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PubMed2002

Microsatellite instability in hematological malignancies.

The replication error (RER+) phenotype, characterized by microsatellite instability (MSI) has been recently related to mutations of genes involved in DNA mismatch repair pathway. These genetic alterations were first described in hereditary non polyposis colorectal cancer (HNPCC). We examined 44 patients with hematological malignancies (27 AML, 9 MDS, 2 CML-BP and 6 T-ALL) for evidence of MSI. Twenty seven percent of our patients showed differences for only one marker. In four cases (9.1%) MSI was observed in multiple markers and these cases were described as RER+ phenotype. Presented data suggest that this phenomenon may play a role in at least a subset of patients with hematological malignancies.

Adolescent↗
PubMed1999

[HNPCC syndrome, microsatellite instability and NF1 gene alteration].

Hereditary predisposition to non polyposis colorectal cancer is caused by a heterozygous germline mutation in a DNA mismatch repair gene (essentially hMLH1 or hMSH2). Cancer progression in predisposed individuals results from the occurrence of a somatic alteration of the normal copy of the gene. Recently, we identified children with a constitutional deficiency of mismatch repair activity, due to a homozygous germline mutation of the hMLH1 gene. These children exhibited clinical features of de novo neurofibromatosis type 1 and early onset of hematopoietic cancers. This observation demonstrates that mismatch repair deficiency is compatible with human development. However, the subsequent genetic instability leads to a high cancer susceptibility. In this context, the NF1 gene appears to be a preferential mutational target. Implications of this observation are discussed.

Adaptor Proteins, Signal Transducing↗
PubMedDate not supplied

Enhanced nucleotide excision repair in cisplatin resistant human KB carcinoma cells.

We previously reported that enhanced active efflux of cisplatin and increased GSH level were observed in KCP-4 cells. In the present study, KCP-4 cells were found to be cross-resistant to ultraviolet (UV) compared with parental KB-3-1 cells. Enhanced nucleotide excision repair (NER) was verified by time-dependent repair of UV-induced DNA damage. In addition, the amount of platinum bound to DNA after exposure to cisplatin decreased in a time-dependent manner in KCP-4 cells and this was reversed by aphidicolin, a DNA polymerase inhibitor. In stationary phase cultures, aphidicolin increased the sensitivity of KCP-4 cells to cisplatin. The expression of xeroderma pigmentosum complementation group F (XPF), an endonuclease involved in NER, was upregulated in KCP-4 cells. In KCP-4 cells the expression of hMSH6, one of the mismatch repair (MMR) factors, was decreased compared to parental KB-3-1 and revertant KCP-4R cells. However, KCP-4 cells were cross-resistant to oxaliplatin, and microsatellite instability was not observed in them. These findings suggest that the enhanced NER activity for DNA damage caused by cisplatin may be involved in cisplatin resistance in KCP-4 cells.

Antineoplastic Agents↗
PubMed2006

Intratumor genomic heterogeneity correlates with histological grade of advanced oral squamous cell carcinoma.

To assess the difference in genetic aberration patterns among the invasive tumor front (ITF), center/superficiality and the stroma adjacent to oral squamous cell carcinoma (OSCC), we studied loss of heterozygosity (LOH) and microsatellite instability (MI) at chromosome 9p21 and 17p13 on the three regions by combining laser capture microdissection (LCM) and PCR. We studied 20 OSCC patients with TP53 on chromosome 17p13 and RPS6 on chromosome 9p21. Genomic DNA samples from the ITF, center/superficial and stromal cells adjacent to the tumor were prepared from cryosections using laser-assistant microdissection, then LOH and MI were determined. Cells at the ITF, center/superficiality and stroma showed a high frequency of LOH and MI on chromosomes 17p13 (TP53) and 9p21 (RPS6). Comparison of the patterns of allelic loss and MI encountered at the ITF, center/superficial and stromal cells revealed no concordance. The frequency of RPS6 and TP53 aberration at the epithelial compartment (both ITF and center, 64.7%, 11/17; 70.6%, 12/17) was statistically higher than the stroma (23.5%, 4/17; 43.8%, 7/16) (p<0.05). Furthermore, for the epithelial compartment, the aberrations proportions of TP53 rose from 60.0% (9/15) to 64.7% (11/17) between the center/superficial part and ITF. Also the rate of RPS6 increased from 29.4% (5/17) to 58.8% (10/17) between the center/superficial parts and ITF. The overall frequency of the two markers was statistically higher at the ITF (20/32) than the center/superficial part (15/34) (p<0.05). The current study revealed that intratumor genetic heterogeneity exists in the different histological areas of OSCCs and some particular tumor cell genotypes have correlation with histological patterns.

Adult↗
PubMed1997

Infrequent microsatellite instability in oesophageal cancers.

Alterations of microsatellites have been found at relatively high frequency in hereditary and sporadic colorectal cancer and gastric and pancreatic cancers and at lower frequency in some other cancers. We determined the frequency of instability at 39 poly-CA microsatellite loci in 20 squamous cell carcinomas and 26 Barrett's adenocarcinomas of the oesophagus. None of the tumours presented instability for a high percentage of the tested loci. Four squamous cell carcinomas and six Barrett's adenocarcinomas showed microsatellite instability at one locus, and three Barrett's adenocarcinomas showed microsatellite instability at two loci. The presence of few loci showing microsatellite instability could be due to an instability background. We conclude that genetic defects in the DNA mismatch repair system do not play an important role in oesophageal cancers.

Adenocarcinoma↗
PubMed1998

[Microsatellite instability of genome in cells of sporadic and hereditary carcinoma of the gastrointestinal tract].

Microsatellite instability (MIN) of human genome, i.e. instability of very short (1-5 nt) DNA tandem repeats, points to a deficiency in the mismatch repair system (MMR). To investigate the role of MMR in sporadic and hereditary carcinogenesis in the gastrointestinal tract, four types of carcinomas were compared: sporadic (GC), familial (FGC) gastric carcinoma, sporadic colorectal (CC) and hereditary nonpolyposis colorectal (HNPCC) carcinoma. No significant difference in MIN frequency was found between GC (9 out of 27) (33%) and CC (7 out of 29) (24%). In hereditary carcinoma group, MIN occurrence appeared 2-3 times as high: FGC in 7 out of 10 (70%) and HNPCC in 6 out of 8 patients (75%). No significant differences were recorded in MIN occurrence at early and later stages of the disease in all groups. Therefore, it can be suggested that disorders in the MMR develop at earlier stages of carcinogenesis and may be responsible for tumor progression.

Base Sequence↗
PubMed2000

Microsatellite instability of dinucleotide tandem repeat sequences is higher than trinucleotide, tetranucleotide and pentanucleotide repeat sequences in prostate cancer.

In order to investigate whether the change in length of simple repetitive genomic sequences (microsatellite instability) is associated with prostate cancer, we analyzed 40 prostate cancer samples with 44 microsatellite loci markers on chromosomes 1, 3, 5, 6, 8, 9, 11, 13, 16, 17 and X. DNA was extracted from normal and tumor cells of 40 microdissected cancer samples, amplified by PCR and analyzed for microsatellite instability using 44 primers for dinucleotide, trinucleotide, tetranucleotide and pentanucleotide repeat sequences. The results of this study demonstrate that 45% of the prostate cancer specimens (18 out of 40) showed microsatellite instability (MSI) at a minimum of one locus using dinucleotide repeat sequences. Two out of 40 samples (5%) showed MSI at a minimum of one locus using three different trinucleotide repeat primers (AR, SR and TBP). Ten out of 40 (25%) samples showed MSI at a minimum of one locus using five different tetranucleotide repeat primers (HPRT1, HPRTII, MYCL1, RB, REN). There were no MSI observed in samples using pentanucleotide repeat sequences. There were no MSI in benign prostatic hyperplasia samples (25 samples). These experiments suggest that the microsatellite instability of dinucleotide tandem repeat sequences is much higher than trinucleotide, tetranucleotide and pentanucleotide repeat sequences in prostate cancer. The MSI with different lengths of nucleotide repeat sequences did not correlate with the stage and grades of prostate cancer.

Dinucleotide Repeats↗
PubMed1996

Clinico-pathological features and p53 expression in left-sided sporadic colorectal cancers with and without microsatellite instability.

Defects in mismatch repair (MMR) can result in the development of a 'mutator phenotype', manifest as an increase in DNA replication errors (RERs). Patients with hereditary non-polyposis colorectal cancer (HNPCC) have germline mutations in MMR genes. These patients develop carcinomas of the colon and other specific sites at a significantly earlier age than patients with sporadic carcinomas. RERs are found in the cancers from patients with HNPCC and have been demonstrated in 10-20 per cent of sporadic colorectal cancers (CRCs). Loss of MMR may simply accelerate tumour development, but it is also possible that these tumours follow a different carcinogenetic pathway from tumours with intact MMR. In particular, it has been suggested that p53 mutations occur less often in RER-positive (RER+) sporadic colorectal cancers. In this study, the clinico-pathological features and frequency of p53 overexpression in 17 left-sided RER+ CRCs were compared with 35 left-sided RER- CRCs. No differences were found in the age and tumour stage at presentation, mucinous differentiation, or Jass prognostic grouping between these two types of CRC. Thirteen out of 17 (76 per cent) RER+ and 19/35 (54 per cent) RER- tumours showed overexpression of p53, a non-significant difference (chi 2 test). Although some previous studies have suggested differences in the clinico-pathological features and p53 expression of RER+ and RER- right-sided CRCs, our results show that these differences do not exist in left-sided cancers.

Aged↗
PubMed2006

Enhanced detection of microsatellite instability and mismatch repair gene expression in cutaneous squamous cell carcinomas.

BACKGROUND: Microsatellite instability (MSI) is a phenotypic characteristic of tumors with biallelic inactivation of mismatch repair genes, such as MSH2 or MLH1, and contributes to malignant transformation. AIMS: The aim of this study was to examine the prevalence of MSI in cutaneous squamous cell carcinoma (SCC) using a PCR and fluorescent-based detection system. These methods of analysis offer several advantages over the use of silver staining and autoradiographic techniques. We also aimed to determine if MSI status correlated with expression of the MSH2 and MLH1 mismatch repair proteins in these cutaneous SCC samples. METHODS: The MSI status of 22 histologically confirmed invasive cutaneous SCC samples were analyzed at five microsatellite markers (the National Cancer Institute's Bethesda panel of two mononucleotide and three dinucleotide markers) using a PCR and fluorescent-based detection system. Immunohistochemical analysis of MSH2 and MLH1 protein expression was also carried out on the SCC samples. RESULTS: Only one case of cutaneous SCC displayed MSI. This was found at just one of five markers, and thus was low frequency MSI. All 22 cutaneous SCC cases strongly expressed MSH2 protein. Eighteen (82%) of the cutaneous SCC cases showed moderate to strong expression of MLH1 protein. The remaining four cases of cutaneous SCC were negative for MLH1 protein. Therefore, the majority of the SCC patients analyzed showed a correlation between absence of MSI and expression of MSH2 and MLH1 proteins. CONCLUSIONS: MSI is uncommon in cutaneous SCC. In addition, MSH2 was strongly expressed in all SCC samples analyzed and appeared to be upregulated when compared with the corresponding normal tissue. MLH1 protein was not detected in 4 of 22 SCC cases, although it was expressed in the corresponding normal tissue, suggesting that inactivation of MLH1 may be a late event in a subset of invasive SCC cases.

Adaptor Proteins, Signal Transducing↗
PubMed2003

The genomic damage estimated by arbitrarily primed PCR DNA fingerprinting is useful for the prognosis of gastric cancer.

BACKGROUND & AIMS: Genomic instability and the accompanying alteration of cancer genes play a major role in tumorigenesis. We evaluated the prognostic significance in gastric cancer of the degree of accumulation of relative genomic damage, assessed by arbitrarily primed polymerase chain reaction DNA fingerprinting. METHODS: Genomic damage was assessed by comparative analysis of paired normal and tumor tissue DNA fingerprints. The total number of alterations, scored as decreases and increases of band intensity with 2 arbitrary primers, were used as an estimation of the genomic damage fraction in 74 primary gastric cancers. Increases in DNA copy number were also analyzed by array comparative genomic hybridization in a subset of 30 cases. RESULTS: The number of altered bands varied among the tumors from none or a few to more than one third of the approximately 40 fingerprint bands. The relative values of genomic damage were consistent with the quantitative chromosomal alterations observed by array comparative genomic hybridization. When the tumors were stratified into 2 groups-above or below the cutoff of 0.22 for average genomic damage fraction-genomic damage fraction was a valuable prognostic indicator regardless of microsatellite instability status. Multivariate Cox analysis showed that the genomic damage fraction was a prognostic indicator, as well as a stage indicator (P = 0.0189). Survival was significantly diminished in tumors with a genomic damage fraction >0.22 (P = 0.0009). Moreover, in the 46 curative cases, genomic damage fraction was the only independent factor for predicting survival (P = 0.0061). CONCLUSIONS: Our results indicate that the degree of genomic damage estimated by arbitrarily primed polymerase chain reaction fingerprinting is a useful prognostic indicator for gastric cancer.

Adult↗
PubMed2001

hMLH1 and hMSH2 expression in human hepatocellular carcinoma.

The role of microsatellite instability (MSI) in the pathogenesis of hepatocellular carcinoma (HCC) is incompletely defined. Although high-frequency MSI (MSI-H) is infrequently seen in HCC, some studies have suggested a role for MSI in HCC development. While MSI has been clearly defined for a subset of tumors, in particular colorectal, gastric and endometrial cancers, generally accepted criteria have not been developed for other tumors. Colorectal cancers (CRC) are classified as MSI-H if >30-40% of >5 microsatellite loci analyzed show instability. The MSI-H phenotype is associated with defective DNA mismatch repair (MMR) and is observed in the majority of tumors from patients with hereditary non-polyposis colon cancer (HNPCC) and also in 15% of sporadic CRCs. Inactivating mutations of the hMLH1 or hMSH2 genes lead to defects in MMR in HNPCC. In sporadic CRCs, MMR is usually due to hypermethylation of the hMLH-1 promoter. The role of defective MMR in hepatocellular carcinogenesis is controversial. Immunohistochemistry for hMLH1 and hMSH2 reliably indicates hMLH1 or hMSH2 loss in MSI-H CRC tumors. To investigate the role of defective MMR in HCC carcinogenesis, we performed immunohistochemistry for hMLH1 and hMSH2 on 36 HCCs. BAT26, a microsatellite marker that reliably predicts MSI-H was also examined. All 36 of the tumors stained positively for both hMLH1 and hMSH2, strongly suggesting an absence of either inactivating mutations of hMLH1 and hMSH2 or promoter hypermethylation of hMLH1. None of the tumors showed MSI at the BAT26 locus. These findings suggest that defective MMR does not contribute significantly to hepatocellular carcinogenesis.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Microsatellite instability, immunohistochemistry, and additional PMS2 staining in suspected hereditary nonpolyposis colorectal cancer.

PURPOSE: Immunohistochemistry (IHC) and microsatellite instability (MSI) analysis can be used to identify patients with a possible DNA mismatch repair defect [hereditary nonpolyposis colorectal carcinoma (HNPCC)]. The Bethesda criteria have been proposed to select families for determination of MSI. The aims of this study were to assess the yield of MSI analysis in families suspected for HNPCC, to compare the results of immunohistochemical staining and MSI analysis, and to assess the additional value of PMS2 staining. EXPERIMENTAL DESIGN: Clinical data and tumors were collected from 725 individuals from 631 families with suspected HNPCC. MSI analysis was performed using eight markers including the 5 National Cancer Institute markers. Four immunohistochemical staining antibodies were used (MLH1, MSH2, MSH6 and PMS2). RESULTS: A MSI-H (tumors with instability for >30% of the markers) phenotype in colorectal cancers (CRCs) was observed in 21-49% of families that met the various Bethesda criteria. In families with three cases of CRC diagnosed at age > 50 years, families with a solitary case of CRC diagnosed between ages 45 and 50 years, and families with one CRC case and a first-degree relative with a HNPCC-related cancer, one diagnosed between ages 45 and 50 years (all Bethesda-negative families), the yield of MSI-H was 10-26%. Immunohistochemical staining confirmed the MSI results in 93% of the cases. With IHC, adding PMS2 staining led to the identification of an additional 23% of subjects with an hMLH1 germ-line mutation (35 carriers were tested). CONCLUSIONS: The Bethesda guidelines for MSI analysis should include families with three or more cases of CRC diagnosed at age > 50 years. The age at diagnosis of CRC in the original guidelines should be raised to 50 years. Routine IHC diagnostics for HNPCC should include PMS2 staining.

Adenosine Triphosphatases↗
PubMed2007

Explaining the familial colorectal cancer risk associated with mismatch repair (MMR)-deficient and MMR-stable tumors.

PURPOSE: There is a paucity of data quantifying the familial risk of colorectal cancer associated with mismatch repair (MMR)-deficient and MMR-stable tumors. To address this, we analyzed a population-based series of 1,042 colorectal cancer probands with verified family histories. EXPERIMENTAL DESIGN: Constitutional DNA from probands was systematically screened for MYH variants and those with cancers displaying microsatellite instability (MSI) for germ-line MMR mutations; diagnoses of familial adenomatous polyposis and juvenile polyposis were established based on clinical phenotype and mutational analysis. Familial colorectal cancer risks were enumerated from age-, sex-, and calendar-specific population incidence rates. Segregation analysis was conducted to derive a model of the residual familial aggregation of colorectal cancer. RESULTS: Germ-line predisposition to colorectal cancer was identified in 37 probands [3.4%; 95% confidence interval (95% CI), 2.4-4.6]: 29 with MLH1/MSH2 mutations, 2 with familial adenomatous polyposis, 1 with juvenile polyposis, and 5 with biallelic MYH variants. The risk of colorectal cancer in first-degree relatives of probands with MSI and MMR-stable cancers was increased 5.01-fold (95% CI, 3.73-6.59) and 1.31-fold (95% CI, 1.07-1.59), respectively. MSH2/MLH1 mutations were responsible for 50% of the overall excess familial risk and 80% of the risk associated with MSI cancers but 32% of the familial risk was unaccounted for by known loci. Genetic models based on major gene loci did not provide a better explanation of the residual familial aggregation than a simple polygenic model. CONCLUSIONS: The information from our analyses should be useful in quantifying familial risks in clinical practice and in the design of studies to identify novel disease alleles.

Adenomatous Polyposis Coli↗
PubMed2006

The mismatch repair protein status of colorectal small cell neuroendocrine carcinomas.

Small cell neuroendocrine carcinoma (SCNC) of the colorectum is a rare and highly aggressive malignancy. It can be associated with conventional-type adenocarcinoma, and an overlying adenoma can often be identified. A disproportionate number has been noted to arise in the right colon. Although some phenotypes (eg, mucinous adenocarcinoma) have been shown to be associated with deficient mismatch repair (MMR) and thus microsatellite instability (MSI), the MMR protein status of colorectal SCNCs has not been investigated. This study investigated the status of 3 MMR proteins, hMLH1, hMSH2, and hMSH6, in SCNCs of the colorectum. Fifteen SCNCs were identified on the basis of previous descriptions and the World Health Organization histologic criteria for the diagnosis of pulmonary small cell carcinoma and immunohistochemical evidence of epithelial and neuroendocrine differentiation. Patient age and sex and tumor size and location were recorded. Immunohistochemistry was performed with antibodies to pancytokeratin (cocktail), CD56, neuron specific enolase, synaptophysin, chromogranin, hMLH1, hMSH2, and hMSH6. Patients' ages ranged from 44 to 87 years (mean age = 73 y) and there were 9 men and 6 women. Tumors were located in the right colon (6), sigmoid colon (4), and rectum (3) (the locations of 2 cases were not recorded) and ranged in size from 0.4 to 15 cm in greatest dimension (mean = 6.6 cm). All tumors showed immunoreactivity with antibodies to pancytokeratin and with antibodies to at least 1 neuroendocrine antigen. MMR proteins were intact by immunohistochemistry in all but a single case that had neither an identifiable precursor lesion nor positive internal control (hMLH1 loss). Colorectal SCNCs are rare and are often right-sided. They are aggressive and tend to occur in older individuals. Most colorectal SCNCs have intact MMR proteins, suggesting that they develop secondary to chromosomal instability rather than MSI. Our single case showing potential MMR protein loss suggests that this phenotype may be independent of the developmental pathway (ie, chromosomal instability vs. MSI). This may explain the rare cases of SCNC that have been identified in patients with hereditary nonpolyposis colon cancer.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Possible association between tumor-suppressor gene mutations and hMSH2/hMLH1 inactivation in alveolar soft part sarcoma.

Alveolar soft part sarcoma (ASPS) is a rare soft tissue tumor of unknown origin and pathogenesis. We clinicopathologically analyzed 16 cases of ASPS and screened for the genetic alterations of various tumor-suppressor genes and oncogenes, including p53, adenomatous polyposis coli (APC), E-cadherin, and beta-catenin, in 11 cases of ASPS. We also examined the expression of hMSH2/hMLH1 of DNA mismatch repair genes by immunohistochemistry, and promoter hypermethylation of these DNA mismatch repair genes by methylation-specific polymerase chain reaction (MS-PCR) to elucidate any possible association between mutation status of these genes and inactivation of the hMSH2/hMLH1 genes. Furthermore, microsatellite instability (MSI) analysis and loss of heterozygosity (LOH) on chromosome 5q analysis were used for some cases of ASPS where DNA derived from normal tissue was available. The 5-year overall survival rate for all of the patients in this study was 68.6%. The 5-year overall survival rates for patients presenting with localized ASPS and for patients with distant metastases were 83.3% and 47.6%, respectively. The high nuclear grade of tumor cells was a significantly adverse prognostic factor (P = 0.0085). Single-strand conformation polymorphism analysis followed by DNA direct sequencing revealed 4 point mutations of the p53 gene in 3 of 11 cases (27.3%), composed of 3 missense mutations and 1 silent mutation. In addition, 1 case with the E-cadherin missense mutation and 1 case with the APC missense mutations were observed, respectively. None of the cases harbored mutation of exon 3 of the beta-catenin gene. Loss of expression of the hMSH2 and hMLH1 genes was observed in 2 (18.2%) and 3 (27.3%) of 11 cases, respectively. All 3 cases with loss of hMLH1 gene expression harbored mutations of the p53 gene. There was a statistically significant correlation between the genetic alteration positive in these tumor-suppressor genes and loss of hMLH1 gene expression (P = 0.024). Methylation-specific PCR did not reveal hypermethylation of the hMSH2/hMLH1 promoter region in any of the cases examined. Three of 8 (37.5%) ASPS cases showed low MSI, and 2 of these 3 cases showed immunohistochemical lack of expression for either hMSH2 or hMLH1. LOH on 5q was present in 2 of 6 (33.3%) informative cases, and both cases showed LOH on the D5S346 marker, a microsatellite marker near the APC locus. Thus, inactivation of hMSH2/hMLH1 of DNA mismatch repair genes seems to have an important role to play in the mutagenesis of the tumor-suppressor genes in ASPS.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Instability of microsatellites is an infrequent event in uveal melanoma.

Microsatellite instability (MSI) is a distinct tumour phenotype that is associated with alterations of DNA mismatch repair and is being increasingly reported in a number of hereditary and sporadic tumours. Numerous reports have suggested that melanocytic neoplasms, including cutaneous melanomas, frequently demonstrate low frequency MSI, whilst a small number of tumours exhibit high frequency MSI. Furthermore, loss of expression of DNA mismatch repair proteins has been associated with progression from benign to malignant disease in melanocytic neoplasms, but the presence or absence of mismatch repair defects in uveal melanomas has yet to be determined. This study was designed to establish whether MSI is a feature of these ocular melanomas. To investigate the prevalence of MSI in uveal melanomas, 52 tumours were analysed by polymerase chain reaction amplification of a panel of microsatellite markers selected for their ability to detect tumours exhibiting defects in DNA mismatch repair mechanisms. MSI was rarely detected in the 52 uveal melanomas analysed. All tumours demonstrated stable microsatellites at five of the six microsatellite markers tested (BAT26, BAT40, APC, D2S123 and Mfd15CA). Only one tumour showed the presence of a single unstable allele at a tetranucleotide marker (MYCL1). These data suggest that high frequency MSI does not occur in these tumours, and that low frequency MSI, in contrast to cutaneous melanoma, is a rare event in malignant melanomas of the uveal tract.

Base Pair Mismatch↗
PubMed2000

Microsatellite instability is a late event in the carcinogenesis of uterine cervical cancer.

OBJECTIVE: The purpose of this study was to elucidate the role of genetic instability and LOH in the progression of cervical cancer and also to analyze for correlations between these genetic abnormalities and the clinicopathological characteristics of cervical cancers. METHODS: Seventy-two DNA samples were obtained from 29 carcinoma in situ, 8 microinvasive carcinoma, and 35 invasive cancers. Seven highly polymorphic microsatellite markers representing the chromosome 3p, 6p, and 6q arms were examined by PCR amplification. RESULTS: Microsatellite instability was detected in 8 of 35 (22.9%) invasive cancers and in 1 of 37 (2.7%) early stage cancers (microinvasive cancer and carcinoma in situ). The incidence of MI was statistically higher in invasive cancers (P < 0.02). On the other hand, loss of heterozygosity (LOH) of chromosome 3p was identified in 6/41 (14.6%) invasive cancers and in 3/27 (11.1%) carcinomas in situ. There was no statistical difference between the two groups. There were no significant correlations between the presence of MI or 3p LOH and clinicopathological characteristics including the histological type, FIGO stage, depth of myometrial invasion, lymphovascular involvement, lymph node metastasis, and recurrence. CONCLUSION: Our results indicate that genomic instability is a late event during the carcinogenesis of cervical cancer and is associated with the conversion of cervical intraepithelial neoplasia to an invasive phenotype. To the contrary, LOH of chromosome 3p plays an early role in the development of cervical intraepithelial neoplasia. No significant correlation was observed between the presence of MI or LOH and clinicopathological characteristics.

Adult↗