Altered Expression of MLH1, MSH2, and MSH6 in Predisposition to Hereditary Nonpolyposis Colorectal Cancer

2003 ◽  
Vol 21 (19) ◽  
pp. 3629-3637 ◽  
Author(s):  
Elise Renkonen ◽  
Yange Zhang ◽  
Hannes Lohi ◽  
Reijo Salovaara ◽  
Wael M. Abdel-Rahman ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Protein Expression ◽  
Mrna Expression ◽  
Messenger Rna ◽  
Hereditary Nonpolyposis Colorectal Cancer ◽  
Population Based ◽  
Altered Expression ◽  
Dna Mismatch ◽  
Mmr Genes ◽  
Hereditary Nonpolyposis

Purpose: A considerable fraction (30% to 70%) of families with verified or putative hereditary nonpolyposis colorectal cancer fails to show mutations in DNA mismatch repair (MMR) genes. Our purpose was to address the genetic etiology of such families. Materials and Methods: We scrutinized a population-based cohort of 26 families from Finland that had screened mutation-negative by previous techniques. Blood was tested for allelic messenger RNA (mRNA) expression of MLH1, MSH2, and MSH6 by single nucleotide primer extension (SNuPE), and tumor tissue for MMR protein expression by immunohistochemistry (IHC) as well as for microsatellite instability (MSI). Full-length cDNAs of genes implicated by SNuPE or IHC were cloned and sequenced. Results: Unbalanced mRNA expression of MLH1 alleles was evident in two families. An inherited nonsense mutation was subsequently identified in one family, and complete silencing of the mutated allele was identified in the other family. Extinct protein expression by IHC implicated MLH1 in these two and in four other families, MSH2 in four families, and MSH6 in one family. Although no unequivocal genomic mutations were detected in the latter families, haplotype and other findings provided support for heritable defects. With one exception, all tumors with IHC alterations showed MSI, in contrast to the remaining families, which showed neither IHC changes nor MSI. Conclusion: Our expression-based strategy stratified the present “mutation-negative” cohort into two discrete categories: families linked to the major MMR genes MLH1, MSH2, and MSH6 (11 [42%] of 26) and those likely to be associated with other, as yet unknown susceptibility genes (15 [58%] of 26).

Microsatellite Instability in Colorectal Carcinoma

2003 ◽  
Vol 127 (6) ◽  
pp. 694-700 ◽  
Author(s):  
Valérie Rigau ◽  
Nicole Sebbagh ◽  
Sylviane Olschwang ◽  
François Paraf ◽  
Najat Mourra ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Protein Expression ◽  
Microsatellite Instability ◽  
Hereditary Nonpolyposis Colorectal Cancer ◽  
Screening Method ◽  
Molecular Testing ◽  
Cancer Syndrome ◽  
Simple Method ◽  
Mmr Genes ◽  
Hereditary Nonpolyposis

Abstract Context.—Microsatellite instability (MSI) due to defective mismatch repair (MMR) genes has been reported in the majority of colorectal tumors from patients with hereditary nonpolyposis colorectal cancer syndrome and in 10% to 15% of sporadic colorectal cancers. The identification of cancers associated with MSI requires classical molecular testing as the gold standard. Objective.—The aim of this study was to evaluate the role of immunohistochemistry with antibodies directed against 4 MMR proteins as a screening tool for carcinomas with MSI. Methods.—In this study, 204 formalin-fixed, paraffin-embedded colorectal carcinomas were examined for MMR protein expression (hMLH1, hMSH2, hMSH6, and hPMS2) and analyzed for MSI (MSI-H indicates at least 2 of 6 markers affected). These results were correlated with histopathologic parameters. Results.—Immunohistochemical analysis revealed that loss of expression of at least 1 protein was present in 17% of cases. One hundred percent of carcinomas that showed high instability (MSI-H) showed loss of expression of hMLH1, hMSH2, or hMSH6. Loss of expression of 2 proteins was present in 59.4% of MSI-H cases, with only 2 combinations, namely, hMLH1/hPMS2 and hMSH2/hMSH6. Isolated loss of hMSH6 expression was present in 2 MSI-H cases. Conclusions.—These findings confirm that examination of MMR protein expression by immunohistochemistry is a simple method to diagnose colorectal cancer with MSI. Our data suggest that the study of hMSH6 may be useful, in addition to hMLH1 and hMSH2. Moreover, immunohistochemistry could represent a screening method with which to direct research on the mutations of MMR genes observed in hereditary nonpolyposis colorectal cancer syndrome.

scholarly journals A Dynamic Family History model Of Hereditary Nonpolyposis Colorectal Cancer and Critical Illness Insurance

2007 ◽  
Vol 2 (2) ◽  
pp. 289-325 ◽  
Author(s):  
L. Lu ◽  
A. S. Macdonald ◽  
H. R. Waters ◽  
F. Yu
Keyword(s):  
Colorectal Cancer ◽  
Critical Illness ◽  
Family History ◽  
Hereditary Nonpolyposis Colorectal Cancer ◽  
Familial Aggregation ◽  
Family History Information ◽  
Dna Mismatch ◽  
Genetic Test Results ◽  
Hereditary Nonpolyposis ◽  
History Of

ABSTRACTHereditary nonpolyposis colorectal cancer (HNPCC) is characterised by the familial aggregation of cancer of the colon and rectum (CRC). It may be caused by any of five mutations in DNA mismatch repair (MMR) genes or by non-genetic factors, such as life style. However, it accounts for only about 2% of CRC, which is a very common cancer. Previous actuarial models, of diseases with only genetic causes, assumed that a family history of the disease shows mutations to be present, but this is not true of HNPCC. This is a significant limitation, since the best information available to an underwriter (especially if the use of genetic test results is banned) is likely to be knowledge of a family history of CRC. We present a Markov model of CRC and HNPCC, which includes the presence of a family history of CRC as a state, and estimate its intensities allowing for MMR genotype. Using this we find the MMR mutation probabilities for an insurance applicant with a family history of CRC. Our model greatly simplifies the intensive computational burden of finding such probabilities by integrating over complex models of hidden family structure. We estimate the costs of critical illness insurance given the applicant's genotype or the presence of a family history. We then consider what the cost of adverse selection might be, if insurers are unable to use genetic tests or family history information. We also consider the effect of using alternative definitions of a family history in underwriting.

scholarly journals Functional domains of the Saccharomyces cerevisiae Mlh1p and Pms1p DNA mismatch repair proteins and their relevance to human hereditary nonpolyposis colorectal cancer-associated mutations.

1997 ◽  
Vol 17 (8) ◽  
pp. 4465-4473 ◽  
Author(s):  
Q Pang ◽  
T A Prolla ◽  
R M Liskay
Keyword(s):  
Colorectal Cancer ◽  
Saccharomyces Cerevisiae ◽  
Mismatch Repair ◽  
Hereditary Nonpolyposis Colorectal Cancer ◽  
Dna Mismatch Repair ◽  
Functional Domains ◽  
Dna Mismatch ◽  
Amino Terminal ◽  
Enzymatic Function ◽  
Hereditary Nonpolyposis

The MutL protein is an essential component of the Escherichia coli methyl-directed mismatch repair system but has no known enzymatic function. In the yeast Saccharomyces cerevisiae, the MutL equivalent, an Mlh1p and Pms1p heterodimer, interacts with Msh2p bound to mismatch-containing DNA. Little is known of the functional domains of Mlh1p and Pms1p. In this report, we define the Mlh1p and Pms1p domains required for Mlh1p-Pms1p interaction. The Mlh1p-interactive domain of Pms1p is comprised of 260 amino acids near the carboxyl terminus while the Pms1p-interactive domain of Mlh1p resides in the final 212 residues. The two domains are sufficient for Mlh1p-Pms1p interaction, as determined by the two-hybrid assay and by in vitro protein affinity chromatography. Deletions within the domains completely eliminated Mlh1p-Pms1p interaction. Using site-directed mutagenesis, we altered a number of highly conserved residues in the Mlh1p and Pms1p proteins, including some alterations that mimic germline mutations observed for human hereditary nonpolyposis colorectal cancer. Alterations either in the consensus MutL box located in the amino-terminal portion of each protein or in the carboxyl-terminal homology motif of Mlh1p eliminated DNA mismatch repair function but had no effect on Mlh1p-Pms1p interaction. In addition, certain MLH1 and PMS1 mutant alleles caused a dominant negative mutator effect when overexpressed. We discuss the implications of these findings for the structural organization of the Mlh1p and Pms1p proteins and the importance of Mlh1p-Pms1p interaction.

Molecular Analysis of Familial Endometrial Carcinoma: A Manifestation of Hereditary Nonpolyposis Colorectal Cancer or a Separate Syndrome?

2005 ◽  
Vol 23 (21) ◽  
pp. 4609-4616 ◽  
Author(s):  
Miina Ollikainen ◽  
Wael M. Abdel-Rahman ◽  
Anu-Liisa Moisio ◽  
Annette Lindroos ◽  
Reetta Kariola ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Endometrial Carcinoma ◽  
Hereditary Nonpolyposis Colorectal Cancer ◽  
Germline Mutations ◽  
Unknown Etiology ◽  
Cancer Syndrome ◽  
Site Specific ◽  
Mmr Genes ◽  
Hereditary Nonpolyposis ◽  
Mlh1 Protein

Purpose Familial clustering of endometrial carcinoma (EC) may occur as part of hereditary nonpolyposis colorectal cancer (HNPCC), a multiorgan cancer syndrome with mismatch repair (MMR) deficiency. Clustering of EC alone, termed as familial site-specific EC, may constitute a separate entity. Because its genetic basis is unknown, our purpose was to characterize such families molecularly. Materials and Methods Twenty-three families with site-specific EC were identified among 519 consecutive patients diagnosed with EC during 1986 to 1997. Tumor tissues were examined for MMR protein expression by immunohistochemical (IHC) analysis, and MMR genes pinpointed by IHC changes were screened for germline mutations by exon-by-exon sequencing, multiplex ligation-dependent probe amplification, and direct tests for mutations common in the population. Results Among 33 ECs from 23 families, MLH1 protein was lost in seven tumors (21%), MSH2 together with MSH6 was lost in four tumors (12%), and MSH6 alone was lost in five tumors (15%). A truncating germline mutation in MSH6 (3261insC) was identified in one family and a likely pathogenic missense mutation in MSH2 (D603N) was identified in another family. Among the original 519 patients, nine (all with colon cancer in the family) were diagnosed with HNPCC at the outset—six with MLH1 and three with MSH2 mutations. Conclusion Our study gives a minimum overall frequency of 2.1% (11 of 519) for germline MMR defects ascertained through EC in the index patients. The fact that only two of 23 families with site-specific EC (8.7%) had germline mutations in MMR genes suggests another as yet unknown etiology in most families with site-specific EC.

scholarly journals A combined proteomics and Mendelian randomization approach to investigate the effects of aspirin-targeted proteins on colorectal cancer

2020 ◽  
Author(s):  
Aayah Nounu ◽  
Alexander Greenhough ◽  
Kate J Heesom ◽  
Rebecca C Richmond ◽  
Jie Zheng ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Protein Expression ◽  
Mendelian Randomization ◽  
Population Based ◽  
Stable Isotope Labelling ◽  
Standard Deviation Increase ◽  
Altered Expression ◽  
Cancer Cell Death ◽  
Proteomic Approach ◽  
Cytoskeletal Regulation

AbstractBackgroundEvidence for aspirin’s chemopreventative properties on colorectal cancer (CRC) is substantial, but its mechanism of action is not well-understood. We combined a proteomic approach with Mendelian randomization (MR) to identify possible new aspirin targets that decrease CRC risk.MethodsHuman colorectal adenoma cells (RG/C2) were treated with aspirin (24 hours) and a stable isotope labelling with amino acids in cell culture (SILAC) based proteomics approach identified altered protein expression. Protein quantitative trait loci (pQTLs) from INTERVAL (N=3,301) and expression QTLs (eQTLs) from the eQTLGen Consortium (N=31,684) were used as genetic proxies for protein and mRNA expression levels. Two-sample MR of mRNA/protein expression on CRC risk was performed using eQTL/pQTL data combined with CRC genetic summary data from the Colon Cancer Family Registry (CCFR), Colorectal Transdisciplinary (CORECT), Genetics and Epidemiology of Colorectal Cancer (GECCO) consortia and UK Biobank (55,168 cases and 65,160 controls).ResultsAltered expression was detected for 125/5886 proteins. Of these, aspirin decreased MCM6, RRM2 and ARFIP2 expression and MR analysis showed that a standard deviation increase in mRNA/protein expression was associated with increased CRC risk (OR:1.08, 95% CI:1.03-1.13, OR:3.33, 95% CI:2.46-4.50 and OR:1.15, 95% CI:1.02-1.29, respectively).ConclusionMCM6 and RRM2 are involved in DNA repair whereby reduced expression may lead to increased DNA aberrations and ultimately cancer cell death, whereas ARFIP2 is involved in actin cytoskeletal regulation indicating a possible role in aspirin’s reduction of metastasis.ImpactOur approach has shown how laboratory experiments and population-based approaches can combine to identify aspirin-targeted proteins possibly affecting CRC risk.

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