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Expression of DNA Double-Strand Break Repair Proteins ATM and BRCA1 Predicts Survival in Colorectal Cancer

Authors' Affiliations: ¹ Academic Unit of Pathology, University of Leeds; ² Department of Histopathology, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom; ³ Department of Surgery, Marien-Hospital, and ⁴ Institute of Pathology, Heinrich-Heine-University, Duesseldorf, Germany; and ⁵ Gemeinschaftspraxis Pathologie, Starnberg, Germany

Requests for reprints: Wolfram Mueller, Gemeinschaftspraxis Pathologie Starnberg, Am Fuchsengraben 3, 82319 Starnberg, Germany. Phone: 49-8151-36-12-24; Fax: 49-8151-7-84-20; E-mail: w.mueller{at}pathologie-starnberg.de.

Purpose: The double-strand break (DSB) is the major DNA lesion leading to chromosomal aberrations and faithful repair is crucial for maintaining genomic instability. Very little is known about the expression of DNA DSB repair proteins in colorectal cancer. To address this issue, we examined the expression pattern of DSB repair key proteins ATM, BRCA1, BRCA2, Ku70, and Ku80 and their putative role in patients survival in a large series of colorectal cancer.

Experimental Design: 342 sporadic colorectal cancer were subjected to immunohistochemistry by using specific antibodies for the various proteins investigated. Staining results were compared with clinicopathologic data, patient survival, as well as expression of mismatch repair proteins MLH1 and MSH2.

Results: The expression pattern of both ATM and BRCA1 predicted survival in all colorectal cancer patients as well as in the small subgroup of patients that received adjuvant therapy. Low expression of ATM and BRCA1 was associated with loss of MLH1 or MSH2 expression.

Conclusions: This is the first study to show a relationship between the expression of DNA DSB repair proteins ATM and BRCA1 and survival in colorectal cancer patients. Studies in tumors from large randomized trials are now necessary to validate our pilot data and establish the clinical usefulness of the immunohistochemical assay in predicting response to a particular adjuvant therapy regimen. Furthermore, our results indicate a possible link between expression of DNA mismatch repair and DNA DSB repair proteins in sporadic colorectal cancer, which warrants further investigation.

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