signals indicating the presence of chromosome 17 by using probe CEP-17 in Squamous cell carcinoma of the cervix showing frequent loss|
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|Table 1: Results of CEP 3 probe in Squamous cell carcinoma of the cervix|
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|Table 2: Results of CEP 17 probe in Squamous cell carcinoma of the cervix|
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FISH technique was also carried out in 10 healthy samples (control) to make a comparison between the diseased condition and the normal samples. The average percentage frequencies of different types of the cells (Normal, Nullisomic, Monosomic, Trisomic and Polysomic) by using CEP 3 and CEP-17 in SCC was found to be the highest 93% each [Table 3] and [Table 4].
ANOVA results were found to be significant for both CEP 3 and CEP-17 in squamous cell carcinoma of the cervix [Table 5] and [Table 6]. Chi square test (disease v/s control) was also used to study the significant difference between the patients and the controls and it was found to be significant for both chromosomes 3 and 17 [Table 7] and [Table 8].
|Table 5: ANOVA analysis for the FISH results by using CEP 3 probe for Squamous cell carcinoma of the cervix|
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|Table 6: ANOVA analysis for the FISH results by using CEP 17 probe for Squamous cell carcinoma of the cervix|
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|Table 7: Specificity and sensitivity of CEP 3 probe in the diagnosed cases of cervical cancer and their relative significance with the controls|
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|Table 8: Specificity and sensitivity of CEP 17 probe in the diagnosed cases of cervical cancer and their relative significance with the controls|
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| > Discussion|| |
Carcinoma of the cervix although life threatening and one of the leading causes of female death has not been intensively subjected to cytogenetic study in J and K state. To know as to what are the main chromosomal changes that take place during its origin as well as progression, the present study was taken up in Jammu, J and K state. Available data on the prevalence of cervical cancer amongst the females of J and K state shows that the disease affects about 11% females of the state.  This information was based on the Pap smear. There is no report on the chromosomal changes taking place in CaCx amongst the females of J and K therefore it was for the first time that work on the cytogenetics of CaCx was taken up.
Study of the cellular genetics of cancer has advanced rapidly spurred by the advances in methods of chromosome analysis by the integration of molecular genetics with the cytogenetics. Cytogenetics examination of solid tumors is technically more difficult compared to Leukemias and lymphomas. The cytogenetics of solid tumors has been hampered by difficulties in obtaining high quality chromosome preparations from surgical specimens or cultured cells. Therefore, advances in culture techniques and methods of analysis have been improved to increase the success rate for the analysis of solid tumors.
Classical cytogenetic techniques have their own limitations in solid tumors. The preparation of slides from the biopsies taken out from the solid tumors for the study of chromosomes are not good and for most of the time it is difficult to get well spread metaphase plates for chromosomal analysis. This difficulty has been eased by the use of FISH which is used both on the interphase and metaphase nuclei. Since the introduction of 'in situ hybridization', the technique has been used for the localization of DNA sequence in interphase and metaphase nuclei from many different cell types. The availability of satellite DNA probes specific for individual chromosome has provided a new class of molecular markers for the cytogenetic analysis of the various genetic diseases including cancers.
FISH technology has been used for the study of chromosomal changes in a wide variety of tumors such as ovary,  breast,  uroepithelial carcinomas  and present study is an addition to the list of the existing workers in this area.
In accordance with earlier reports on the use of FISH probes for the evaluation of chromosomal changes in cancers, during the present study, Centromeric Enumeration Probes for chromosomes 3 and 17 were used. Study of the available data on the application of FISH in CaCx generally showed the involvement of chromosome 3 and 17 in the CaCx. This necessitated the earlier workers to use only these two FISH probes. Also in the present study the same FISH probes were selected to know more about the involvement of chromosome 3 and 17 in CaCx. During the present study, Centromeric Enumeration Probes (CEP) for chromosome 3 and 17 were used. Both these chromosomes 3 and 17, have been largely studied in the cervical carcinomas by various workers like. ,,, Centromeric enumeration probes (CEP) have also been utilized in the analysis of cells from a variety of tumors like breast, , hepatocellular carcinoma,  lung cancers.  CEP probes not only make possible to illustrate the nucleus structure in the precondition of preserving the nucleus shape but also allow the quantitative evaluation of target gene amplification by using Centromeric probes. Fluorescent in situ hybridization (FISH) with chromosome specific or chromosomal break point specific DNA probes facilitate the confirmation of presumed chromosomal aberrations with high sensitivity and specificity.  The introduction of automated microscopic FISH scanning systems has also facilitated the developments of FISH based assays, which could serve as surveillance tools in the patients suffering from various diseases including cancers. Therefore FISH becomes an essential tool for relative DNA copy number change estimation and in addition it detects balanced structural rearrangements and assesses ploidy level.
DNA probes for chromosome 3 and 17 have been previously reported to exhibit non-random chromosomal alteration in cervical cancer cells. ,,
FISH results of CEP 3 in the present study showed the frequent gains in squamous cell carcinoma over the chromosome 17. The average percentage frequencies of the signals scored by using CEP in SCC was found to be the highest in Trisomic cells (25.32%) followed by Polysomic cells (21.66%) [Figure 3]. Numerical changes in the form of Trisomy 3 were the most consistent chromosomal aberrations reported in the diagnosed cases of the cervical carcinoma. Our findings have been found to be more or less similar with the findings made by ,,,,,, who used CEP 3(D3Z1) in cervical carcinoma.
Heselmeyer and colleagues  1996 while working on the CaCx proposed that a gain on the chromosome arm 3q is an event in the cervical carcinogenesis that occurs during the transition from premalignant lesions to the invasive carcinoma. Gain of chromosome arm 3q material was the most frequent copy number change that was detected by the molecular cytogenetic techniques like Comparative Genomic Hybridization thus showing the importance of long arm of chromosome no. 3 in carcinoma cervix. This copy number change of chromosome 3 has also been frequently observed in the head and neck tumors , and ovarian tumors. , This involvement of 3q in various cancers suggests that chromosome no. 3 harbors novel genes that are important in the carcinogenic process of human cancers.
One distinguishing characteristic of the current study was the preferential loss of chromosome 17. The average %age frequencies of the monosomic signals scored by using CEP-17 in case of squamous cell carcinoma of the cervix were 28.7% in the interphase cells it was concluded that the loss of chromosome 17 was the most frequent observation made during the present study in the diagnosed cases of the cervical carcinoma. Study of the available literature shows that our findings were in accordance with the observations ,, where it was stated that the loss of chromosome 17 is likely to be a relatively an early event in cervical carcinogenesis. Both the structural and numerical chromosomal abnormalities targeting chromosome 17 are often observed in the tumors from a wide variety of tissues and therefore suggest that this loss may represent a common event in carcinogenesis.
FISH technique was also carried out in 10 healthy samples (control) by using both CEP 3 and CEP 17 probe. The average %age frequencies of the disomic signals by using the said probes were found to be 93%. ANOVA test was used to analyze the data on the numerical chromosome aberration data obtained by FISH analysis. ANOVA (analysis of variance) is a collection of statistical models, and their associated procedures, in which the observed variance in a particular variable is partitioned into components attributable to different sources of variation. In its simplest form ANOVA provides a statistical test of whether or not the means of several groups are all equal, and therefore generalizes t-test to more than two groups. ANOVAs are helpful because they possess an advantage over a two-sample t-test. Doing multiple two-sample t-tests would result in an increased chance of committing a type I error. For this reason, ANOVAs are useful in comparing two, three or more means. ANOVA results were found to be significant for CEP 3 in squamous cell carcinoma of the cervix. On the other hand, ANOVA analyses were found to be significant for CEP 17 in squamous cell carcinoma. A Chi-square test (also chi squared test or χ2 test) is any statistical hypothesis test in which the sampling distribution of the test statistic is a Chi-square distribution when the null hypothesis is true, or any in which this is asymptotically true, meaning that the sampling distribution (if the null hypothesis is true) can be made to approximate a Chi-square distribution as closely as desired by making the sample size large enough. Chi square test was also used to study the significant difference between the patients and the controls and it was found to be significant for both chromosomes 3 and 17. Chi square test was used to study the specificity and sensitivity of the FISH technique used during the present study to make a comparison between the disease and normal samples. Chi square statistical test has been used by various workers like. ,,,
Cancer, either sporadic or hereditary, is a genetic disease that develops through multiple genetic changes. Specific genetic defects have been found to be associated non randomly with the predisposition, genesis, progression and metastasis of various kinds of neoplasia. Accurately and efficiently identifying these alterations, therefore, can assist in the early detection, diagnosis, prognosis and therapeutic treatment of human neoplasia. Cytogenetic analysis has helped a great deal in theses respects. The development of various molecular cytogenetic methodologies has facilitated the basic research and clinical application of cancer cytogenetics. In this view the advantages and limitations of each of the various types of conventional and molecular cytogenetic methodologies are discussed with regard to their research and clinical application in human neoplasia.
| > Acknowledgements|| |
Authors are extremely thankful to the J and K State Council for Science and Technology, Department of Science and Technology, J and K State for providing financial support to conduct the research work.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8]