The silence of the genes: Matching mismatch repair defects with tumors

Boland, C. Richard; Goel, Ajay

doi:10.1002/cncr.11769

Cited by 9 publications

(9 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[9][10][11][12][13][14][15] MSH2 is one of the most important members of the MMR gene family. 16 DNA becomes microsatellite unstable when MMR genes are lost or dysfunctional. This type of instability is thought to predispose cells to the accumulation of other genetic alterations, accelerating the process of malignant transformation.…”

mentioning

confidence: 99%

Loss of MSH2 protein expression is a risk factor in early stage cervical cancer

et al. 2007

View full text Add to dashboard Cite

Background: Loss of mismatch repair (MMR) gene expression has been associated with fewer metastases and improved prognosis in various tumour types. Aims: To evaluate the predictive and prognostic significance of loss of MMR protein MSH2 in early stage cervical cancer. Methods: Specimens from 218 consecutive patients with early stage, surgically treated cervical cancer were analysed. Median age was 42 years (interquartile range 35-53). International Federation of Gynecology and Obstetrics (FIGO) stages were IB1 (57%), IB2 (25%) and IIA (18%). Histology was 70% squamous cell, 6% adenosquamous and 24% adenocarcinoma. Pelvic lymph node metastasis was present in 66 (30%) patients. Median follow-up was 5.2 years (interquartile range 2.5-7.9). Tissue microarrays (TMAs) were constructed containing three cores of paraffin-embedded tumour per case. MSH2 expression was assessed by immunohistochemistry on TMAs and full sections. Results: In TMAs MSH2 expression could be analysed in 184/218 (84%) tumours. Loss of MSH2 was observed in 58/184 (32%) tumours, with a moderately strong concordance between TMAs and full sections (k = 0.47). In tumours with loss of MSH2, pelvic lymph node metastasis and cancer invasion beyond 10 mm were more frequent (48% vs 25%, and 59% vs 37%, respectively). However, loss of MSH2 expression was not related to recurrence or survival. Conclusion: TMAs are powerful tools for high throughput screening of biological markers for prognostic value in cervical cancer. Absence of MSH2 expression is associated with a high-risk profile in early stage cervical cancer, but does not predict lymph node status with sufficient accuracy to be used in the clinic.

show abstract

mentioning

confidence: 99%

Loss of MSH2 protein expression is a risk factor in early stage cervical cancer

et al. 2007

View full text Add to dashboard Cite

show abstract

“…Epigenetics provide a new perspective for the early diagnosis, treatment and prognosis of these tumors. Studies indicate that CpG island methylation in the MMR genes are also a mechanism underlying gene inactivation and tumorigenesis [30,31]. With the development of epigenetics in recent years, DNA methylation has gradually become a new research focus.…”

Section: Discussionmentioning

confidence: 99%

Alterations of Copy Number of Methylation Pattern in Mismatch Repair Genes by Methylation Specific-Multiplex Ligation-Dependent Probe Amplification in Cases of Colon Cancer

Onrat¹,

Çeken²,

Ellidokuz³

et al. 2011

Balkan Journal of Medical Genetics

View full text Add to dashboard Cite

Genetic alterations and changes in genomic DNA cytosine methylation patterns are associated with all types of cancer and are caused by germline mutations in DNA mismatch repair (MMR) genes, predominantly MLH1 (MutL homolog 1, 19 exons) and MSH2 (MutS homolog 2, 16 exons). Genomic DNA was extracted from tissue samples embedded in paraffin from 49 patients with adenocarcinoma and from 21 patients with carcinoma for the study group; genomic DNA was extracted from lymphocytes from 10 healthy donors for the control group. We used methylation specific multiplex ligation-dependent probe amplification (MS-ML-PA), which allows the detection of copy number changes and unusual methylation levels of 10 to 50 different sequences in one reaction by use of the methylation-sensitive restriction enzyme HhaI and sequence-specific capillary electrophoresis for the study of 24 genes.We found the mean methylation rates for MLH1 (97.14%), MSH2 (24.28%), MSH6 (MutS homolog 6) (67.14%), MSH3 (MutS homolog 3) (78.57%), MLH3 (MutL homolog 3) (75.71%), PMS2 (postmeiotic segregation increased 2) (65.71%), MGMT(O-6-methylguanine-DNA methyltransferase ) (82.85%). We conclude that the mismatch repair (MMR) system is critical for the maintenance of genomic stability.

show abstract

“…Epigenetics provides a new idea for the early diagnosis, treatment and prognosis of tumors. Studies indicate that CpG island methylation in the hMLH1 gene promoter region is also a mechanism underlying gene inactivation and tumorigenesis [29,30] . Therefore, based on traditional micromutation detection, we should further combine large fragment deletion detection.…”

Section: Discussionmentioning

confidence: 99%

Genetic diagnosis strategy of hereditary non-polyposis colorectal cancer

Sheng

Zhang²,

Ji³

et al. 2009

WJG

View full text Add to dashboard Cite

AIM:To study the characteristics of mismatch repair gene mutation of Chinese hereditary non-polyposis colorectal cancer (HNPCC) and hMLH1 gene promoter methylation, and to improve the screening strategy and explore the pertinent test methods. METHODS:A systematic analysis of 30 probands from HNPCC families in the north of China was performed by immunohistochemistry, microsatellite instability (MSI), gene mutation and methylation detection. RESULTS:High frequency microsatellite instability occurred in 25 probands (83.3%) of HNPCC family. Loss of hMLH1 and hMSH2 protein expression accounted for 88% of all microsatellite instability. Pathogenic mutation occurred in 14 samples and 3 novel mutational sites were discovered. Deletion of exons 1-6, 1-7 and 8 of hMSH2 was detected in 3 samples and no large fragment deletion was found in hMLH1. Of the 30 probands, hMLH1 gene promoter methylation occurred in 3 probands. The rate of gene micromutation detection combined with large fragment deletion detection was 46.7%-56.7%. The rate of the two methods in combination with methylation detection was 63.3%. CONCLUSION:Scientific and rational detection strategy can improve the detection rate of HNPCC. Based on traditional molecular genetics and combined with epigenetics, multiple detection methods can accurately diagnose HNPCC.

show abstract

The silence of the genes: Matching mismatch repair defects with tumors

Cited by 9 publications

References 15 publications

Loss of MSH2 protein expression is a risk factor in early stage cervical cancer

Loss of MSH2 protein expression is a risk factor in early stage cervical cancer

Alterations of Copy Number of Methylation Pattern in Mismatch Repair Genes by Methylation Specific-Multiplex Ligation-Dependent Probe Amplification in Cases of Colon Cancer

Genetic diagnosis strategy of hereditary non-polyposis colorectal cancer

Contact Info

Product

Resources

About