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

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.

[1]  Stanley R. Hamilton,et al.  Pathology and genetics of tumours of the digestive system , 2000 .

[2]  Y. Hosoi,et al.  The expression pattern of Ku correlates with tumor radiosensitivity and disease free survival in patients with rectal carcinoma , 2002, Cancer.

[3]  D. Purdie,et al.  Mice heterozygous for mutation in Atm, the gene involved in ataxia-telangiectasia, have heightened susceptibility to cancer , 2002, Nature Genetics.

[4]  Hiroyuki Yamamoto,et al.  Gastrointestinal cancer of the microsatellite mutator phenotype pathway , 2002, Journal of Gastroenterology.

[5]  J. Satagopan,et al.  Frequency of BRCA1 and BRCA2 mutations in unselected Ashkenazi Jewish patients with colorectal cancer. , 2004, Journal of the National Cancer Institute.

[6]  I. Gaemers,et al.  Cloning of novel mammary tumor progression and metastasis genes , 2001 .

[7]  P. Johnston,et al.  The role of BRCA1 in the cellular response to chemotherapy. , 2004, Journal of the National Cancer Institute.

[8]  Y. Shiloh ATM and related protein kinases: safeguarding genome integrity , 2003, Nature Reviews Cancer.

[9]  David J. Chen,et al.  Ku70 Is Required for DNA Repair but Not for T Cell Antigen Receptor Gene Recombination In Vivo , 1997, The Journal of experimental medicine.

[10]  G. Hommel,et al.  Immunohistochemical study on the prognostic value of MIB-1 in gastric carcinoma. , 1996, British Journal of Cancer.

[11]  R. Kanaar,et al.  Homologous recombination-mediated double-strand break repair. , 2004, DNA repair.

[12]  Y. Shiloh ATM AND RELATED PROTEIN KINASES : SAFEGUARDING GENOME , 2003 .

[13]  S. Elledge,et al.  The DNA damage response: putting checkpoints in perspective , 2000, Nature.

[14]  Lichun Yang,et al.  Aberrant splicing of the ATM gene associated with shortening of the intronic mononucleotide tract in human colon tumor cell lines: A novel mutation target of microsatellite instability , 2000, International journal of cancer.

[15]  E. Kaplan,et al.  Nonparametric Estimation from Incomplete Observations , 1958 .

[16]  Kyungjae Myung,et al.  Maintenance of Genome Stability in Saccharomyces cerevisiae , 2002, Science.

[17]  J. Nickoloff,et al.  Interactive competition between homologous recombination and non-homologous end joining. , 2003, Molecular cancer research : MCR.

[18]  M. Baek,et al.  Frameshift mutations at coding mononucleotide repeats of the hRAD50 gene in gastrointestinal carcinomas with microsatellite instability. , 2001, Cancer research.

[19]  S. Jackson,et al.  Sensing and repairing DNA double-strand breaks. , 2002, Carcinogenesis.

[20]  Y. Hosoi,et al.  Up-regulation of DNA-dependent protein kinase activity and Sp1 in colorectal cancer. , 2004, International journal of oncology.

[21]  Ronit Almog,et al.  BRCA1 and BRCA2 founder mutations and the risk of colorectal cancer. , 2004, Journal of the National Cancer Institute.

[22]  B. Rosen,et al.  Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer. , 2001, American journal of human genetics.

[23]  R. Weichselbaum,et al.  Relevance and irrelevance of DNA damage response to radiotherapy. , 2004, DNA repair.

[24]  J. Hoeijmakers,et al.  Chromosomal stability and the DNA double-stranded break connection , 2001, Nature Reviews Genetics.

[25]  H. Grabsch,et al.  Expression of BUB1 protein in gastric cancer correlates with the histological subtype, but not with DNA ploidy or microsatellite instability , 2004, The Journal of pathology.

[26]  Thomas Ried,et al.  DNA repair protein Ku80 suppresses chromosomal aberrations and malignant transformation , 2000, Nature.

[27]  T. Rebbeck,et al.  Cancer risk estimates for BRCA1 mutation carriers identified in a risk evaluation program. , 2002, Journal of the National Cancer Institute.

[28]  T. Sugai,et al.  Frequent allelic imbalance at the ATM locus in DNA multiploid colorectal carcinomas , 2001, Oncogene.

[29]  H. Gabra,et al.  Identification of a region of frequent loss of heterozygosity at 11q24 in colorectal cancer. , 1999, Cancer research.

[30]  J. García,et al.  The GADD45, ZBRK1 and BRCA1 pathway: quantitative analysis of mRNA expression in colon carcinomas , 2005, The Journal of pathology.

[31]  M. Lipkin,et al.  Decreased expression of DNA-dependent protein kinase, a DNA repair protein, during human colon carcinogenesis. , 2001, Cancer research.

[32]  S. Lees-Miller,et al.  Repair of DNA double strand breaks by non-homologous end joining. , 2003, Biochimie.

[33]  T. Ørntoft,et al.  DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis , 2005, Nature.

[34]  Hai-Ri Li,et al.  Hypersensitivity of Tumor Cell Lines with Microsatellite Instability to DNA Double Strand Break Producing Chemotherapeutic Agent Bleomycin , 2004, Cancer Research.

[35]  Y. Bignon,et al.  Loss of heterozygosity at the ATM locus in colorectal carcinoma. , 1999, Oncology reports.

[36]  D.,et al.  Regression Models and Life-Tables , 2022 .

[37]  Ronald Simon,et al.  Tissue Microarrays , 2010, Methods in Molecular Biology.

[38]  K. Kinzler,et al.  Genetic instabilities in human cancers , 1998, Nature.

[39]  A. Bhattacharyya,et al.  Deoxycholate, an Endogenous Tumor Promoter and DNA Damaging Agent, Modulates BRCA-1 Expression in Apoptosis-Sensitive Epithelial Cells: Loss of BRCA-1 Expression in Colonic Adenocarcinomas , 2003, Nutrition and cancer.

[40]  S. Elledge,et al.  BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures. , 2000, Genes & development.

[41]  J. Sung,et al.  Promoter hypermethylation of tumor‐related genes in the progression of colorectal neoplasia , 2004, International journal of cancer.

[42]  Douglas F Easton,et al.  Cancer Incidence in BRCA1 mutation carriers. , 2002, Journal of the National Cancer Institute.

[43]  Martin A. Nowak,et al.  The significance of unstable chromosomes in colorectal cancer , 2003, Nature Reviews Cancer.

[44]  F. Alt,et al.  The role of DNA breaks in genomic instability and tumorigenesis , 2003, Immunological reviews.

[45]  S. Gruber,et al.  BRCA 1 and BRCA 2 Founder Mutations and the Risk of Colorectal Cancer , 2003 .

[46]  H. Olsson Cancer risks in BRCA2 mutation carriers. , 1999, Journal of the National Cancer Institute.

[47]  M. Moynahan,et al.  The cancer connection: BRCA1 and BRCA2 tumor suppression in mice and humans , 2002, Oncogene.

[48]  M. Provencio,et al.  Prognostic significance of the allelic loss of the BRCA1 gene in colorectal cancer , 2003, Gut.