Model-based prediction of defective DNA mismatch repair using clinicopathological variables in sporadic colon cancer patients

Frank Sinicrope, Nathan R. Foster, Daniel J. Sargent, Stephen N. Thibodeau, Thomas C. Smyrk, Michael J. O'Connell

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

BACKGROUND: 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. METHODS: 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. RESULTS: 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%. CONCLUSIONS: 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.

Original languageEnglish (US)
Pages (from-to)1691-1698
Number of pages8
JournalCancer
Volume116
Issue number7
DOIs
StatePublished - Apr 1 2010

Keywords

  • Colon cancer
  • DNA mismatch repair
  • Microsatellite instability
  • Sporadic
  • Tumor-infiltrating lymphocytes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Model-based prediction of defective DNA mismatch repair using clinicopathological variables in sporadic colon cancer patients'. Together they form a unique fingerprint.

Cite this