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]

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.

scholarly journals Association of Obesity With DNA Mismatch Repair Status and Clinical Outcome in Patients With Stage II or III Colon Carcinoma Participating in NCCTG and NSABP Adjuvant Chemotherapy Trials

2012 ◽  
Vol 30 (4) ◽  
pp. 406-412 ◽  
Author(s):  
Frank A. Sinicrope ◽  
Nathan R. Foster ◽  
Harry H. Yoon ◽  
Thomas C. Smyrk ◽  
George P. Kim ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Adjuvant Chemotherapy ◽  
Mismatch Repair ◽  
Dna Mismatch Repair ◽  
Disease Free Survival ◽  
Stage Ii ◽  
Prognostic Impact ◽  
Obese Patients ◽  
Tumor Site ◽  
Dna Mismatch

Purpose Although the importance of obesity in colon cancer risk and outcome is recognized, the association of body mass index (BMI) with DNA mismatch repair (MMR) status is unknown. Patients and Methods BMI (kg/m2) was determined in patients with TNM stage II or III colon carcinomas (n = 2,693) who participated in randomized trials of adjuvant chemotherapy. The association of BMI with MMR status and survival was analyzed by logistic regression and Cox models, respectively. Results Overall, 427 (16%) tumors showed deficient MMR (dMMR), and 630 patients (23%) were obese (BMI ≥ 30 kg/m2). Obesity was significantly associated with younger age (P = .021), distal tumor site (P = .012), and a lower rate of dMMR tumors (10% v 17%; P < .001) compared with normal weight. Obesity remained associated with lower rates of dMMR (odds ratio, 0.57; 95% CI, 0.41 to 0.79; P < .001) after adjusting for tumor site, stage, sex, and age. Among obese patients, rates of dMMR were lower in men compared with women (8% v 13%; P = .041). Obesity was associated with higher recurrence rates (P = .0034) and independently predicted worse disease-free survival (DFS; hazard ratio [HR], 1.37; 95% CI, 1.14 to 1.64; P = .0010) and overall survival (OS), whereas dMMR predicted better DFS (HR, 0.59; 95% CI, 0.47 to 0.74; P < .001) and OS. The favorable prognosis of dMMR was maintained in obese patients. Conclusion Colon cancers from obese patients are less likely to show dMMR, suggesting obesity-related differences in the pathogenesis of colon cancer. Although obesity was independently associated with adverse outcome, the favorable prognostic impact of dMMR was maintained among obese patients.

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]

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

Trifluridine to enhance cytotoxicity by DNA mismatch repair deficiency and subsequent MBD4 frameshift mutation in colorectal cancer.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 608-608 ◽  
Author(s):  
Satoshi Suzuki ◽  
Moriya Iwaizumi ◽  
Yasushi Hamaya ◽  
Kosuke Takagaki ◽  
Satoshi Osawa ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Mismatch Repair ◽  
Frameshift Mutation ◽  
Dna Mismatch Repair ◽  
Clonogenic Assay ◽  
Dna Mismatch ◽  
Cell Clones ◽  
Human Colorectal Cancer Cell ◽  
Mmr Deficiency ◽  
Colorectal Cancer Patients

608 Background: TAS-102 is composed of trifluridine (FTD) and tipiracil hydrochloride and was shown to prolong survival of patients with refractory metastatic colorectal cancer (CRC). FTD is the active antitumor component of TAS102 and its metabolite TF-TTP chemically resembles 5FU-derived metabolite FdUTP in that both of them are misincorporated into DNA and lead to cytotoxicity. Several groups have reported that stage II-III colorectal cancer patients with tumors that lost DNA mismatch repair (MMR) function do not derive a benefit from 5-FU based chemotherapy. Although FTD is reported to be misincorporated into DNA, it is not known if MMR deficient CRC cells have chemoresistance for FTD. Methods: We first utilized human colorectal cancer cell lines HCT-116 (hMLH1-deficient cells) and HCT116+ch3 (hMLH1-retained cells), and compared cytotoxicity for FTD by clonogenic assay. To further analyze if 5FU refractory CRC cells have chemosensitivity for FTD, we established 5FU refractory HCT116 cells by continuous 5FU treatment for 10 month and analyzed cytotoxicity for FTD. Finally we constructed an expression plasmid of truncated DNA grycosylase MBD4, (MBD4tru) by frameshift mutation with MMR deficiency and stably transfected the construct into HCT116 CRC cells and selected HCT116MBD4tru cell clones. The HCT116MBD4tru cells were treated with FTD and analyzed for cytotoxicity by clonogenic assay. Results: In hMLH1-deficient cells, the number of colony was reduced by FTD treatment to a same degree of hMLH1-proficient cells whereas the number of colony by 5FU treatment is higher in hMLH1-deficitent cells than hMLH1-retained cells (p< 0.05). In 5FU refractory cells, treatment of FTD showed cytotoxicity to the same degree of non-5FU refractory cells. Interestingly, HCT116MBD4tru cells led to cytotoxicity with a higher sensitivity than control cells (p< 0.05). Conclusions: FTD induces cytotoxisity independently of MMR status as well as under 5FU refractory condition, and MBD4 frameshift mutation by MMR deficiency enhances FTD sensitivity. These results suggest that FTD may be useful for patients with MSI-H/MBD4 mutant CRC as well as for those with 5FU refractory CRC.

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