Microsatellite instability but not thymidylate synthase is a prognostic variable in primary colon cancers from patients treated in 5-FU-based adjuvant studies

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 10019-10019
Author(s):  
F. A. Sinicrope ◽  
R. L. Rego ◽  
K. C. Halling ◽  
N. R. Foster ◽  
D. J. Sargent ◽  
...  
Keyword(s):  
Overall Survival ◽  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Thymidylate Synthase ◽  
Dna Mismatch Repair ◽  
Histologic Grade ◽  
Dna Mismatch ◽  
Colon Cancers ◽  
Lower Stage ◽  
Primary Colon

10019 Background: Colon cancers with microsatellite instability (MSI) display resistance to 5-fluorouracil (5-FU), and in vitro resistance can be reversed by restoring DNA mismatch repair proficiency. 5-FU inhibits the thymidylate synthase (TS) enzyme and TS may predict clinical outcome after 5-FU-based chemotherapy. To define molecular predictors of prognosis, we analyzed TS, p53, chromosome 17p allelic imbalance (AI), and patient survival stratified by MSI status. Methods: Primary colon carcinomas from patients enrolled in five 5-FU-based adjuvant therapy trials were analyzed for MSI and 17p AI using 11 microsatellite markers (MSI-H: ≥ 30% of the loci demonstrating instability). For 17p AI, markers included D17S261 and TP53 at or near the p53 locus. Expression of DNA mismatch repair (hMLH1, PharMingen; hMSH2; Oncogene), TS (TS106, Zymed), and p53 (D07, Novacastra) proteins were analyzed by immunohistochemistry. Correlations between markers and associations with overall survival (OS) were determined. Patients were censored at 5 years for DFS and at 8 years post study randomization for overall survival (OS) data. Results: Of 320 Dukes’ stage B2 and C cancers studied, 60 of 320 (19%) were MSI-H. TS expression variables (intensity, extent, weighted score) were similar in MSI-H and MSI stable/low frequency (MSS/MSI-L) cancers; similar results were found using DNA mismatch repair (dMMR) proteins. MSI-H tumors had lower stage (p= 0.0007), fewer metastatic lymph nodes (p= 0.004), and improved OS (vs. MSS/MSI-L tumors; p= 0.01). Loss of dMMR proteins was also associated with better OS (p= 0.006). None of the TS variables were prognostic for OS. Histologic grade (p= 0.0008) and nodal status (p= 0.0002) were associated with OS in contrast to 17p LOH or p53. Only MSI status or dMMR, histologic grade, and tumor stage were independent markers for OS. Conclusions: MSI-H tumors show earlier stage at presentation and better stage-adjusted survival rates. MSI status and TS expression were unrelated and TS was not prognostic, suggesting that TS levels cannot explain therapeutic resistance to 5-FU reported in MSI-H colon cancers. [Table: see text]

Model-based prediction of defective DNA mismatch repair using clinicopathological variables in stage II and III colon cancers

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 11093-11093
Author(s):  
A. J. French ◽  
F. Sinicrope ◽  
N. R. Foster ◽  
S. N. Thibodeau ◽  
D. J. Sargent ◽  
...  
Keyword(s):  
Logistic Regression ◽  
Mismatch Repair ◽  
Dna Mismatch Repair ◽  
Histologic Grade ◽  
Important Predictor ◽  
Stage Ii ◽  
Tumor Site ◽  
Dna Mismatch ◽  
Colon Cancers ◽  
And Gender

11093 Background: Defective DNA mismatch repair (MMR) results in microsatellite instability (MSI) and is detected in approximately 15% of sporadic colon cancers. MMR status has been shown to provide prognostic and predictive information in primary colon cancers. We sought to develop a model to predict MMR deficiency using clinically available data, and thereby facilitate patient selection for MMR or MSI testing. Methods: TNM stage II and III colon carcinomas (n= 982) were studied from six 5- fluorouracil-based adjuvant therapy trials conducted by the North Central Cancer Treatment Group. MMR status in tumors had been analyzed by MSI (using mono- and dinucleotide markers) or by immunohistochemistry for MMR proteins (hMLH1 and hMSH2). Logistic regression and a recursive partitioning and amalgamation (RPA) analysis was used to identify important predictive factors of MMR status. Factors explored included age, gender, histologic grade, tumor site, stage, lymph node metastases, and T-stage. Results: Defective MMR was found in147 (15%) cancers. Tumor site was the most important predictor of MMR status followed by histologic grade. Distal tumors had a low likelihood of defective MMR (3% rate overall; 13/468), whereas proximal tumors had a greater likelihood of defective MMR (26%; 130/506). For patients with proximal tumors, the addition of histologic grade and gender increased the prediction of defective MMR ( Table ). Using tumor site, histologic grade, and gender, the logistic regression model showed excellent discrimination (c- statistic = 0.81). Conclusions: Tumor site is an important predictor of defective MMR that is rare in distal and increased in proximal tumors. The combination of proximal site, poor differentiation, and female gender resulted in a 51% likelihood of defective MMR. Therefore, this model can facilitate the selection of sporadic colon cancers for MMR or MSI testing to enable its use in clinical decision-making. [Table: see text] No significant financial relationships to disclose.

Detecting deficient DNA mismatch repair in stage II and III colon cancers.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 419-419
Author(s):  
F. Sinicrope ◽  
P. Benatti ◽  
N. R. Foster ◽  
S. Marsoni ◽  
G. Monges ◽  
...  
Keyword(s):  
Logistic Regression ◽  
Mismatch Repair ◽  
Dna Mismatch Repair ◽  
Histologic Grade ◽  
Stage Ii ◽  
Lymph Node Status ◽  
Tumor Site ◽  
Dna Mismatch ◽  
Colon Cancers ◽  
Mmr Deficiency

419 Background: Deficient DNA mismatch repair (MMR) results in microsatellite instability (MSI) that is detected in ∼15% of sporadic colon cancers. MMR status has been shown to provide prognostic and predictive information. We developed a model to predict MMR deficiency using clinically available data, and thereby facilitate the selection of patient tumors for MMR testing. Methods: Data were utilized from stage II and III colon carcinoma patients (n = 2016) who participated in 5-fluorouracil-based adjuvant studies (NCCTG, FFCD, NCIC, GIVIO, NSABP) and an Italian cohort. MMR status in tumors had been determined by MSI testing or by immunohistochemistry for hMLH1 and hMSH2 proteins. Logistic regression and a recursive partitioning and amalgamation analysis was used to identify factors (histologic grade, gender, tumor site, stage, age, lymph node status, T-stage) predictive of MMR status. Results: Of the cancers, 357 (17.7%) showed deficient MMR. Tumor site was the most important predictor of MMR status followed by histologic grade, then stage (II vs. III) and then gender. Distal tumors had a low likelihood of deficient MMR (5% rate overall), whereas proximal tumors had a greater likelihood of deficient MMR (30%). For patients with proximal tumors, the addition of histologic grade and stage increased the prediction of deficient MMR (Table). Using tumor site, histologic grade, and stage, the logistic regression model showed excellent discrimination (c-statistic = 0.80). Conclusions: Routine clinicopathological data can facilitate the identification of MMR deficient cases. Tumor site and histologic grade were the strongest predictors of MMR deficiency. Within proximal, poorly differentiated tumors, stage was highly predictive. These findings suggest that our model can assist in selecting sporadic colon cancers for MMR testing for use in clinical decision-making, especially for stage II patients. [Table: see text] [Table: see text]

scholarly journals Intertumoral Heterogeneity of CD3+ and CD8+ T-Cell Densities in the Microenvironment of DNA Mismatch-Repair–Deficient Colon Cancers: Implications for Prognosis

2018 ◽  
Vol 25 (1) ◽  
pp. 125-133 ◽  
Author(s):  
Harry H. Yoon ◽  
Qian Shi ◽  
Erica N. Heying ◽  
Andrea Muranyi ◽  
Joerg Bredno ◽  
...  
Keyword(s):  
T Cell ◽  
Mismatch Repair ◽  
Dna Mismatch Repair ◽  
Cd8 T Cell ◽  
Dna Mismatch ◽  
Colon Cancers ◽  
Cell Densities

Microsatellite instability in the development of DNA mismatch repair deficient tumors

2006 ◽  
Vol 2 (1-2) ◽  
pp. 69-86 ◽  
Author(s):  
Stefan M. Woerner ◽  
Matthias Kloor ◽  
Magnus von Knebel Doeberitz ◽  
Johannes F. Gebert
Keyword(s):  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Dna Mismatch Repair ◽  
Dna Mismatch

scholarly journals Immunohistochemistry Versus Microsatellite Instability Testing in Phenotyping Colorectal Tumors

2002 ◽  
Vol 20 (4) ◽  
pp. 1043-1048 ◽  
Author(s):  
Noralane M. Lindor ◽  
Lawrence J. Burgart ◽  
Olga Leontovich ◽  
Richard M. Goldberg ◽  
Julie M. Cunningham ◽  
...  
Keyword(s):  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Predictive Value ◽  
Dna Mismatch Repair ◽  
Cost Effective ◽  
Colorectal Tumors ◽  
Dna Mismatch ◽  
Testing Strategies ◽  
Repair Deficiency ◽  
Dna Mismatch Repair Deficiency

PURPOSE: To compare microsatellite instability (MSI) testing with immunohistochemical (IHC) detection of hMLH1 and hMSH2 in colorectal cancer. PATIENTS AND METHODS: Colorectal cancers from 1,144 patients were assessed for DNA mismatch repair deficiency by two methods: MSI testing and IHC detection of hMLH1 and hMSH2 gene products. High-frequency MSI (MSI-H) was defined as more than 30% instability of at least five markers; low-level MSI (MSI-L) was defined as 1% to 29% of loci unstable. RESULTS: Of 1,144 tumors tested, 818 showed intact expression of hMLH1 and hMSH2. Of these, 680 were microsatellite stable (MSS), 27 were MSI-H, and 111 were MSI-L. In all, 228 tumors showed absence of hMLH1 expression and 98 showed absence of hMSH2 expression: all were MSI-H. CONCLUSION: IHC in colorectal tumors for protein products hMLH1 and hMSH2 provides a rapid, cost-effective, sensitive (92.3%), and extremely specific (100%) method for screening for DNA mismatch repair defects. The predictive value of normal IHC for an MSS/MSI-L phenotype was 96.7%, and the predictive value of abnormal IHC was 100% for an MSI-H phenotype. Testing strategies must take into account acceptability of missing some cases of MSI-H tumors if only IHC is performed.

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