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

Abstract

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. Genetic instability has been proposed to be a driving force in colorectal carcinogenesis (1). Two major types of genetic instability have been described in colorectal cancer: chromosomal instability and microsatellite instability (2). Up to 15% of colorectal cancer show a high frequency of microsatellite instability which is caused by a defect of the DNA mismatch repair pathway (3). The vast majority of colorectal cancer, however, shows chromosomal instability, which is characterized by gains and losses of whole chromosomes or large chromosomal regions.Whereas a large number of genes that trigger chromosomal instability have been identified in yeast in the past (reviewed in ref. 4), the underlying mechanisms leading to chromosomal instability in colorectal cancer remain to be characterized. The DNA double-strand break (DSB) is regarded as the most critical of all DNA lesions (5, 6) and it has been shown that defects in the cellular response to DSBs can lead to genetic alteration, chromosomal instability, and ultimately malignant transformation (7).In mammalian cells, DSBs can be repaired by two distinct pathways: homologous recombination and nonhomologous end joining (8). DSB repair by nonhomologous end joining involves the formation of a Ku70/Ku80 protein heterodimer and recruitment of DNA-dependent protein kinase C to the site of DNA damage (9). DSB repair by homologous recombination is mediated by a large number of...

Tumor protein D52 represents a negative regulator of ATM protein levels

“…ATM is frequently altered in hematological cancers, where T-cell prolymphocytic leukemia, B-cell chronic lymphocytic leukemia, and mantle cell lymphoma are all characterized by high rates of inactivating mutations, and/or deletion of ATM. 38 Reduced ATM protein levels have also been reported in breast cancer, 39 glioblastoma, 40 gastric cancer, 41 and colorectal cancer, 42 yet the cellular mechanisms that lead to deregulation of ATM expression are poorly understood. In sporadic breast cancer, although loss of heterozygosity (LOH) in the region of ATM on chromosome 11q22.3 has been reported in up to 40% cases, somatic mutations of ATM are infrequent.…”

Prognostic significance of ataxia‐telangiectasia mutated, DNA‐dependent protein kinase catalytic subunit, and Ku heterodimeric regulatory complex 86‐kD subunit expression in patients with nonsmall cell lung cancer

“…Studies of ATM and Ku80 expression in tumor tissues have yielded inconsistent findings across different cancer types, with some reporting higher expression, some reporting lower expression, and others reporting no changes. 12,19,20,[25][26][27] The inconsistency in ATM and Ku80 regulation in different tumor types suggests a remarkable difference on the molecular alterations related to the progression of cancer at different sites. In addition, the methodology of measuring mRNA expression and the selection of control genes also may contribute to the inconsistency of results.…”

“…[8][9][10][11] In addition, altered ATM expression levels have been identified in colon and pancreatic tumor tissues. 12,13 Accordingly, the prognostic value of ATM expression in colorectal and breast cancer has been investigated. 12,14 However, to our knowledge, its significance in lung cancer has not been studied.…”

“…12,13 Accordingly, the prognostic value of ATM expression in colorectal and breast cancer has been investigated. 12,14 However, to our knowledge, its significance in lung cancer has not been studied.…”

Atm is a negative regulator of intestinal neoplasia

“…Various human solid tumors show a sharp increase in an activated form of Atm protein at early stages, signals that are then diminished or lost in later-stage carcinomas. Other recent evidence in human tumors correlates a decrease in colon tumor-specific Atm protein levels (Grabsch et al, 2006) and an increase in Atm promoter hypermethylation (Bai et al, 2004) with progression to carcinoma and decreased survival. Allelic imbalance at the 11q22-23 interval containing Atm is also associated with polyploidy in colorectal carcinomas (Sugai et al, 2001).…”