Allelic losses and DNA methylation at DNA mismatch repair loci in sporadic colorectal cancer

Benachenhou, Nadia; Guiral, Sébastien; Gorska‐Flipot, Izabella; Michalski, Roman; Labuda, Damian; Sinnett, Daniel

doi:10.1093/carcin/19.11.1925

Cited by 17 publications

(15 citation statements)

References 32 publications

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“…Whereas in SCC the frequency of allelic loss at MLH1 was higher (38%), which was comparable with that detected in breast cancer (46%; Benachenhou et al, 1999) and non-small cell lung cancer (43%; Wieland et al, 1996). The frequency of MSH2 allelic loss in TCC detected in this study (14%) was comparable to that detected in non-small cell cancer (11.5%; Benachenhou et al, 1998a) and also in sporadic colorectal cancer (15%; Benachenhou et al, 1998b). A higher frequency of allelic loss at MSH2 was detected in SCC of the bladder (38%).…”

Section: Discussionsupporting

confidence: 79%

“…This second mutational step may be revealed as LOH, which was previously reported at the hMLH1 locus in HNPCC (Hemminki et al, 1994) as well as at hMLH1 and hMSH2 loci in sporadic colorectal cancers (Tomlinson et al, 1996;Benachenhou et al, 1998b), in non-small cell lung cancer (Benachenhou et al, 1998a) and in breast cancer (Benachenhou et al, 1999). Christensen et al (1998) reported the occurrence of LOH at microsatellites located close to hMSH2 and hMLH1 and suggested a possible role of these genes in causing profound MSI in bladder cancer.…”

Section: Discussionmentioning

confidence: 56%

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Immunohistochemical analysis of expression and allelotype of mismatch repair genes (hMLH1 and hMSH2) in bladder cancer

et al. 2001

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Mutation of human homologues of DNA mismatch repair (MMR) genes in tumours has been shown to be associated with the phenomenon of microsatellite instability (MSI). Several studies have reported the occurrence of MSI in bladder cancer, but evidence of involvement of MMR genes in the pathogenesis of this cancer is still unclear. We therefore utilized quantitative immunohistochemical (IHC) image analysis and PCR-based allelotype analysis to determine hMLH1 and hMSH2 genes alteration in a cohort of Egyptian bladder cancer samples. IHC analysis of 24 TCC and 12 SCC revealed marked- intra and intertumour heterogeneity in the levels of expression of the two MMR proteins. One TCC lost MLH1 expression and one lost MSH2, (1/24, 4%), and one SCC lost MSH2 (1/12, 8%). A large proportion of analysed tumours revealed a percentage positivity of less than 50% for MLH1 and MSH2 expression (44% and 69%, respectively). Complete loss of heterozygosity in three dinucleotide repeats lying within, or in close proximity to, hMLH1 and hMSH2 was rare (2/57, (4%) for MLH1 ; and 1/55, (2%) for MSH2 ), however allelic imbalance was detected in 11/57 ( hMLH1 ) and 10/55 ( hMSH2 ) at any of the informative microsatellite loci. These alterations in structure and expression of DNA MMR genes suggest their possible involvement in the tumorigenesis and/or progression of bladder cancer. © 2001 Cancer Research Campaign http://www.bjcancer.com

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Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 56%

Immunohistochemical analysis of expression and allelotype of mismatch repair genes (hMLH1 and hMSH2) in bladder cancer

et al. 2001

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“…We decided to use two alternative approaches (see below). Benachenhou et al, 1998). The cleavage at the six HpaII/MspI sites located within the 700 bp upstream of the GPC3 transcription initiation site was examined by the means of two PCR reactions (one for the two distal sites and one for the four proximal sites; Figure 1A).…”

Section: Methylation Assaysmentioning

confidence: 99%

Methylation analysis of the glypican 3 gene in embryonal tumours

Boily¹,

Saikali²,

Sinnett³

2004

Br J Cancer

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We have previously shown that the glypican 3 (GPC3) gene was expressed in neuroblastoma (NB) and Wilms' tumour (WT), two embryonal tumours. GPC3 is an X-linked gene that has its peak expression during development and that is downregulated in all investigated tissues after birth. GPC3 expression could be involved in the aetiology of embryonal tumours such as NB and WT. Methylation is known to play a role in gene silencing, notably in chromosome X inactivation. Southern blot-and PCR-based methylation assays were used to assess the methylation status of the GPC3 promoter on genomic DNA from both normal and embryonal tumour cells. In normal cells, the promoter was not methylated in males and partially methylated in females. Our results suggest that DNA methylation of the promoter region is not essential for the transcriptional repression of the GPC3 gene and that the methylation observed in females is probably linked to the inactive X chromosome. In tumour samples, methylation abnormalities have been found exclusively in female NB samples (loss of methylation) and mainly in male WT samples (gain of methylation). Overall, methylation did not significantly correlate with the expression status of GPC3. Although promoter methylation is likely to affect the expression status of the gene, our results suggest that the deregulation of GPC3 transcriptional expression seen in NB and WT involves other regulatory levels.

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“…Although our markers were already shown as sensitive to detecting RER in sporadic colorectal cancers (Benachenhou et al, 1998a), we additionally examined two markers GGAA4D07 and GGAA2E02 recently reported as unstable in 30% (11 out of 37) and 41% (15 out of 37) of breast cancer patients respectively (Paulson et al, 1996). These two markers did not reveal any instability in the 22 tumours examined here (data not shown).…”

Section: Microsatellite Instabilitymentioning

confidence: 99%

Frequent loss of heterozygosity at the DNA mismatch-repair loci hMLH1 and hMSH3 in sporadic breast cancer

et al. 1999

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SummaryTo study the involvement of DNA mismatch-repair genes in sporadic breast cancer, matched normal and tumoral DNA samples of 22 patients were analysed for genetic instability and loss of heterozygosity (LOH) with 42 microsatellites at or linked to hMLH1 (3p21), hMSH2 (2p16), hMSH3 (5q11-q13), hMSH6 (2p16), hPMS1 (2q32) and hPMS2 (7p22) loci. Chromosomal regions 3p21 and 5q11-q13 were found hemizygously deleted in 46% and 23% of patients respectively. Half of the patients deleted at hMLH1 were also deleted at hMSH3. The shortest regions of overlapping (SRO) deletions were delimited by markers D3S1298 and D3S1266 at 3p21 and by D5S647 and D5S418 at 5q11-q13. Currently, the genes hMLH1 (3p21) and hMSH3 (5q11-q13) are the only known candidates located within these regions. The consequence of these allelic losses is still unclear because none of the breast cancers examined displayed microsatellite instability, a hallmark of mismatch-repair defect during replication error correction. We suggest that hMLH1 and hMSH3 could be involved in breast tumorigenesis through cellular functions other than replication error correction.

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Allelic losses and DNA methylation at DNA mismatch repair loci in sporadic colorectal cancer

Cited by 17 publications

References 32 publications

Immunohistochemical analysis of expression and allelotype of mismatch repair genes (hMLH1 and hMSH2) in bladder cancer

Immunohistochemical analysis of expression and allelotype of mismatch repair genes (hMLH1 and hMSH2) in bladder cancer

Methylation analysis of the glypican 3 gene in embryonal tumours

Frequent loss of heterozygosity at the DNA mismatch-repair loci hMLH1 and hMSH3 in sporadic breast cancer

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