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Results for “DNA MICROSATELLITE INSTABILITY”

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PubMed2005

Genetic instability induced by overexpression of DNA ligase I in budding yeast.

Recombination and microsatellite mutation in humans contribute to disorders including cancer and trinucleotide repeat (TNR) disease. TNR expansions in wild-type yeast may arise by flap ligation during lagging-strand replication. Here we show that overexpression of DNA ligase I (CDC9) increases the rates of TNR expansion, of TNR contraction, and of mitotic recombination. Surprisingly, this effect is observed with catalytically inactive forms of Cdc9p protein, but only if they possess a functional PCNA-binding site. Furthermore, in vitro analysis indicates that the interaction of PCNA with Cdc9p and Rad27p (Fen1) is mutually exclusive. Together our genetic and biochemical analysis suggests that, although DNA ligase I seals DNA nicks during replication, repair, and recombination, higher than normal levels can yield genetic instability by disrupting the normal interplay of PCNA with other proteins such as Fen1.

Acetyltransferases↗

PubMed1999

[Genetics of colorectal cancer. II. Hereditary background of sporadic and familial colorectal cancer].

About 15% of patients with colorectal cancer have a positive family history: 5% have hereditary colorectal cancer (hereditary non-polyposis colorectal carcinoma (HNPCC), familial adenomatous polyposis (FAP) or some other hereditary syndrome), while in 10% no clear hereditary pattern can be recognized ('familial colorectal cancer'). In sporadic and in familial intestinal cancer, a demonstrable hereditary predisposition may undoubtedly exist. HNPCC is often characterized by microsatellite instability, i.e. an increased number of short DNA sequences in the DNA indicating a disorder in DNA repair and a mutation in a DNA 'mismatch repair' (MMR) gene. Indicative of hereditary bowel cancer on the basis of such an MMR gene mutation are: (a) presence of bowel cancer in > or = 3 relatives, (b) early age at the time of the diagnosis of 'bowel cancer', (c) multiple primary bowel tumours, (d) uterine cancer in the family and (e) bowel and uterine cancer in a woman. Recent data demand a new subdivision of hereditary bowel cancer, based upon both the clinical picture and the results of DNA-tests. The genetic alterations in colonic adenomas and carcinomas are known to a large extent. In future these insights may be important in clinical practice, such as a more individual determination of the patient's prognosis and accordingly, of the treatment and follow-up.

Adenoma↗

PubMed2003

Methylation of the hMLH1 promoter and its association with microsatellite instability in acute myeloid leukemia.

The hMLH1 and hMSH2 genes are involved in the DNA mismatch repair (MMR) pathway. Defects in either of these genes have been associated with genetic instability in a wide variety of malignancies. A molecular mechanism involved in aberrant MMR gene expression is the epigenetic silencing of transcription by promoter methylation. The importance of MMR promoter methylation in leukemia is presently unclear and we have therefore undertaken a detailed analysis of the promoter regions of hMLH1 and hMSH2 using the technique of bisulfite genomic sequencing. DNA from 55 patients with acute myeloid leukemia (AML) including 23 patients with therapy-related AML (t-AML) have been analyzed. Two patients with de novo AML demonstrated extensive methylation throughout the whole hMLH1 region sequenced, one of whom had previously shown widespread genetic instability, measured as microsatellite instability (MSI). However methylation of hMLH1 was not found in t-AML which has previously been associated with MSI. In addition, methylation was seen at a restricted region of the hMLH1 promoter in both AML patients and healthy controls. The significance of this methylated region of the hMLH1 promoter is uncertain, however, our results confirm that in some patients with AML extensive methylation of hMLH1, but not of hMSH2 may occur, and as is the case in solid tumors this can be associated with the presence of a defective DNA mismatch repair pathway resulting in MSI.

Acute Disease↗

PubMed2003

Distinct patterns of microsatellite instability are seen in tumours of the urinary tract.

To date, two forms of microsatellite instability (MSI) have been described in human cancer. MSI typical of hereditary nonpolyposis colon cancer (HNPCC), is due to deficient DNA mismatch repair (MMR) and is defined with mono- and dinucleotide repeat microsatellites. A second variety of instability is best seen at selective tetranucleotide repeats (EMAST; elevated microsatellite alterations at select tetranucleotides). While MSI occurs infrequently in bladder cancers, EMAST is common. Sporadic tumours with the largest proportion showing MSI are those found most frequently in HNPCC kindreds. While bladder cancer is not frequently seen in HNPCC, upper urinary tract tumours (UTTs) are. Having previously found a low frequency of MSI in bladder cancer, we sought to determine the relative levels of MSI and EMAST in transitional cell carcinoma (TCC) of the upper and lower urinary tracts. Microsatellite analysis was performed at 10 mono- and dinucleotide and eight tetranucleotide loci, in 89 bladder and 71 UTT TCC. Contrasting patterns of instability were seen in urinary tumours. In bladder cancer, MSI was rare and EMAST was common. The presence of EMAST was not related to tumour grade, stage, subsequent outcome or immunohistochemical expression of the MMR proteins. In UTT, while MSI occurred frequently, EMAST was seen less frequently than in bladder cancer. When TCC of the upper and lower urinary tracts are compared, MSI-H is more frequent in UTT and EMAST more frequent in bladder cancer. Our findings show that, as for colorectal cancer, the pattern of MSI varies with location in the urinary tract. In addition, we have confirmed that MSI and EMAST are discrete forms of MSI, and that the presence of EMAST does not affect tumour phenotype.

Adaptor Proteins, Signal Transducing↗

PubMedDate not supplied

Molecular detection of microsatellite instability in basal cell carcinoma.

Several studies have shown that the presence of genetic instability can be associated to carcinogenesis process. The detection of microsatellite instability (MI) that consists of an expansion and/or deletion of DNA within repeat sequences, may constitute a sensitive marker for the presence of gene mutations. A series of 18 basal cell carcinoma (BCC) consecutive patients was examined for the presence of alteration in 12 DNA microsatellite markers, in order to better understand the molecular significance of MI in the genesis and progression of BCC. Molecular alterations were detected in 6 out of 12 analyzed microsatellite loci. Five out of 18 BCC samples showed loss of heterozygosity at chromosome loci localized in the vicinity of the tumor suppressor genes, whereas six out of 18 BCC patients presented at least one altered microsatellite (instability). We demonstrated molecular genetic alterations at 2p16 locus, in the proximity of MSH2 gene and 17p21, in the proximity of the p53 gene. These data validate and confirm a role of MI in genesis and progression of BCC, by analysis of markers localized at specific chromosome region in proximity of oncogenes and tumor suppressor genes.

Adult↗

PubMed2000

Prediction of a mismatch repair gene defect by microsatellite instability and immunohistochemical analysis in endometrial tumours from HNPCC patients.

Instability of microsatellite repeat sequences has been observed in colorectal carcinomas and in extracolonic malignancies, predominantly endometrial tumours, occurring in the context of hereditary non-polyposis colorectal cancer (HNPCC). Microsatellite instability (MSI) as a feature of human DNA mismatch repair (MMR)-driven tumourigenesis of the uterine mucosa has been studied primarily in sporadic tumours showing predominantly somatic hypermethylation of MLH1. The present study shows that all endometrial carcinomas (n=12) from carriers of MLH1 and MSH2 germline mutations demonstrate an MSI-high phenotype involving all types of repeat markers, while in endometrial carcinomas from MSH6 mutation carriers, only 36% (4 out of 11) demonstrate an MSI-high phenotype. Interestingly, an MSI-high phenotype was found in endometrial hyperplasias from MSH2 mutation carriers, in contrast to hyperplasias from MLH1 mutation carriers, which exhibited an MSI-stable phenotype. Instability of only mononucleotide repeat markers was found in both endometrial carcinomas and hyperplasias from MSH6 mutation carriers. In 29 out of 31 (94%) endometrial tumour foci, combined MSI and immunohistochemical analysis of MLH1, MSH2, and MSH6 could predict the identified germline mutation. The observation of MSI in endometrial hyperplasia and of altered protein staining for the MMR genes supports the idea that inactivation of MMR genes is an early event in endometrial tumourigenesis. A correlation was found between the variation in the extent and level of MSI and the age of onset of carcinoma, suggesting differences in the rate of tumour progression. A high frequency of MSI in hyperplasias, found only in MSH2 mutation carriers, might indicate a more rapid tumour progression, correlating with an earlier age of onset of carcinoma. The present study indicates that assessment of altered protein staining combined with MSI analysis of endometrial tumours might direct the mutational analysis of MMR genes.

Adult↗

PubMed2002

Differential involvement of the hypermethylator phenotype in hereditary and sporadic colorectal cancers with high-frequency microsatellite instability.

High-frequency microsatellite instability (MSI-H) due to defective DNA mismatch repair occurs in the majority of hereditary nonpolyposis colorectal cancers (HNPCCs) and in a subset of sporadic malignant tumors. Clinicopathologic and genotypic features of MSI-H colorectal tumors in HNPCC patients and those in sporadic cases are very similar but not identical. Correlation between the MSI phenotype and aberrant DNA methylation has been highlighted recently. A strong association between MSI and CpG island methylation has been well characterized in sporadic colorectal cancers with MSI-H but not in those of hereditary origin. To address the issue, we analyzed hereditary and sporadic colorectal cancers for aberrant DNA methylation of target genes using methylation-specific polymerase chain reaction. DNA methylation of the MLH1, CDKN2A, MGMT, THBS1, RARB, APC, and p14ARF genes was found in 0%, 23%, 10%, 3%, 73%, 53%, and 33% of 30 MSI-H cancers in HNPCC patients and in 80%, 55%, 23%, 23%, 58%, 35%, and 50% of 40 sporadic colorectal cancers with MSI-H, respectively. Cases showing methylation at three or more loci of six genes other than MLH1 were defined as CpG island methylator phenotype-positive (CIMP +), and 23% of HNPCC tumors and 53% of sporadic cancers with MSI-H were CIMP+ (P = 0.018). Differences in the extent of CpG island methylation, coupled with the differential involvement of several genes by methylation, in HNPCC tumors and sporadic MSI-H colorectal cancers may be associated with diverging developmental pathways in hereditary and sporadic cancers despite similar MSI-H phenotypes.

Adenocarcinoma↗

PubMed2003

Methylenetetrahydrofolate reductase polymorphisms and risk of sporadic and hereditary colorectal cancer with or without microsatellite instability.

Methylenetetrahydrofolate reductase (MTHFR) is an essential enzyme in the folate metabolism, which affects DNA synthesis and methylation. Low enzyme activity may reduce the capacity of DNA methylation, and possibly reduce uracil misincorporation into DNA, which can result in double strand breaks. Both processes may be critical for the oncogenic transformation of human cells. Two common amino acid-changing and enzyme activity-reducing nucleotide polymorphisms (677C --> T/Ala222Val and 1298A --> C/Glu428Ala) have been described in MTHFR. We performed estimations of the relative risk associated with these two polymorphisms in samples from 287 colorectal cancer patients, compared to 346 healthy controls. Relative risk were further determined for subpopulations of cancer patients having sporadic (n = 227) or suspected/verified hereditary disease (n = 60) and tumours exhibiting high-level microsatellite instability (n = 41) or not (n = 246). No significant differences for the relative risk of colorectal cancer were observed for the MTHFR genotypes either alone or in combination in the analysed cohorts, although the frequency of the 1298AA + AC genotypes was increased among the 60 cases with hereditary disease. Whereas our results do not support an association of high enzyme activity and increased risk of colorectal cancer in general, we can not exclude an association of patients with hereditary disease and the MTHFR 1298A --> C variant.

Adenoma↗

PubMedDate not supplied

Analysis of microsatellite instability in acquired drug-resistance human tumor cell lines.

Genomic instability characterized as microsatellite instability (MIN) is associated with loss of DNA mismatch repair (MMR) protein. Several studies have shown that loss of DNA MMR protein confers resistance to some interacting DNA chemotherapeutic drugs, but also that exposure of MMR-proficient cells to these drugs can result in loss of MMR protein accompanied by induction of MIN. Such associations were mainly reported for cisplatin, but scarce data are available for doxorubicin (a DNA interacting agent), and nothing is known about vinblastine (an antitubulin agent). Thus, in this study we have analyzed MIN frequency in different type of human tumor cell lines characterized by their MMR protein status and resistant to doxorubicin or to vinblastine. Relationship between MIN occurrence and drug resistance was firstly verified in cisplatin resistant cells, and showed a MIN enrichment (33%) only in the MMR-deficient cells. In order to determine whether treatment of MMR-proficient cells with doxorubicin might lead to induction of MIN, we analyzed two different MMR-proficient cell lines. Variations of MIN frequency were found with either high levels of MIN (66%) or no MIN at all (0%). Effect of vinblastine was analyzed according to the MMR status in two different MMR-proficient and -deficient cells. No major change in MIN frequency was found either in the MMR-proficient (0%) or -deficient (9%) cells. Our results demonstrate that MIN occurs only in tumor cells resistant to cisplatin or doxorubicin, thus supporting earlier findings reporting such associations only with drugs interacting with DNA. Moreover, the data show that MIN does not appear in all tumor cell lines, suggesting that induction of MIN in relation to MMR status is a complex phenomenon which does not only depend on the drug considered (interacting or not with DNA), but also on the tumor cell variant.

Alleles↗

PubMed2002

Distinct clinical features and outcomes of gastric cancers with microsatellite instability.

Microsatellite instability (MSI) is a hallmark of the DNA mismatch repair deficiency that is one of the pathways of gastric carcinogenesis. Clinicopathologic characteristics of MSI+ gastric cancers remain unclear. To determine the correlation between MSI status and clinical features, we analyzed 327 consecutive gastric cancers for the occurrence of MSI in the BAT-26 marker. Because it has been proven that MSI at BAT-26 reflects the MSI+ phenotype, cancers with alteration at BAT-26 were categorized as having the MSI+ phenotype. The expressions of hMLH1, hMSH2, p53, MUC1, MUC2, and CEA were evaluated immunohistochemically using the tissue array method. The MSI+ phenotype was found in 9.5% (31/327) of gastric cancers examined. MSI+ gastric cancers were significantly associated with older age, antral location, Borrmann's gross Type II, intestinal subtype, lower prevalence of lymph node metastasis, and lower pTNM stage (P <.05). By multivariate logistic regression, MSI+ gastric cancers had a lower prevalence of lymph node metastasis independent of tumor invasion (P <.001). MSI+ gastric cancers displayed frequent frameshift mutations of transforming growth factor-beta type II receptor (90.3%), BAX (61.3%), hMSH3 (38.7%), and E2F4 (61.3%) genes and diminished hMLH1 (24/31) or hMSH2 (4/31) expressions. The MSI+ phenotype correlated with patient survival in advanced gastric carcinoma (P =.046). In conclusion, MSI+ phenotype in gastric cancers was found to have distinct clinicopathologic characteristics and to be predictive of a favorable outcome in advanced carcinoma.

Adaptor Proteins, Signal Transducing↗

PubMed1996

Frequent microsatellite instabilities and analyses of the related genes in familial gastric cancers.

Microsatellite instability or replication error seems to be related to defective DNA mismatch repair genes, such as hMSH2, hMLH1, hPMS1 and hPMS2, which have been identified as causative genes of hereditary nonpolyposis colorectal cancers (HNPCC). Recently, it was reported that mutations at the simple repeated sequences in the transforming growth factor-beta type II receptor (TGF-beta RII) gene occurred in replication error-positive colorectal cancers. To determine genetic alterations in familial gastric cancers (FGC, we examined replication error using eight microsatellite DNA markers, and screened mutations in the hMSH2, hMLH1 and TGF-beta RII genes in six cases from four FGC kindreds. Moreover, hMTH1, a human homolog of the bacterial mutT gene, was also screened. Four of six (67%) cancers showed the replication error-positive phenotype, indicating that microsatellite instability is highly associated with not only HNPCC, but also FGC. No germline mutation was found in the whole coding sequences of hMSH2 and hMTH1, or in the conservative regions of hMLH1 in any patient, while one cancer DNA showed a somatic mutation at codon 682 (threonine to alanine) in hMSH2. No alteration was found at the small repeated sequences in TGF-beta RII in FGC tumor DNA. These results indicate that the carcinogenetic process of FGC may be different from that of HNPCC.

Adaptor Proteins, Signal Transducing↗

PubMed1998

The application of microsatellites in molecular pathology.

Present within the genome are large numbers of seemingly unimportant DNA segments arranged in repetitive units. Furthermore, these stretches of DNA contain variations or polymorphisms that are characteristic for an individual and results in a unique DNA fingerprint. Approximately 30% of the DNA repeat sequences are arranged as short tandem repeat sequences, which are called microsatellites. Microsatellites may consist of 1, 2 or 3 nucleotides; dinucleotides being the commonest. Microsatellites are characterised by being: stably inherited and hence highly conserved from one generation to the next, and unique to an individual and the same in different cells from the same individual. As a result of the above features, microsatellites can be used for personal identification, population genetic analysis and construction of evolutionary trees. In addition, they are located in several important gene loci and this allows microsatellites to be used as markers of disease and to provide information about individual gene status, especially in tumors. This can be accomplished by assessing allelic imbalance or loss of heterozygosity of a particular gene by analysing microsatellites located at specific loci in the gene. Recently, mutations within microsatellites have been described as a result of defective DNA repair mechanisms, resulting in the phenomenon of microsatellite instability. This has been implicated in the aetiopathogenesis of several hereditary and non-hereditary conditions. There are several ways of analysing microsatellites, the popular using radioactively-labelled primers and autoradiography. This method has several drawbacks, especially the use of radioactivity and interpretative/technical problems. The use of fluorescently-labelled primers, automated DNA sequencing coupled with a computer software package obviates these problems. This technique has the added advantage of analysing several microsatellites in large numbers of cases, simultaneously. Thus, microsatellite analysis has become an important investigative tool for the molecular biologist and has provided new information in many diseases.

Autoradiography↗

PubMed1998

Microsatellite instability in an animal model of mammary carcinogenesis.

Alterations in the length of simple repetitive genomic sequences (microsatellite instability, MSI) may characterize a distinct mechanism of mammary carcinogenesis. In order to investigate whether MSI is associated with chemically-induced mammary carcinogenesis in the rat, 30 microdissected mammary carcinomas were analyzed using 27 different microsatellite markers from chromosomes 1, 3, 5, 7 and 8. DNA was extracted from rat mammary cancer and adjoining microscopically normal tissues from the same slide, amplified by PCR, using different polymorphic DNA markers and the reaction products were analyzed for microsatellite instability. The results of this study indicate that 30% of cases (9 out of 30) showed microsatellite instability at a minimum of 1 locus. Three cases (out of 30) showed microsatellite instability at only three loci or less, called MSI-L (low frequency MSI). Six cases (out of 30) showed MSI at four loci or more, called MSI-H (high frequency MSI). Six cases showed MSI at D5Mit11 and D5Mgh3 loci, five cases showed MSI at D1Mit14, D1Mgh6, D5Mgh5 and D8Mgh10 loci, four cases had MSI at D1Mgh2, and D3Mgh7 loci, three cases had MSI at D3Mit3, D3Mgh5, D7Mgh1 loci, two cases had MSI at D7Mit11 locus and one case had MSI at D3Mgh9 locus. The results of these experiments suggest that MSI may be an important etiological event in the pathophysiology of mammary carcinogenesis.

Animals↗

PubMed2003

[Mutation analysis on MSH2 and MLH1 genes in patients of colorectal cancer at early age].

OBJECTIVE: To investigate the etiological role of function and construction alteration in mismatch repair genes MSH2 and MLH1 in the patients onset of colorectal cancers (CRC) at early ages. METHODS: The genomic DNA was extracted from the tumor tissues and normal colon tissues during operation and subjected to analysis of microsatellite instability (MSI) in 42 Chinese patients aged less than 50 with CRC. Mutation screenings were performed with denaturing high-performance liquid chromatography (DHPLC) followed by DNA sequencing of DNA samples with variant peaks, and genomic deletion detection with quantitative multiplex PCR (Q-M-PCR) in the patients uncovered with MSI(+). RESULTS: 22 out of the 42 (52.4%) patients investigated were microsatellite instability positive (MSI(+)), 10/42 MSI(+)-H and 12/42 MSI(+)-L. 8 kinds of DNA germline alterations, 5 polymorphisms and 3 novel point mutations, were found in 9 patients with MSI(+). A large DNA (exon 1-6) deletion in MSH2 gene and a missense mutation Met242Ile in MLH1 gene were unveiled in CRC tissues of two patients with MSI(+)-H. CONCLUSION: Mutations of mismatch repair genes are frequent in Chinese patients of CRC with onset at early ages.

Adaptor Proteins, Signal Transducing↗

PubMed1998

The clinicopathological features of gastric carcinomas with microsatellite instability may be mediated by mutations of different "target genes": a study of the TGFbeta RII, IGFII R, and BAX genes.

Gastric carcinomas with DNA replication errors (RER phenotype) display a particular clinicopathologic profile and carry a putative favorable prognosis. The RER phenotype has been identified as microsatellite instability in noncoding regions, as well as in repeat sequences within exons of several "target genes": TGFbeta RII, IGFII R, and BAX. In an attempt to find out whether the RER status is a significant prognostic factor in gastric carcinoma in a multivariate analysis and whether the clinicopathological features of the RER+ tumors are associated with mutations in the "target genes," we evaluated a series of 152 cases of sporadic gastric carcinoma. Five or six microsatellite loci and/or BAT 26, a poly(A) tract, were analyzed in each case using polymerase chain reaction and electrophoresis. Thirty-five cases (23.0%) were RER+. The RER phenotype was closely associated with a low pTNM stage and carried a significantly better prognosis. The repeat sequences of the target genes were screened for mutations in 28 RER+ and 13 RER-tumors. Mutations in TGFbeta RII occurred in 67.9% of the RER+ tumors and were significantly associated with the glandular histotype. IGFII R and BAX mutations occurred, respectively, in 25.0% and 32.1% of the cases; there was a trend toward an association between mutations in these genes and decreased nodal metastization and wall invasiveness, respectively. We conclude that the RER status is a significant prognostic indicator in gastric carcinoma and that such prognostic influence may be mediated by mutations in TGFbeta RII, IGFII R, and BAX genes.

Aged↗

PubMed2001

[From gene to disease; from DNA 'mismatch' repair genes to hereditary non-polyposis colorectal carcinoma].

Hereditary non-polyposis colorectal cancer (HNPCC), also known as Lynch syndrome, is the most common autosomal dominant condition associated with early-onset colorectal cancer and the occurrence of cancer at other anatomical sites, i.e. endometrium, stomach, small intestine, urinary tract and ovaries, at an early age. Germline mutations in one of five DNA mismatch repair genes: MSH2, MLH1, PMS1, PMS2, and MSH6, predispose to HNPCC. Tumours of HNPCC patients display a high level of genomic instability, usually observed as changes in repeat numbers of simple repetitive sequences (microsatellite instability), which is a reflection of the malfunction of the DNA mismatch repair machinery.

Age of Onset↗

PubMed2004

Microsatellite instability in esophageal adenocarcinoma.

The frequency of microsatellite instability (MSI), a result of defective mismatch repair during DNA replication, has been reported inconsistently in primary esophageal adenocarcinoma (EADC). Using a panel of 15 markers, the primary aim of this study was to analyze the frequency of MSI in a well-characterized series of 27 primary EADCs, defined according to strict clinicopathologic criteria. Polymerase chain reaction was used to amplify the following microsatellite repeat loci: D2S123, D10S197, D2S119, D11S904, D2S147, D3S1764, D7S1830, D7S1805, D2S434, D9S299, BAT25, BAT26, D5S346, D17S250, and TGF-beta-RII. Tumors were classified as microsatellite-stable (MSS) when no alterations were seen in tumor DNA compared to matched normal tissues, low-level MSI (MSI-L) when 1-5 of 15 markers were altered, and high-level MSI (MSI-H) when more than five markers were altered. Using these stringent criteria, 9/27 (33%) tumors were MSS, 18/27 (67%) tumors were MSI-L, and no tumor was MSI-H. Immunohistochemistry demonstrated cell nuclear expression of DNA mismatch repair proteins (both hMLH1 and hMSH2) in 78% (21/27) of tumors. No associations were seen between MSI and immunohistochemical expression of hMLH1, hMSH2, alterations in p53 or MBD4, tumor grade, pathologic stage, or patient survival. In conclusion, the finding of low levels of MSI in most tumors suggests an inherent baseline genomic instability, and potentially increased susceptibility to mutations during the progression of esophageal adenocarcinoma.

Adaptor Proteins, Signal Transducing↗

PubMed2000

Genetic changes in sweat gland carcinomas.

The molecular pathogenesis of malignant appendageal tumors is poorly understood. Immunohistochemical staining, polymerase chain reaction (PCR)-based loss of heterozygosity (LOH) and sequencing analyses were performed in a mixed group of 21 sweat gland carcinomas. LOH was mostly confined to the chromosome arm 17p. None of the remaining 17 tumors showed LOH at any loci. Nuclear accumulation of p53 protein was observed in 3 tumors, all of which also showed LOH of 17p. One eccrine gland adenocarcinoma showed allelic loss of 17p and a Cys 176 Arg mutation in the p53 gene. The other three tumors that showed LOH of 17p, however, had wild-type p53 genes. A clear transition from benign eccrine poroma to porocarcinoma that was associated with p53 protein stabilization and allelic loss was observed in one tumor. One eccrine porocarcinoma/undifferentiated adnexal carcinoma showed prominent microsatellite instability, probably reflecting an underlying defect in DNA mismatch repair. Overexpression of erbB-2 was observed in three tumors. The low frequencies of LOH and p53 alterations in sweat gland carcinomas contrasted with the multiple genetic defects normally observed in cutaneous squamous cell carcinomas, and may be partly explained by the relative protection of cutaneous appendages from ultraviolet light and other environmental mutagens.

Adenocarcinoma↗