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Updated: May 10, 2026
Deficient Pms2, ERCC1, Ku86, CcOI in Field Defects During Progression to Colon Cancer
Published on: July 28, 2010
MMR deficiency is frequent in colorectal carcinomas with diffuse SLFN11 immunostaining: clinicopathologic and
Maciej Kaczorowski1,2, Małgorzata Chłopek1, Ondřej Daum3,4
1Laboratory of Pathology, National Cancer Institute, Bethesda, MD, USA.
Abstract:
Schlafen 11 (SLFN11), a regulator of cell fate following DNA injury, sensitizes tumor cells to DNA-damaging agents. Patients with SLFN11-positive tumors may benefit from DNA-damaging chemotherapies. SLFN11 has been studied in different types of cancer including colorectal carcinomas. However, colorectal carcinomas with diffuse positivity (expression in ≥80% of tumor cells) have not been meticulously characterized. SLFN11 immunostaining of tumor microarrays (TMAs) with 3,300 primary CRCs identified 65 (~2.0%) tumors with focal staining (<10% of tumor nuclei positive), 83 (~2.5%) with patchy (≥10% and <80%) and 51 (~1.5%) with diffuse (≥80%) SLFN11 positivity. The latter was confirmed on full sections from donor blocks in 31 (~1%) cases, which were further studied including evaluation of additional immunohistochemical markers, genotyping with targeted DNA sequencing, and assessment of microsatellite instability. SLFN11-positive carcinomas were mostly (21/31, 68%) right-sided tumors with a female predominance (21/31, 68%) and median age of 67 years. Eighteen of 31 (58%) contained areas of mucinous differentiation. Deficiency of mismatch repair proteins was detected in 65% (20/31) of SLFN11-positive carcinomas. Moreover, MLH1 (n = 2), MSH2, MSH6, and PMS2 germline mutations were identified in 25% (5/20) of patients with mismatch repair deficient tumors. BRAF p.V600E mutation was found in 45% (9/20) of mismatch repair deficient, but only 1 of 11 proficient tumors. Colorectal carcinomas with diffuse SLFN11 positivity were often mismatch repair deficient tumors with their typical clinical, morphological, and molecular characteristics.
Insights
Schlafen 11 (SLFN11) expression in colorectal cancer predicts response to DNA-damaging chemotherapy. Diffusely SLFN11-positive tumors often exhibit mismatch repair deficiency and specific molecular features, suggesting targeted therapeutic strategies.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Schlafen 11 (SLFN11) is a key regulator of cell fate after DNA damage, sensitizing tumor cells to DNA-damaging agents.
- SLFN11 expression levels can predict patient response to certain chemotherapies, particularly in tumors with high SLFN11 positivity.
- While SLFN11's role in various cancers is recognized, diffuse SLFN11 positivity in colorectal carcinomas (CRCs) remains undercharacterized.
Purpose of the Study:
- To meticulously characterize colorectal carcinomas exhibiting diffuse SLFN11 positivity (≥80% of tumor cells).
- To investigate the clinical, morphological, and molecular features associated with diffuse SLFN11 expression in CRCs.
- To explore the potential link between diffuse SLFN11 positivity and mismatch repair deficiency (dMMR) in colorectal cancer.
Main Methods:
- Immunohistochemical staining for SLFN11 on a large cohort of primary colorectal cancer tumor microarrays (TMAs) from 3,300 patients.
- Confirmation of diffuse SLFN11 positivity on full tissue sections for selected cases.
- Evaluation of additional immunohistochemical markers, targeted DNA sequencing for genotyping, and microsatellite instability assessment in diffuse SLFN11-positive CRCs.
Main Results:
- Approximately 1.5% of CRCs showed diffuse SLFN11 positivity (51/3,300), confirmed in 31 cases (1%).
- These tumors were predominantly right-sided (68%), with a female predominance (68%), and a median age of 67 years.
- A significant proportion (65%) of diffuse SLFN11-positive CRCs were mismatch repair deficient (dMMR), often associated with BRAF V600E mutations (45% of dMMR cases).
Conclusions:
- Colorectal carcinomas with diffuse SLFN11 positivity frequently display characteristics of mismatch repair deficient tumors.
- The findings highlight a distinct subgroup of CRCs with specific clinical, morphological, and molecular profiles.
- Diffuse SLFN11 expression may serve as a predictive biomarker for response to DNA-damaging agents in a subset of MMR-deficient colorectal cancers.
