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.

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.

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).

Clinicopathologic and Pedigree Differences in Amsterdam I–Positive Hereditary Nonpolyposis Colorectal Cancer Families According to Tumor Microsatellite Instability Status

2007 ◽  
Vol 25 (7) ◽  
pp. 781-786 ◽  
Author(s):  
Laura Valle ◽  
Jose Perea ◽  
Pablo Carbonell ◽  
Victoria Fernandez ◽  
Ana M. Dotor ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Protein Expression ◽  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Hereditary Nonpolyposis Colorectal Cancer ◽  
Repair System ◽  
Primary Tumors ◽  
Multiple Primary Tumors ◽  
Hereditary Nonpolyposis ◽  
Multiple Primary

Purpose To establish the clinicopathologic and familial differences within Amsterdam I–positive families, showing either tumor microsatellite instability (MSI) or microsatellite stability (MSS) in order to confirm or deny the existence of hereditary nonpolyposis colorectal cancer (HNPCC) without defects in the mismatch repair system. Patients and Methods Sixty-four Amsterdam I–positive families were included in the study for which full, three-generation, family medical histories and colorectal paraffin-embedded tumors were obtained. Both personal and clinicopathologic information of patients were collected. In all cases, both the MSI status and the mismatch repair (MMR) protein expression were analyzed. MMR genetic testing was performed on the MSI families. Results Of the Amsterdam I–positive families, 59.4% were tumor MSI, and 40.6% were tumor MSS. When comparing both groups, the statistical differences were observed in the age of onset (MSI, 41 years; MSS, 53 years); in the colorectal tumor location, more frequently proximal in MSI cases; in fewer mucinous tumors in MSS; and loss of MMR protein expression in the MSI tumors. Regarding the individual and familial cancer history, we observed a predominance of individuals with multiple primary tumors in MSI pedigrees, as well as differences in the type of tumors developed within the family. Conclusion Our findings support the suspicion of another hereditary colorectal syndrome different from HNPCC and characterized by MSS, the normal MMR immunohistochemical expression, the presence of only colorectal tumors, and the absence of individuals with multiple primary tumors. All these circumstances suggest the existence of a non-MMR gene being responsible for this new syndrome.

The detection of microsatellite instability in blind endometrial samples—a potential novel screening tool for endometrial cancer in women from hereditary nonpolyposis colorectal cancer families?

2006 ◽  
Vol 16 (3) ◽  
pp. 1393-1400
Author(s):  
M. J. Hewitt ◽  
N. Wood ◽  
N. D. Quinton ◽  
R. Charlton ◽  
G. Taylor ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Endometrial Cancer ◽  
Microsatellite Instability ◽  
Hereditary Nonpolyposis Colorectal Cancer ◽  
Screening Tool ◽  
Endometrial Biopsy ◽  
Cancer Syndrome ◽  
Normal Endometrium ◽  
Increased Risk ◽  
Hereditary Nonpolyposis

Microsatellite instability (MSI) is the phenotypic molecular characteristic of the majority of tumors associated with the hereditary nonpolyposis colorectal cancer syndrome (HNPCC). Women in this group have an increased risk of endometrial cancer (EC). This study aimed to determine whether MSI could be demonstrated in blind endometrial samples from women with EC, HNPCC kindreds undergoing screening for EC, and women with normal endometrium. Twenty-four women with EC, 20 women from HNPCC kindreds, and 20 women undergoing gynecological surgery for benign indications underwent blind sampling. MSI analysis was performed by conventional polymerase chain reaction using fluorescent-labeled primers and automated analysis. Twelve microsatellites were studied with MSI defined as evident when novel alleles were seen in endometrial biopsy samples compared to genomic DNA. Of the 24 EC samples obtained, sufficient DNA for analysis was extracted in 17 cases. Three cases had evidence of MSI in at least 7/12 loci. None of the endometrium from the two other study groups revealed evidence of MSI. This is the first demonstration of MSI in blind endometrial biopsies. The ability to demonstrate MSI in heterogenous endometrial samples suggests potential for the development of a novel EC screening tool for women in HNPCC kindreds.

Mutations of hMLH1 and hMSH2 in Patients With Suspected Hereditary Nonpolyposis Colorectal Cancer: Correlation With Microsatellite Instability and Abnormalities of Mismatch Repair Protein Expression

2002 ◽  
Vol 20 (5) ◽  
pp. 1203-1208 ◽  
Author(s):  
Mario Scartozzi ◽  
Francesca Bianchi ◽  
Saverio Rosati ◽  
Eva Galizia ◽  
Annalisa Antolini ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Protein Expression ◽  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Hereditary Nonpolyposis Colorectal Cancer ◽  
Germ Line ◽  
Missense Mutations ◽  
Hereditary Nonpolyposis ◽  
Germ Line Mutations

PURPOSE: The relationship between germ-line mutations of hMSH2 and hMLH1, microsatellite instability (MSI), and loss of DNA mismatch repair (MMR) gene expression were studied to formulate an effective selection protocol for patients with suspected hereditary nonpolyposis colorectal cancer who should be offered genetic testing. PATIENTS AND METHODS: Patients eligible for germ-line analysis of hMLH1 and hMSH2 were selected. Tumor specimens were obtained to assess MSI and loss of MMR gene expression. RESULTS: Among 37 patients who participated in the study, two hMSH2 and two hMLH1 missense mutations (11%) were detected, none of which was found in a panel of 60 healthy volunteers. High MSI was found in five tumors (19%) and low MSI in 10 tumors (39%); 12 tumors (46%) were microsatellite stable. Four tumors demonstrated loss of hMLH1, and three tumors demonstrated loss of hMSH2 protein expression. CONCLUSION: No relationship was found between MMR gene mutations and MSI; low or no MSI was found in the four patients with germ-line mutations, and none of the five patients with high MSI demonstrated abnormalities of MMR genes. On the contrary, loss of hMLH1 or hMSH2 expression was found in the tumors from three of the four patients demonstrating germ-line mutations. These data suggest that germ-line mutations of the MMR gene can occur in people with MSI-negative tumors. Sensitive clinical criteria and the study of MMR gene expression may be useful to identify this subset of patients.

Hereditary Nonpolyposis Colorectal Cancer Syndrome in a Patient With Urothelial Carcinoma of the Upper Urothelial Tract

2003 ◽  
Vol 127 (2) ◽  
pp. e60-e63
Author(s):  
Arndt Hartmann ◽  
John C. Cheville ◽  
Wolfgang Dietmaier ◽  
Ferdinand Hofstädter ◽  
Lawrence J. Burgart ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Urinary Tract ◽  
Urothelial Carcinoma ◽  
Hereditary Nonpolyposis Colorectal Cancer ◽  
Upper Urinary Tract ◽  
Cancer Syndrome ◽  
Tract Cancer ◽  
Hereditary Nonpolyposis ◽  
History Of ◽  
History Of Cancer

Abstract Urothelial carcinoma of the upper urinary tract is relatively uncommon but may develop as a manifestation of the hereditary nonpolyposis colorectal cancer syndrome (HNPCC), which is characterized by mutations in a number of DNA mismatch repair genes and detectable as microsatellite instability or loss of the respective protein by immunostaining. No well-established screening test is available for urothelial carcinomas of the upper urinary tract, and little is known of the clinical impact of screening for HNPCC in patients with upper urinary tract cancer. We describe herein a patient with a urothelial carcinoma of the ureter and a strongly positive history of cancer, who was subsequently found to have HNPCC. Our findings reinforce the importance of obtaining a comprehensive history of cancer in patients with urothelial carcinoma of the renal pelvis and ureter. Subsequent identification of individuals with HNPCC enables the patient and at-risk relatives to benefit from targeted surveillance and management programs.

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