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PubMed2003

[The role of the immunohistochemistry for hMLH1 and hMSH2 with detection of microsatellite instability to identify the kindreds with hereditary nonpolyposis colorectal cancer].

OBJECTIVE: To investigate the specificity and sensitivity of the immunohistochemistry for hMLH1 and hMSH2 with detection of microsatellite instability (MSI) to identify the kindreds with hereditary nonpolyposis colorectal cancer and to analyse its value in clinical practice. METHOD: Specimens of 16 cases with HNPCC and 16 cases with sporadic colorectal cancer were detected by immunostaining with hMLH1 and hMSH2 and MSI was also detected. RESULTS: The specificity and sensitivity of the immunohistochemistry for hMLH1 and hMSH2 were 91.7% and 87.5% respectively. The specificity and sensitivity of MSI were 100% and 75.0%. By combining two methods, the specificity and sensitivity were 91.7% and 93.8% respectively. CONCLUSIONS: By combination of the immunohistochemistry for hMLH1 and hMSH2 and detection of MSI to identify the kindreds with HNPCC, the specificity and sensitivity are improved which is better than to use either of them alone. And it is very easy and cheap that it can be used in clinics.

Adaptor Proteins, Signal Transducing↗

PubMed1995

Molecular basis of endometrial cancer.

BACKGROUND: Most human cancers are thought to arise from alterations in oncogenes and tumor suppressor genes. METHODS: Molecular techniques have been used to identify specific genetic alterations in endometrial cancers. RESULTS: Overexpression of the HER-2/neu oncogene occurs in 10% of endometrial cancers and correlates with poor survival. Alterations in other receptor tyrosine kinases (c-fms and epidermal growth factor receptor) also occur in some cases. The c-myc oncogene, which encodes a nuclear transcription factor, also may be overexpressed in some invasive cancers. Mutations in the K-ras oncogene occur in 10% and in 20-30% of American and Japanese endometrial cancers, respectively. K-ras mutations also have been observed in endometrial hyperplasias, and this may represent an early event in the development of some cancers. Mutation of the p53 tumor suppressor gene, with resultant overexpression of mutant p53 protein, occurs in 20% of endometrial adenocarcinomas. Overexpression of p53 is associated with advanced stage and poor survival. Because p53 mutations do not occur frequently in endometrial hyperplasias, this may be a relatively late event in endometrial carcinogenesis. Recent studies have shown that mutations occur in microsatellite sequences in some endometrial cancers. Because microsatellite instability in hereditary nonpolyposis colon cancer has been found to be caused by mutations in DNA repair genes, similar mutations are being sought in endometrial cancers. CONCLUSIONS: Although several molecular alterations have been identified, the molecular pathogenesis of endometrial cancer remains poorly understood.

Amidohydrolases↗

PubMed2001

Molecular detection of cervical intraepithelial neoplasia and cervical carcinoma by microsatellite analysis of Papanicolaou smears.

Carcinoma of the uterine cervix is one of the most common malignancies worldwide, yet it is clearly preventable by population screening. The Papanicolaou (Pap) smear has proved to be the most successful test for the detection of precancerous lesions and is largely responsible for the reduction of cervical cancer mortality and morbidity rates. However, the Pap smear is not perfect; false-negative results of various rates are reported. To improve the diagnostic efficacy of cervical cytology, we performed microsatellite analysis on paired Pap smear samples from cervical lesions. Nine microsatellite markers were chosen from chromosomal regions commonly displaying loss of heterozygostity (LOH) in cervical cancer and those displaying microsatellite instability (MI) in other squamous cell cancer. Microsatellite alterations were detected in 16/21 (76%) Pap smear DNA samples including 11 of 13 (85%) smears from invasive squamous cell carcinomas (SCCs) and 5 of 8 (63%) from squamous intraepithelial lesions (SILs). Microsatellite alterations detected in the Pap smear DNA were identical to those identified in seven paired primary tumors available for analysis. Moreover, this molecular approach detected genetic alterations in two cases apparently negative by cytologic examination. None (0/25) of the control patients displayed microsatellite alterations in paired Pap smears. Microsatellite analysis of cervical cytologic samples may provide a complementary method to analyze suspicious but not diagnostic cytologic samples further.

Adenocarcinoma↗

PubMed1995

Biomarkers in the endometrium.

A number of oncogenes and tumor suppressor genes that may serves as surrogate biomarkers of transformation are altered during the process of endometrial carcinogenesis. Overexpression of HER-2/neu occurs in 10% of endometrial adenocarcinomas and correlates with intraperitoneal spread of disease and poor survival. The c-myc oncogene is amplified in 10% of cases. Point mutations in codon 12 of the K-ras oncogene have been reported to occur in 10-20% of endometrial cancers. K-ras mutations also have been noted in some endometrial hyperplasias, which may represent an early event in the development of some endometrial cancers. Mutation of the p53 tumor suppressor gene, with resultant overexpression of mutant p53 protein, occurs in 20% of endometrial adenocarcinomas. Overexpression of p53 is associated with advanced stage and poor survival. Because p53 mutations have not been observed in endometrial hyperplasias, this is thought to be a relatively late event in endometrial carcinogenesis. Microsatellite instability has also been noted in approximately 15% of sporadic endometrial cancers, but mutations in DNA repair genes have not yet been reported. Chemoprevention trials in endometrial cancer may be feasible due to the existence of a premalignant lesion and surrogate biomarkers.

Biomarkers, Tumor↗

PubMed1998

Reciprocal relationship between the tumor suppressors p53 and BAX in primary colorectal cancers.

Though most colorectal cancers show allelic losses, a subset of colorectal cancers (microsatellite instability or MSI-positive cancers) develop numerous small insertion and deletion mutations in repetitive DNA. Some of these sequences occur in coding regions of cancer related genes which, when targeted by frameshift mutations, produce truncations in their protein product. Such a gene is the proapoptotic tumor suppressor, BAX, mutated by frameshifts within a polyG sequence in approximately 50% of MSI-positive colorectal cancers. BAX is directly transactivated by p53, a gene commonly mutated in colorectal cancers but not often in MSI-positive lesions. Here we sought to characterize the relationship between BAX and p53 by simultaneously analysing a selected series of 65 colorectal tumors for mutations in the entire coding regions of both genes. The tumors comprised 19 MSI-high, 12 MSI-low and 34 MSI-null cancers. Eight of 19 MSI-high sporadic colorectal cancers (42%) contained insertions and deletions at the polyG tract in the BAX gene. In addition, three somatic BAX missense mutations were identified in two tumors. A single missense mutation was detected in an MSI-high tumor that also contained a frameshift microdeletion, and two missense mutations were identified in an MSI-null tumor wild-type for p53. p53 mutations were detected in 5/12 MSI-low tumors (42%) and 12/34 MSI-null tumors (35%). Of significance, no p53 mutations were detected in MSI-high tumors. This study demonstrates that a reciprocal relationship exists between p53 and BAX in sporadic colorectal cancers, and further supports the hypothesis that MSI-low tumors are biologically similar to MSI-null tumors.

Amino Acid Sequence↗

PubMed2000

Molecular genetics of hereditary nonpolyposis colorectal cancer.

The initial paradigm developed for colorectal carcinogenesis was derived from the observation that these tumors suffer a large number of chromosomal losses. This phenomenon results from unbalanced mitoses, and to date there is no clear explanation for this type of genomic instability. In 1993, a second type of genomic instability was detected and linked to 12-15% of sporadic tumors, as well as 90% or more of the colon cancers in hereditary nonpolyposis colorectal cancer (HNPCC). HNPCC tumors are typically diploid and do not have the inactivating mutations at the tumor suppressor genes commonly found in the other cancers. These tumors were found because they have a very large number (perhaps in excess of 10(5)) of insertion or deletion mutations at microsatellite sequences; as a result, this has been termed microsatellite instability (MSI). The majority of HNPCC families can be linked to germline mutations in the DNA mismatch repair (MMR) genes hMSH2 or hMLH1. Germline mutations in hMSH6 and hPMS2 in HNPCC families are much less common. HNPCC tumors develop through the accumulation of mutations at genes that control cellular growth, and these genes are not the same as those recognized in the initial pathway outlined by Vogelstein et al. The genetic targets of MSI all contain repetitive sequences in coding regions that are unstable when the DNA MMR system is inoperative. Certain pathological features have been identified that suggest that colon cancers have developed in the setting of defective DNA MMR.

Adaptor Proteins, Signal Transducing↗

PubMed2002

Loss of DNA mismatch repair proteins in skin tumors from patients with Muir-Torre syndrome and MSH2 or MLH1 germline mutations: establishment of immunohistochemical analysis as a screening test.

Muir-Torre syndrome (MTS) is a rare autosomal-dominant disorder characterized by the predisposition to both sebaceous skin tumors (or multiple keratoacanthomas) and internal malignancies. A subtype of MTS is allelic to hereditary nonpolyposis colorectal cancer and is caused by germline mutations in the DNA mismatch repair genes MSH2 or MLH1. In these cases both internal and skin tumors show characteristic microsatellite instability (MSI). The aim of the present study was to determine whether immunohistochemical examination of MSH2 or MLH1 protein expression in MTS-associated skin tumors can be used as a diagnostic screening tool to identify patients with germline mutations in MSH2 or MLH1. In the present study 28 skin lesions from 17 patients (20 sebaceous gland tumors, 4 sebaceous hyperplasias, 3 keratoacanthomas, and 1 squamous cell carcinoma) were tested immunohistochemically with antibodies against MSH2 and MLH1. Eighteen of these tumors were from eight patients with known MSH2 germline mutations, two tumors were from a patient with a germline mutation in MLH1, and eight microsatellite stable sporadic skin tumors served as controls. One sample had to be excluded because of a lack of immunoreactivity. All eight microsatellite stable tumors expressed both DNA repair proteins. In 15 of the tumors from MSH2 germline mutation carriers, loss of MSH2 expression was observed, one tumor showed reduced MSH2 expression, and one tumor displayed positive immunoreactivity to MSH2. Both tumors of the MLH1 germline mutation carrier showed loss of the MLH1 protein. In conclusion, our findings demonstrate that immunohistochemical testing of MTS-related skin tumors is a reliable screening method with high predictive value for the diagnosis of the DNA mismatch repair-deficient MTS.

Adaptor Proteins, Signal Transducing↗

PubMed2004

Mechanism of carcinogenesis in familial tumors.

It is thought that malignant tumors occur through interactions of multiple environmental factors and a personal genetic factor. A normal somatic cell having an intrinsic function is able to acquire the characteristics of a malignant cell under the influence of many factors. A small percentage of all tumors have obvious familial aggregation. These entities are called familial cancer. The familial cancer syndrome is well defined for colorectal cancer, breast cancer, endocrine neoplasia, and so on. Traits of familial tumors are sequentially inherited by offspring through gametes in a Mendelian fashion, most commonly in an autosomal-dominant manner. Carcinogenesis requires multiple genetic events. A patient with a familial tumor is ahead of an individual without any germline mutation in the carcinogenesis process. In such a situation, patients frequently suffer from multiple malignant tumors at a young age. It is well known that three major genes are closely related to the cell cycle and tumorigenesis. These gene types are protooncogenes, tumor suppressor genes, and DNA mismatch repair genes. Proto-oncogenes function to accelerate cells during the G1 or growth phase of the cell cycle. Tumor suppressor genes act as blocks against cell growth and proliferation. Inactivation of tumor suppressor genes requires alterations in both alleles. These phenomena are known as Knudson's two-hits theory. However, DNA mismatch repair genes are known as caretaker genes and correct mismatch pair generation during DNA replication. Germline mutation of DNA mismatch repair genes causes hereditary nonpolyposis colorectal cancer. The tumor phenotype from patients with hereditary nonpolyposis colorectal cancer is demonstrated to be microsatellite instability positive.

Cell Transformation, Neoplastic↗

PubMedDate not supplied

Immunohistochemical and DNA sequencing analysis on human mismatch repair gene MLH1 in cervical squamous cell carcinoma with LOH of this gene.

BACKGROUND: The human MLH1 gene (hMLH1) is one of the DNA mismatch repair genes. Defects in these genes are believed to be the underlying cause of microsatellite instability (MSI). MSI has been demonstrated in many human cancers such as colon cancer and some female-specific tumors. The hMLH1 gene can be inactivated by genetic mutation or by hypermethylation of its promoter region, which often causes cessation of hMLH1 protein production. We were prompted by our previous finding of 43% of cervical cancers and their precursors with a loss of heterozygosity (LOH) of the hMLH1 gene to investigate whether it is inactivated during the carcinogenesis of cervical cancer. MATERIALS AND METHODS: hMLH1 protein production was assessed by immunohistochemistry, and nucleotide sequence analysis were performed on all exons of the hMLH1 gene. RESULTS: In 11 cases of invasive cervical cancer, among which 7 had LOH of the hMLH1 gene, immunohistochemistry provided no evidence for cessation of hMLH1 protein production. In addition, no mutations were found in any of the 19 hMLH1 gene exons. CONCLUSIONS: The activity of hMLH1 gene might not be disturbed in the development of cervical cancer although a proportion of the cases had lost one of its hMLH1 gene copies.

Adaptor Proteins, Signal Transducing↗

PubMed1994

Microsatellite instabilities at five chromosomes in primary breast tumors.

The microsatellite instabilities at nine loci of chromosomes 2p, 8p, 10p and 11p and the nm23-H1 locus on 17q21.3 were studied in primary breast tumors. Alterations in the short interspersed tandem repeats in tumor DNA in the form of either larger allele, smaller allele or LOH were observed. Significantly, a high occurrence of alterations in microsatellite polymorphisms at the ANK1, D8S135 and LPL loci of chromosome 8p (46-54%), the D2S119 locus of chromosome 2p (56%), the D10S197 locus at chromosome 10p (88%), and the nm23-H1 locus of chromosome 17q21.3 (46%) were observed in breast tumors. These results provide the first evidence for genomic instabilities at 2p, 8p and 10p in primary ductal and lobular breast carcinomas. No correlation has been found between the stage of the tumor and microsatellite instability, suggesting that microsatellite instability is an early genetic event in breast carcinogenesis.

Breast Neoplasms↗

PubMed2004

[DHPLC analysis of microsatellite instability in gastric cancer].

To establish a fast, simple and solid method of studying microsatellite instability (MSI) in gastric cancer, a panel of 12 microsatellite sites, D1S548, D1S552, D5S346, TP53, IGF II R(G)(8), IGF II R(CT)(5), TGFbetaR II(GT)(3), TGFbetaR II(A)(10), hMSH3(A)(8), hMSH6(G)(8), BAX(G)(8) and Bat26, were detected by denatured polyacrymide gel electrophoresis-silver stain in 28 gastric cancers. Bat26 was also analyzed by denatured high performance liquid chromatograph (DHPLC) at 50 degrees in the DNASep Cartridge. Two MSI-H (7.14%) and 15 MSI-L cancers (53.6%) were identified in 28 gastric cancers. Bat26 was positive only in 2 MSI-H cancers. The alterations of Bat26 and MSI-H status were coincident (P<0.01). The two Bat26+ cancers were also confirmed by DHPLC. Results obtained from DHPLC and gel electrophoresis were completely consistent. Thus, DHPLC analysis of Bat26 site may be a favorable method of detecting MSI-H status in gastric cancer, and be of clinical importance.

Adult↗

PubMed2005

Microsatellite instability and colorectal cancer prognosis.

PURPOSE: Many studies have evaluated the role of high levels of microsatellite instability (MSI) as a prognostic marker and predictor of the response to chemotherapy in colorectal cancer (CRC); however, the results are not conclusive. The aim of this study was to analyze the prognostic significance of high levels of MSI (MSI-H) in CRC patients in relation to fluorouracil-based chemotherapy. EXPERIMENTAL DESIGN: In three different institutions, 1,263 patients with CRC were tested for the presence of MSI, and CRC-specific survival was then analyzed in relation to MSI status, chemotherapy, and other clinical and pathologic variables. RESULTS: Two hundred and fifty-six tumors were MSI-H (20.3%): these were more frequently at a less advanced stage, right-sided, poorly differentiated, with mucinous phenotype, and expansive growth pattern than microsatellite stable carcinomas. Univariate and multivariate analyses of 5-year-specific survival revealed stage, tumor location, grade of differentiation, MSI, gender, and age as significant prognostic factors. The prognostic advantage of MSI tumors was particularly evident in stages II and III in which chemotherapy did not significantly affect the survival of MSI-H patients. Finally, we analyzed survival in MSI-H patients in relation to the presence of mismatch repair gene mutations. MSI-H patients with hereditary non-polyposis colorectal cancer showed a better prognosis as compared with sporadic MSI-H; however, in multivariate analysis, this difference disappeared. CONCLUSIONS: The type of genomic instability could influence the prognosis of CRC, in particular in stages II and III. Fluorouracil-based chemotherapy does not seem to improve survival among MSI-H patients. The survival benefit for patients with hereditary non-polyposis colorectal cancer is mainly determined by younger age and less advanced stage as compared with sporadic MSI-H counterpart.

Adaptor Proteins, Signal Transducing↗

PubMed2001

The role of the DNA mismatch repair system in the cytotoxicity of the topoisomerase inhibitors camptothecin and etoposide to human colorectal cancer cells.

The DNA mismatch repair (MMR) system is involved in the correction of base/base mismatches and insertion/deletion loops arising during replication. In addition, some of the MMR components participate in recombination and double-strand break repair as well as cell cycle regulation and apoptosis. The inactivation of MMR genes, usually hMSH2 or hMLH1, is associated with human colorectal cancers and is responsible for the characteristic microsatellite instability (MSI)+ phenotype of these tumors. Because MMR is assumed to modulate cytotoxicity to various chemotherapeutic agents that act upon DNA, our objectives have been to define its possible involvement in the cytotoxicity of topoisomerase inhibitors. We have shown that colorectal cancer cell lines defective in DNA MMR exhibit an increased sensitivity to both camptothecin, a topoisomerase I inhibitor, and etoposide, a topoisomerase II inhibitor. Sensitivity to these drugs cannot be predicted by measuring endogenous levels of topoisomerase I and II. Our results also indicate that neither p53 status, nor cell cycle alterations correlate with the sensitivity of colorectal cancer cells to topoisomerase inhibitors. On the other hand, our data showing that resistance to these drugs can be achieved by the functional complementation of hMLH1 in an hMLH1-defective cell line have allowed us to establish that MMR is a critical determinant for chemosensitivity. Interestingly, our observations provide the rationale for the better responsiveness of MSI+ tumors to CPT-11, a camptothecin derivative, which we have observed in patients with metastatic colorectal cancers.

Adaptor Proteins, Signal Transducing↗

PubMed2001

Detection of head and neck squamous cell carcinoma among exfoliated oral mucosal cells by microsatellite analysis.

Prompt detection of head and neck squamous cell carcinoma (HNSCC) is vital to successful patient management. In this feasibility study, we used microsatellite analysis to detect tumor-specific genetic alterations in exfoliated oral mucosal cell samples from patients with known cancer. Exfoliated mucosal cells in pretreatment oral rinse and swab samples were collected from 44 HNSCC patients and from 43 healthy control subjects (20 nonsmokers and 23 smokers). We tested a panel of 23 informative microsatellite markers to assay DNA from the matched lymphocyte, tumor (from cancer cases), and oral test samples. Loss of heterozygosity or microsatellite instability of at least one marker was detected in 38 (86%) of 44 primary tumors. Identical alterations were found in the saliva samples in 35 of these 38 cases (92% of those with markers; 79% overall) including 12 of 13 cases with small primaries [stage Tt or Tx (occult primary)] and 4 of 4 cases of patients that had undergone prior radiation. Microsatellite instability was detectable in the saliva in 24 (96%) of 25 cases in which it was present in the tumor, and loss of heterozygosity was identified in the test sample in 19 (61%) of 31 cases. No microsatellite alterations were detected in any of the samples from the healthy control subjects. This approach must now be refined and validated for the detection of clinically occult disease. Microsatellite analysis of oral samples may then become a valuable method for detecting and monitoring HNSCC.

Carcinoma, Squamous Cell↗

PubMed2000

The mismatch repair gene hMSH2 is mutated in the prostate cancer cell line LNCaP.

PURPOSE: Mismatch repair genes are responsible for the coordinated correction of misincorporated nucleotides formed during DNA replication. Inactivating and inherited mutations in the prototypic mismatch repair gene hMSH2 have been described in a cancer predisposition syndrome known as hereditary nonpolyposis colon cancer. Patients with hereditary nonpolyposis colon cancer are at increased risk for colon cancer and extracolonic cancers such as upper tract transitional cell carcinoma but not prostate cancer. We investigated expression of hMSH2 in prostate cancer cell lines using genetic and molecular analysis. MATERIALS AND METHODS: We used the 3 well described prostate cancer cell lines, DU145, LNCaP and PC3. Western blot analysis with monoclonal antibody to hMSH2 was used to assess expression. Southern blot and polymerase chain reaction of genomic DNA were used to identify genetic alterations in the hMSH2 gene. Single cell cloning, dinucleotide repeats and BAT-26 were used to assess the cell lines for microsatellite instability. RESULTS: The prostate cancer cell line LNCaP did not express hMSH2 and was found to have a homozygous deletion of hMSH2 exons 9 to 16, resulting in truncation of the protein. While microsatellite analysis did not reveal alterations at the BAT-26 locus, single cell cloning produced several LNCaP subclones with alteration at 1 dinucleotide repeat. CONCLUSIONS: The well described prostate cancer cell line LNCaP has a mutation in the hMSH2 gene, resulting in loss of expression and possible evidence of microsatellite instability. To our knowledge our finding is the first demonstration of a genetic alteration in hMSH2 in a prostate cancer cell line.

Base Pair Mismatch↗

PubMed2002

Mutation analysis of APC gene in gastric cancer with microsatellite instability.

AIM: To evaluate the role of APC mutation in gastric carcinogenesis and to correlate APC mutation with microsatellite instability (MSI) in gastric carcinomas. METHODS: APC mutation was measured with multiplex PCR, denaturing gradient gel electrophoresis and DNA sequencing; and MSI was analyzed by PCR-based methods. RESULTS: Sixty-eight cases of sporadic gastric carcinoma were studied for APC mutation at exon 15 and MSI. APC mutations were detected in 15(22.1 %) gastric cancers. Frequence of APC mutation (33.3 %) in intestinal type of gastric cancer was significantly higher than that in diffuse type (13.1 %, P<0.05). On the contrary, no association was observed between APC mutation and tumor size, differentiation, depth of invasion, metastasis or clinical stages. Using five microsatellite markers, MSI in at least one locus was detected in 17 of 68 (25 %) of the tumors analyzed. APC mutations were all detected in MSI-L (only one locus, n=9) or MSS(tumor lacking MSI or stable, n=51), but no mutation was found in MSI-H (> or =2 loci, n=8). CONCLUSION: APC mutation is involved in carcinogenesis of intestinal type of gastric cancer and is independent of MSI phenotype but related to the LOH pathway in gastric cancer.

Adenomatous Polyposis Coli Protein↗

PubMed2001

Cancer-specific genomic instability in bronchial lavage: a molecular tool for lung cancer detection.

We examined genomic instability in DNA from 80 bronchial lavage samples from patients with lung cancer and individuals with no malignant lung disease. We used a multiplex assay of eight fluorescent-tagged microsatellite markers that have a very high incidence of allelic imbalance in lung tumors. When genomic instability at individual loci was analyzed statistically against diagnosis, markers D3S1289 (P = 0.033), D3S1300 (P = 0.001), D13S171 (P = 0.009), and D17S2179E (P = 0.017) demonstrated significantly higher frequency of instability in bronchial lavage specimens from lung cancer cases than those with nonmalignant conditions. In contrast, markers D9S157, D9S161, D13S153, and D5S644 demonstrated lower specificity (P > 0.05) for lung tumors. These results suggest that genomic instability in some loci may be related to high proliferation rates but not necessarily to cell commitment to malignancy. When genomic instability was scored with only the four cancer-specific markers, the assay produced a sensitivity of 73.9% and a specificity of 76.5%. On combining the results from the cytological examination and the molecular assay, the sensitivity reached 82.6%. These results indicate that in our efforts to investigate genomic instability as a potential marker for the early detection of lung cancer, we need to identify cancer-specific genomic instability markers. This paper has shown that these first four markers may be considered to form an individual set of cancer-specific genomic instability markers.

Adult↗

PubMed2005

Evidence that both genetic instability and selection contribute to the accumulation of chromosome alterations in cancer.

Cancer cells contain many genetic alterations, and genetic instability may be important in tumourigenesis. We evaluated 58 breast and ovarian cancer cell lines for microsatellite instability (MSI) and chromosomal instability (CIN). MSI was identified in 3/33 breast and 5/25 ovarian cell lines, and 7/8 MSI lines showed an inactivation of mismatch repair. Average ploidy by centromeric fluorescence in situ hybridization (FISH) of MSI (n = 8, average ploidy = 2.65) and microsatellite stable (MSS; n = 7, average ploidy = 3.01) cell lines was not different, due to the presence of three aneuploid MSI lines, and two near-diploid MSS lines. However, the variability of the centromeric FISH data was different between MSI and MSS (P = 0.049). The complexity of structural chromosomal rearrangements was not different between MSI and MSS. Thus, MSI and numerical CIN are not mutually exclusive, and structural CIN occurs independently of MSI or numerical CIN. Dynamic genetic instability was evaluated in three cell lines-MSI diploid (MT-3), MSS diploid (SUM159) and MSS aneuploid (MT-1). Ten clones of each of these cell lines were analysed by centromeric FISH and six-colour chromosome painting. The variation in chromosome number was different among all three cell lines (P < 0.001). MT-3 appeared numerically constant (94% of centromeric FISH signals matched the mode). SUM159 was 88% constant; however, 7% of cells had duplicated chromosomes. MT-1 was 82% constant; most changes were chromosomal losses. The six-colour FISH data showed that SUM159 had more stable structural chromosomal alterations (e.g. chromosomal translocations) compared with MT-3 and MT-1, but had no increase in unstable changes (e.g. chromatid breaks) when compared with MT-3. MT-1 had fewer unstable changes than both MT-3 and SUM159. These data suggest that numerical CIN may contribute to aneuploidy, but that selection plays an important role, particularly for the accumulation of structural chromosomal changes.

Breast Neoplasms↗