MSI Status (msi + status)

Distribution by Scientific Domains

Selected Abstracts

Mutations in the ataxia telangiectasia and rad3-related,checkpoint kinase 1 DNA damage response axis in colon cancers

Kriste A. Lewis
In response to certain types of DNA damage, ataxia telangiectasia and rad3-related (ATR) phosphorylates checkpoint kinase 1 (CHEK1) resulting in cell cycle arrest and subsequent DNA repair. ATR and CHEK1 contain mononucleotide microsatellite repeat regions, which are mutational targets in tumors with defective mismatch repair (MMR). This study examined the frequency of such mutations in colon cancers and their impact on biologic behavior. Screening for ATR mutations in 48 tumors was performed using denaturing high-performance liquid chromatography (DHPLC) and confirmed with sequencing analysis. The CHEK1 exon 7 A(9) region was sequenced in 20 of the 27 (74%) tumors with high frequency of microsatellite instability (MSI-H). Univariate and multivariate analyses were used to examine associations with clinical outcomes. Frequent mutations in MSI-H colon cancers were identified within the ATR (37%)/CHEK1(5%) damage response pathway. Stage and MSI status both independently predicted overall survival (OS) and disease-free survival (DFS). ATR status was not associated with stage, but was associated with a trend toward improved DFS: 0/9 cancers recurred in MSI-H cases harboring ATR mutations vs. 4/18 recurrences in MSI-H cases without ATR mutations. This suggests that ATR mutations may affect clinical behavior and response to therapy in MSI-H colon cancers. 2007 Wiley-Liss, Inc. [source]

Combined analysis of specific KRAS mutation, BRAF and microsatellite instability identifies prognostic subgroups of sporadic and hereditary colorectal cancer

Inti Zlobec
Abstract Confounding effects of specific KRAS gene alterations on colorectal cancer (CRC) prognosis stratified by microsatellite instability (MSI) and BRAFV600E have not yet been investigated. The aim of our study was to evaluate the combined effects of MSI, BRAFV600E and specific KRAS mutation (Gly , Asp; G12D, Gly , Asp, G13D; Gly , Val; G12V) on prognosis in 404 sporadic and 94 hereditary CRC patients. MSI status was determined according to the Bethesda guidelines. Mutational status of KRAS and BRAFV600E was assessed by direct DNA sequencing. In sporadic CRC, KRAS G12D mutations had a negative prognostic effect compared to G13D and wild-type cancers (p = 0.038). With MSI, specific KRAS and BRAFV600E mutations, 3 distinct prognostic subgroups were observed in univariate (p = 0.006) and multivariable (p = 0.051) analysis: patients with (i) KRAS mutation G12D, G12V or BRAFV600E mutation, (ii) KRAS/BRAFV600E wild-type or KRAS G13D mutations in MSS/MSI-L and (iii) MSI-H and KRAS G13D mutations. Moreover, none of the sporadic MSI-H or hereditary patients with KRAS G13 mutations had a fatal outcome. Specific KRAS mutation is an informative prognostic factor in both sporadic and hereditary CRC and applied in an algorithm with BRAFV600E and MSI may identify sporadic CRC patients with poor clinical outcome. [source]

Distinct CpG island methylation profiles and BRAF mutation status in serrated and adenomatous colorectal polyps

Yong Ho Kim
Abstract A subset of colorectal cancers with CpG island methylator phenotype-high (CIMP-H) is frequently associated with MSI and BRAF V600E mutation. Since limited data are available on different histological types of colorectal polyps, we compared the pattern and the frequency of promoter methylation, CIMP-H, MSI, KRAS and BRAF V600E mutations and the relationship among these molecular parameters and the clinicopathologic characteristics in 110 serrated polyps (48 hyperplastic polyps, 32 sessile serrated adenomas and 30 serrated adenomas) and 32 tubular adenomas using 7 commonly used tumor-associated gene loci. No significant difference in the frequency of overall methylation frequency (86% vs. 100%) and CIMP-H (39% vs. 28%) between serrated polyps and tubular adenomas was observed, but proximally located serrated polyps showed more frequent methylation at 5 of 7 loci examined, and were more likely to be CIMP-H (62% vs. 22%). MGMT methylation was more common in tubular adenomas while MLH1 and HIC1 were more frequently methylated in serrated polyps. BRAF mutation was frequently present in all types of serrated polyps (80%), but was absent in tubular adenomas and was not associated with CIMP or MSI status. These results show comparable frequencies of promoter methylation of tumor-associated genes and CIMP-H, but distinct differences in gene-specific or colonic site-specific methylation profiles occur in serrated polyps and tubular adenomas. BRAF mutation occurs independently of CIMP and MSI in all types of serrated polyps and may serve as a marker of serrated pathway of colorectal carcinogenesis. 2008 Wiley-Liss, Inc. [source]

Evidence for an age-related influence of microsatellite instability on colorectal cancer survival

Susan M. Farrington
Abstract It is well established that microsatellite instability (MSI), the hallmark of defective DNA mismatch repair (MMR), is associated with prolonged survival in colorectal cancer compared with tumours that are microsatellite stable (MSS). MSI in sporadic colorectal tumours is primarily due to epigenetic silencing of MLH1. However, there are no prospective population-based studies of survival in patients with germline MMR gene mutations who develop cancer. Although MSI is almost universal in tumours from HNPCC family members, there is a potential confounding effect of ascertainment and other biases that could explain the apparent survival benefit in HNPCC families. Resolving whether germline MMR gene mutations impact on survival is important because it potentially undermines the rationale for surveillance of mutation carriers. Here, we report an investigation of the influence of MSI on survival in cohorts of cancer patients (aged < 30 years at diagnosis, n = 118; non-age-selected, n = 181) in the context of clinicopathologic variables. There was a substantial age-related influence of tumour MSI status on survival. In young patients with tumour MSI, 65% of patients with MSI tumours had germline MSH2 or MLH1 mutations. Clinicopathologic variables and tumour MSI of the cohort were studied with respect to survival and compared with control groups. Young patients had excess MSI tumours (p < 0.000001), mucinous tumours (p < 0.01), advanced disease (p , 0.001) and poorer 5-year survival compared with older cases. Cox proportional hazard analysis identified Dukes' stage, age at diagnosis and calendar year of treatment as independent predictors of survival. There was no detectable association between tumour MSI and survival in young patients, although we confirmed previous observations that MSI is associated with better prognosis in later onset cohorts. These findings underscore the rationale for surveillance and early identification of tumours in MMR gene carriers as well as refining understanding of the influence of MSI on cancer progression. 2002 Wiley-Liss, Inc. [source]

Fas ligand and tumour counter-attack in colorectal cancer stratified according to microsatellite instability status

Julie M Michael-Robinson
Abstract Expression of membrane-bound Fas ligand (FasL) by colorectal cancer cells may allow the development of an immune-privileged site by eliminating incoming tumour-infiltrating lymphocytes (TILs) in a Fas-mediated counter-attack. Sporadic colorectal cancer can be subdivided into three groups based on the level of DNA microsatellite instability (MSI). High-level MSI (MSI-High) is characterized by the presence of TILs and a favourable prognosis, while microsatellite-stable (MSS) cancers are TIL-deficient and low-level MSI (MSI-Low) is associated with an intermediate TIL density. The purpose of this study was to establish the relationship between MSI status and FasL expression in primary colorectal adenocarcinoma. Using immunohistochemistry and a selected series of 101 cancers previously classified as 31 MSI-High, 30 MSI-Low, and 40 MSS, the present study sought to confirm the hypothesis that increased TIL density in MSI-High cancers is associated with low or absent membrane-bound FasL expression, while increased FasL in MSS cancers allows the killing of host TILs. TUNEL/CD3 double staining was also used to determine whether MSS cancers contain higher numbers of apoptotic TILs in vivo than MSI-High or MSI-Low cancers. Contrary to the initial hypothesis, it was found that MSI-High cancers were associated with higher FasL expression (p = 0.04) and a stronger intensity of FasL staining (p = 0.007). In addition, mucinous carcinomas were independently characterized by increased FasL expression (p = 0.03) and staining intensity (p = 0.0005). Higher FasL expression and staining intensity did not correlate with reduced TIL density or increased numbers of apoptotic TILs. However, consistent with the hypothesis that curtailment of the host anti-tumour immune response contributes to the poor prognosis in MSS cancers, it was found that apoptotic TILs were most abundant in MSS carcinomas and metastatic Dukes' stage C or D tumours (p = 0.004; p = 0.046 respectively). This study therefore suggests that MSS colorectal cancers are killing incoming TILs in an effective tumour counter-attack, but apparently not via membrane-bound FasL. Copyright 2003 John Wiley & Sons, Ltd. [source]

Microsatellite instability and DNA ploidy in colorectal cancer

CANCER, Issue 2 2009
Potential implications for patients undergoing systematic surveillance after resection
Abstract BACKGROUND: Appropriate stratification tools for targeted surveillance after resection for colorectal cancer (CRC) are lacking. The objective of the current study was to investigate the effect of microsatellite instability (MSI) and DNA ploidy on surveillance after surgery. METHODS: The authors evaluated 186 consecutive, population-based patients with stage I through III CRC who underwent surgery with curative intent and who entered a systematic surveillance program. MSI was analyzed with polymerase chain reaction for 5 known quasimonomorphic markers (BAT-26, BAT-25, NR-21, NR-24, and NR-27), and DNA ploidy was analyzed with automated cytometry. Recurrence, recurrence-free survival (RFS), and disease-specific survival (DSS) were evaluated by univariate and multivariate statistical tests. RESULTS: Patients with MSI (20%) were significantly younger than patients without MSI (median age, 61 years vs 67 years; P = .016). Proximal location (adjusted odds ratio [AOR], 5.4; 95% confidence interval [95% CI], 2.1-14.1 [P = .001]), large tumor size (,5 cm: AOR, 3.5; 95% CI, 1.3,9.6 [P = .015]), and poor tumor differentiation (AOR, 6.6; 95% CI, 2,21.8 [P = .002]) were associated with MSI. MSI conveyed an increased risk for locoregional recurrence (OR, 2.9; 95% CI, 1.2,7 [P = .016]), with a trend toward a shorter time to recurrence (P = .060). Neither MSI status nor DNA ploidy predicted distant metastasis, RFS, or DSS. Lymph node status was the best predictor of distant spread (AOR, 3.9; 95% CI, 2,7.9 [P < .001]) and DSS (hazard ratio, 4.9; 95% CI, 2.6,9 [P < .001]). CONCLUSIONS: Patients who had microsatellite instable tumors were at increased risk for locoregional recurrence, whereas lymph node status was the best predictor of distant metastasis. Clinical surveillance and choice of modality (ie, endoscopy vs radiologic imaging) may be improved when patients are stratified according to these cancer features. Cancer 2009. 2009 American Cancer Society. [source]

The role of SMAD4 in early-onset colorectal cancer

S. G. Royce
Abstract Objective, Chromosomal loss within the region of 18q and loss of SMAD4 expression have been reported to be frequent somatic events during colorectal cancer tumour progression; however, their associations with age at onset have not been widely studied. Method, We analysed 109 tumours from a population-based case-family study based on colorectal cancers diagnosed before the age of 45 years. These patients with early-onset colorectal cancer had been previously screened for germ-line mismatch repair gene mutations, microsatellite instability (that included the mononucleotide repeat in TGF,RII) and somatic k-ras mutations. We measured SMAD4 protein expression using immunohistochemistry and SMAD4 copy number using quantitative real-time PCR. Results, Loss of SMAD4 protein expression was observed in 27/109 (25%) of cancers tested and was more commonly observed in rectal tumours (15/41, 36%) when compared with tumours arising in the colon (11/66, 17%) (P = 0.04). There was no association between SMAD4 protein expression and TGF,R11 mutation status, SMAD4 copy number, family history, MSI status, tumour stage or grade. Conclusion, Loss of SMAD4 expression is a common feature of early-onset colorectal tumours as it is in colorectal cancers diagnosed in other age-groups. Taken together, the molecular pathways (genetic and epigenetic) now known to be involved in early-onset colorectal cancer only explain a small proportion of the disease and require further exploration. [source]