Microsatellite instability in ovarian neoplasms

King, Bonnie L.; Carcangiu, Maria Luisa; Carter, D.; Kiechle, Marion; Pfisterer, Jacobus; Pfleiderer, Albrecht; Kacinski, Barry M.

doi:10.1038/bjc.1995.341

Cited by 88 publications

(62 citation statements)

References 30 publications

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“…We found 12.5% of ovarian tumours showed hMLH1 hypermethylation, and a corresponding loss of hMLH1 expression, only slightly below the frequency (15%) at which the MIN+ phenotype is estimated to occur in sporadic ovarian cancer (Hatta et al, 1997;Fujita et al, 1995;King et al, 1995). Furthermore, we found that in all the tumours in which we did not detect promoter hypermethylation hMLH1 expression was high.…”

Section: Discussioncontrasting

confidence: 62%

“…About 15% of sporadically occurring ovarian tumours show microsatellite instability (Hatta et al, 1997;Fujita et al, 1995;King et al, 1995), suggesting that there is a defect in mismatch repair in these tumours. To determine if methylation of the promoter region of hMLH1 could be a potential cause of mismatch repair defects in ovarian tumours, DNA was extracted from 24 ovarian tumour samples and used for Southern blot analysis.…”

Section: Methylation Status Of Hmlh1 In Ovarian Tumoursmentioning

confidence: 99%

“…For many tumour types the MIN+ phenotype has also been detected in sporadically occurring disease (Eshleman and Markowitz, 1995). For example in ovarian cancer about 15% of sporadic tumours exhibit the MIN+ phenotype (Hatta et al, 1997;Fujita et al, 1995;King et al, 1995). This suggests that these tumours are also mismatch repair-defective, however, mutations of mismatch repair genes have only been observed at low frequency in MIN+ sporadic tumours (Liu et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

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A role for methylation of the hMLH1 promoter in loss of hMLH1 expression and drug resistance in ovarian cancer

Strathdee¹,

Mackean²,

Illand³

et al. 1999

Oncogene

307

208

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Experimental evidence from several sources has identi®ed a link between mismatch repair de®ciency and cytotoxic drug resistance. Selection for cisplatin resistance in the human ovarian cancer cell line A2780, results in loss of expression of the mismatch repair protein hMLH1 in most (90%) of the resultant cisplatin-resistant cell lines. Here we demonstrate that the cisplatin sensitive parental cell line displays methylation of the promoter of only one hMLH1 allele, but that the resistant cell lines all exhibit hyper-methylation of the promoters of both hMLH1 alleles. Full methylation of all sites tested was found to be invariably associated with loss of hMLH1 expression, whereas a partial increase in methylation appears compatible with either loss or maintenance of expression. In addition treatment of two of the resistant cell lines with 5-azacytidine, a known inhibitor of methylation, results in re-expression of hMLH1. Clonogenic assays demonstrate that the 5-azacytidine treated cells show increased sensitivity to cisplatin. Furthermore, 12.5% (3/ 24) of ovarian tumours show hypermethylation of the hMLH1 promoter. Expression of hMLH1 is absent in the tumours that are hypermethylated, while all the unmethylated tumours still express the protein. This analysis suggests that methylation of the hMLH1 promoter may be a common mechanism for loss of hMLH1 expression, and possibly for cisplatin-resistance, in ovarian cancer.

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Section: Discussioncontrasting

confidence: 62%

Section: Methylation Status Of Hmlh1 In Ovarian Tumoursmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A role for methylation of the hMLH1 promoter in loss of hMLH1 expression and drug resistance in ovarian cancer

Strathdee¹,

Mackean²,

Illand³

et al. 1999

Oncogene

307

208

View full text Add to dashboard Cite

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“…Alterations in the length of these sequences, either by expansion or contraction of the repeat motifs, are characteristic of hereditary non-polyposis colorectal cancer (HNPCC) and a proportion of sporadic carcinomas of the colon, breast, ovary, prostate, stomach, lung, bladder, endometrium and oesophagus (Aaltonen et al, 1993;Ionov et al, 1993;Patel et al, 1994;Thibodeau et al, 1993;King et al, 1995;Uchida et al, 1995;Han et al, 1993;Merlo et al, 1994;Gonzalez-Zulueta et al, 1993;Risinger et al, 1993;Meltzer et al, 1994).…”

mentioning

confidence: 99%

Apparent protection from instability of repeat sequences in cancer-related genes in replication error positive gastrointestinal cancers

et al. 1997

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Genomic instability at simple repeated sequences has been observed in various types of human cancers and is considered an important mechanism in tumorigenesis. Alterations at microsatellite loci have been reported scattered throughout the genome. Recently, the transforming growth factor-b receptor type II (TGF-b RII) and the insulin-like growth factor II receptor (IGF-IIR) genes were shown to have inactivating mutations within coding microsatellite sequences. The demonstration of mutations in two growth regulatory genes supports the idea that other regulatory genes with repeat sequences may also be targets in tumours with defective mismatch repair. We examined genes involved in tumour suppression, cell adhesion and cell cycle regulation for mutations at small repeat sequences in replication error positive gastrointestinal cancers. Several polymorphisms were found which exhibited instability, but no other instability was present in the regions examined.Keywords: microsatellite instability; repeats; colorectal cancer; gastric cancer Microsatellites are short tandemly repeated nucleotide sequences widely distributed throughout the genome. Alterations in the length of these sequences, either by expansion or contraction of the repeat motifs, are characteristic of hereditary non-polyposis colorectal cancer (HNPCC) and a proportion of sporadic carcinomas of the colon, breast, ovary, prostate, stomach, lung, bladder, endometrium and oesophagus (Aaltonen et al

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“…Allelotyping studies have identified common sites of LOH on chromosomes 5q, 6q, 11p, 13q, 14q, 15q, 18q, Xp (Cliby et al, 1993;Osborne and Leech, 1994), and particularly on chromosome 7q (Zenklusen et al, 1995), 9q (Schultz et al, 1995) and 17p (Phillips et al, 1993). The occurrence of novel alleles at microsatellite loci, due to either a replication error phenotype (RER + ) resulting from defective mismatch repair or general genetic instability, has been described in 17-37% of ovarian tumours (Fujita et al, 1995;King et al, 1995;Sood and Buller, 1996). However, MI may occur in up to 75% of stage I ovarian tumours, and 71% of uncommon histopathological types such as endometrioid or mixed serous and mucinous tumours (King et al, 1995).…”

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confidence: 99%

Molecular detection of tumour DNA in serum and peritoneal fluid from ovarian cancer patients

et al. 1999

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We have analysed DNA extracted from the serum and peritoneal fluid of 20 ovarian cancer patients for the presence of tumour-specific genetic alterations. The 20 patients included six with stage Ia disease. Using six polymorphic microsatellite loci we were able to detect novel alleles or loss of heterozygosity in 17/20 serum samples and 12/19 peritoneal fluid samples. Tumour-specific abnormalities were detected in the serum of all but one of the stage Ia cases. Half of the occurrences of loss of heterozygosity identified in primary tumour material were detectable in the serum samples. Novel alleles indicative of microsatellite instability were found in 3/6 patients with stage Ia disease but in only 1/14 of patients with more advanced disease. One of the eight patients in the control group displayed abnormalities in her serum DNA. The ease with which tumour-specific alterations were detected in serum and peritoneal samples from ovarian cancer patients, using a panel of only six polymorphic microsatellite markers on four chromosomes, suggests that molecular detection methods could prove useful in the staging, monitoring and screening of this disease. © 1999 Cancer Research Campaign

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Microsatellite instability in ovarian neoplasms

Cited by 88 publications

References 30 publications

A role for methylation of the hMLH1 promoter in loss of hMLH1 expression and drug resistance in ovarian cancer

A role for methylation of the hMLH1 promoter in loss of hMLH1 expression and drug resistance in ovarian cancer

Apparent protection from instability of repeat sequences in cancer-related genes in replication error positive gastrointestinal cancers

Molecular detection of tumour DNA in serum and peritoneal fluid from ovarian cancer patients

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