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Model-based prediction of defective DNA mismatch repair using clinicopathological variables in sporadic colon cancer patients
Article first published online: 22 FEB 2010
Copyright © 2010 American Cancer Society
Volume 116, Issue 7, pages 1691–1698, 1 April 2010
How to Cite
Sinicrope, F., Foster, N. R., Sargent, D. J., Thibodeau, S. N., Smyrk, T. C. and O'Connell, M. J. (2010), Model-based prediction of defective DNA mismatch repair using clinicopathological variables in sporadic colon cancer patients. Cancer, 116: 1691–1698. doi: 10.1002/cncr.24913
- Issue published online: 19 MAR 2010
- Article first published online: 22 FEB 2010
- Manuscript Accepted: 28 JUL 2009
- Manuscript Revised: 26 JUN 2009
- Manuscript Received: 16 APR 2009
- National Cancer Institute. Grant Number: CA104683-02
- Mayo Clinic Cancer Center. Grant Number: CA15083
- microsatellite instability;
- DNA mismatch repair;
- colon cancer;
- tumor-infiltrating lymphocytes
Colon cancers with defective DNA mismatch repair (MMR) have a favorable prognosis and may lack benefit from 5-fluorouracil–based adjuvant chemotherapy. The authors developed models to predict MMR deficiency in sporadic colon cancer patients using routine clinical and pathological data.
TNM stage II and III colon carcinomas (n = 982) from 6 5-fluorouracil–based adjuvant therapy trials were analyzed for microsatellite instability and/or MMR protein expression. Tumor-infiltrating lymphocytes (TILs) were quantified (n = 326). Logistic regression and a recursive partitioning and amalgamation analysis were used to identify predictive factors for MMR status.
Defective MMR was detected in 147 (15%) cancers. Tumor site and histologic grade were the most important predictors of MMR status. Distal tumors had a low likelihood of defective MMR (3%; 13 of 468); proximal tumors had a greater likelihood (26%; 130 of 506). By using tumor site, grade, and sex, the logistic regression model showed excellent discrimination (c statistic = 0.81). Proximal site, female sex, and poor differentiation showed a positive predictive value (PPV) of 51% for defective MMR. In a patient subset (n = 326), a model including proximal site, TILs (>2/high-power field), and female sex showed even better discrimination (c statistic = 0.86), with a PPV of 81%.
Defective MMR is rare in distal, sporadic colon cancers, which should generally not undergo MMR testing. Proximal site, poor differentiation, and female sex detect 51% of tumors with defective MMR; substituting TILs for grade increases the PPV to 81%. These data can increase the efficiency of MMR testing to assist in clinical decisions. Cancer 2010. © 2010 American Cancer Society.