HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

The role of MLH1, MSH2 and MSH6 in the development of multiple colorectal cancers.

Abstract
There is increased incidence of microsatellite instability (MSI) in patients who develop multiple primary colorectal cancers (CRC), although the association with hereditary nonpolyposis colon cancer (HNPCC) is unclear. This study aims to evaluate the underlying genetic cause of MSI in these patients. Microsatellite instability was investigated in 111 paraffin-embedded CRCs obtained from 78 patients with metachronous and synchronous cancers, and a control group consisting of 74 cancers from patients with a single CRC. Tumours were classified as high level (MSI-H), low level (MSI-L) or stable (MSS). MLH1, MSH2 and MSH6 gene expression was measured by immunohistochemistry. Methylation of the MLH1 promoter region was evaluated in MSI-H cancers that failed to express MLH1, and mutational analysis performed in MSI-H samples that expressed MLH1, MSH2 and MSH6 proteins. The frequency of MSI-H was significantly greater in the multiple, 58 out of 111 (52%), compared to the single cancers, 10 out of 74 (13.5%), P < 0.01. Of the 32 patients from whom two or more cancers were analysed, eight (25%) demonstrated MSI-H in both cancers, 13 (41%) demonstrated MSI-H in one cancer and 11 (34%) failed to demonstrate any MSI-H. MSI-H single cancers failed to express MLH1 or MSH2 in seven out of nine (78%) cases and MSI-L/MSS cancers failed to express MLH1 or MSH2 in one out of 45 (2.2%) cases, all cancers expressed MSH6. MSI-H multiple cancers failed to express MLH1 or MSH2 in 21 out of 43 (48%) cases and MSI-L/MSS cancers failed to express MLH1 or MSH2 in four out of 32 (12.5%) cases. MSH6 expression was lost in five MSI-H multiple cancers, four of which also failed to express MLH1 or MSH2. Loss of expression of the same mismatch repair (MMR) gene was identified in both cancers from six out of 19 (31%) patients. Methylation was identified in 11 out of 17 (65%) multiple and three out of six (50%) single MSI-H cancers that failed to express MLH1. Mutational analysis of 10 MSI-H multiple cancers that expressed MLH1, MSH2 and MSH6 failed to demonstrate mutations in the MLH1 or MSH2 genes. We suggest that, although MSI-H is more commonly identified in those with multiple colorectal cancers, this does not commonly arise from a classical HNPCC pathway.
AuthorsD A Lawes, T Pearson, S Sengupta, P B Boulos
JournalBritish journal of cancer (Br J Cancer) Vol. 93 Issue 4 Pg. 472-7 (Aug 22 2005) ISSN: 0007-0920 [Print] England
PMID16106253 (Publication Type: Journal Article)
Chemical References
  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • DNA-Binding Proteins
  • G-T mismatch-binding protein
  • MLH1 protein, human
  • Neoplasm Proteins
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • MSH2 protein, human
  • MutL Protein Homolog 1
  • MutS Homolog 2 Protein
Topics
  • Adaptor Proteins, Signal Transducing
  • Adult
  • Aged
  • Aged, 80 and over
  • Carrier Proteins
  • Case-Control Studies
  • Colorectal Neoplasms (genetics)
  • Colorectal Neoplasms, Hereditary Nonpolyposis (genetics, physiopathology)
  • DNA Methylation
  • DNA Mutational Analysis
  • DNA Repair
  • DNA-Binding Proteins (biosynthesis, genetics)
  • Female
  • Gene Expression Profiling
  • Humans
  • Immunohistochemistry
  • Male
  • Microsatellite Repeats
  • Middle Aged
  • MutL Protein Homolog 1
  • MutS Homolog 2 Protein
  • Neoplasm Proteins (biosynthesis, genetics)
  • Neoplasms, Multiple Primary (genetics)
  • Neoplasms, Second Primary (genetics)
  • Nuclear Proteins (biosynthesis, genetics)
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins (biosynthesis, genetics)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: