Analysis of the Oxidative Damage Repair Genes NUDT1, OGG1, and MUTYH in Patients from Mismatch Repair Proficient HNPCC Families (MSS-HNPCC)

Purpose: Several studies have described molecular differences between microsatellite stable hereditary nonpolyposis colorectal cancer (MSS-HNPCC) and microsatellite unstable Lynch syndrome tumors (MSI-HNPCC). These differences highlight the possibility that other instability forms could explain cancer susceptibility in this group of families. The base excision repair (BER) pathway is the major DNA repair pathway for oxidative DNA damage. A defect in this pathway can result in DNA transversion mutations and a subsequent increased cancer risk. Mutations in MUTYH have been associated with increased colorectal cancer (CRC) risk while no association has been described for OGG1 or NUDT1. Experimental Design: We performed mutational screening of the three genes involved in defense against oxidative DNA damage in a set of 42 MSS-HNPCC families. Results: Eight rare variants and 5 frequent variants were found in MSS-HNPCC patients. All variants were previously described by other authors except variant c.285C>T in OGG1. Segregation studies were done and in silico programs were used to estimate the level of amino acid conservation, protein damage prediction, and possible splicing alterations. Variants OGG1 c.137G>A; MUTYH c.1187G>A were detected in Amsterdam I families and cosegregate with cancer. Analysis of OGG1 c.137G>A transcripts showed an inactivation of the splicing donor of exon 1. Conclusions: Two rare variants (OGG1 c.137G>A; MUTYH c.1187G>A) and one common polymorphism (NUDT1 c.426C>T) were associated with CRC risk. We show that the BER pathway can play a significant role in a number of MSS-HNPCC colorectal cancers. More studies could be of interest in order to gain further understanding of yet unexplained CRC susceptibility cases. Clin Cancer Res; 17(7); 1701–12. ©2011 AACR.

[1]  J. Houwing-Duistermaat,et al.  Comprehensive genetic analysis of seven large families with mismatch repair proficient colorectal cancer , 2010, Genes, chromosomes & cancer.

[2]  J. Błasiak,et al.  Common polymorphisms in the XPD and hOGG1 genes are not associated with the risk of colorectal cancer in a Polish population. , 2009, The Tohoku journal of experimental medicine.

[3]  J. Potter,et al.  Germline MutY human homologue mutations and colorectal cancer: a multisite case-control study. , 2009, Gastroenterology.

[4]  K. Hemminki,et al.  DNA repair genetic polymorphisms and risk of colorectal cancer in the Czech Republic. , 2008, Mutation research.

[5]  R. Duggirala,et al.  Genetic polymorphisms in OGG1 and their association with angiomyolipoma, a benign kidney tumor in patients with tuberous sclerosis , 2008, Cancer biology & therapy.

[6]  H. Morreau,et al.  Molecular Analysis of Colorectal Cancer Tumors from Patients with Mismatch Repair–Proficient Hereditary Nonpolyposis Colorectal Cancer Suggests Novel Carcinogenic Pathways , 2007, Clinical Cancer Research.

[7]  I. König,et al.  Analysis of the base excision repair genes MTH1, OGG1 and MUTYH in patients with squamous oral carcinomas. , 2007, Oral oncology.

[8]  M. Gassull,et al.  Performance of different microsatellite marker panels for detection of mismatch repair-deficient colorectal tumors. , 2007, Journal of the National Cancer Institute.

[9]  Jukka-Pekka Mecklin,et al.  Explaining the Familial Colorectal Cancer Risk Associated with Mismatch Repair (MMR)-Deficient and MMR-Stable Tumors , 2007, Clinical Cancer Research.

[10]  J. Yokota,et al.  Association of polymorphisms in the MTH1 gene with small cell lung carcinoma risk. , 2006, Carcinogenesis.

[11]  K. Offit,et al.  Increased frequency of disease-causing MYH mutations in colon cancer families. , 2006, Carcinogenesis.

[12]  E. Guinó,et al.  Polymorphisms in Genes of Nucleotide and Base Excision Repair: Risk and Prognosis of Colorectal Cancer , 2006, Clinical Cancer Research.

[13]  U. Vogel,et al.  GPX Pro198Leu and OGG1 Ser326Cys polymorphisms and risk of development of colorectal adenomas and colorectal cancer. , 2005, Cancer letters.

[14]  A. Roca,et al.  Differential Features of Colorectal Cancers Fulfilling Amsterdam Criteria without Involvement of the Mutator Pathway , 2005, Clinical Cancer Research.

[15]  J. Godino,et al.  Low prevalence of germline hMSH6 mutations in colorectal cancer families from Spain. , 2005, World journal of gastroenterology.

[16]  J. Prendergast,et al.  Germline susceptibility to colorectal cancer due to base-excision repair gene defects. , 2005, American journal of human genetics.

[17]  J. Potter,et al.  Lower cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency: familial colorectal cancer type X. , 2005, JAMA.

[18]  S. Knuutila,et al.  Comprehensive characterization of HNPCC-related colorectal cancers reveals striking molecular features in families with no germline mismatch repair gene mutations , 2005, Oncogene.

[19]  P. Peltomäki,et al.  Mutations Associated with HNPCC Predisposition — Update of ICG-HNPCC/INSiGHT Mutation Database , 2004, Disease markers.

[20]  J. Yokota,et al.  Suppression of chemically induced and spontaneously occurring oxidative mutagenesis by three alleles of human OGG1 gene encoding 8-hydroxyguanine DNA glycosylase. , 2004, Mutation research.

[21]  M. Benito,et al.  Immunohistochemistry and microsatellite instability testing for selecting MLH1, MSH2 and MSH6 mutation carriers in hereditary non-polyposis colorectal cancer. , 2004, Oncology reports.

[22]  Siân Jones,et al.  Autosomal recessive colorectal adenomatous polyposis due to inherited mutations of MYH , 2003, The Lancet.

[23]  Young-Jin Park,et al.  hOGG1 Ser326Cys polymorphism modifies the significance of the environmental risk factor for colon cancer. , 2003, World journal of gastroenterology.

[24]  T. Eisen,et al.  Inherited variants in MYH are unlikely to contribute to the risk of lung carcinoma , 2003, Human Genetics.

[25]  J. Eshleman,et al.  8-Hydroxyguanosine repair is defective in some microsatellite stable colorectal cancer cells. , 2002, Cancer research.

[26]  Siân Jones,et al.  Biallelic germline mutations in MYH predispose to multiple colorectal adenoma and somatic G:C-->T:A mutations. , 2002, Human molecular genetics.

[27]  E. Bleecker,et al.  Associations between hOGG1 sequence variants and prostate cancer susceptibility. , 2002, Cancer research.

[28]  M. Benito,et al.  Prevalence of germline mutations of MLH1 and MSH2 in hereditary nonpolyposis colorectal cancer families from Spain , 2002, International journal of cancer.

[29]  L. Le Marchand,et al.  Association of the hOGG1 Ser326Cys polymorphism with lung cancer risk. , 2002, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[30]  Alison L. Livingston,et al.  Inherited variants of MYH associated with somatic G:C→T:A mutations in colorectal tumors , 2002, Nature Genetics.

[31]  Y. Nakabeppu.  Molecular genetics and structural biology of human MutT homolog, MTH1. , 2001, Mutation research.

[32]  W. Tan,et al.  Ser326Cys polymorphism in hOGG1 gene and risk of esophageal cancer in a Chinese population , 2001, International journal of cancer.

[33]  H. Dienemann,et al.  hOGG1 polymorphism and loss of heterozygosity (LOH): Significance for lung cancer susceptibility in a caucasian population , 2000, International journal of cancer.

[34]  G. Gyapay,et al.  Alterations of the DNA repair gene OGG1 in human clear cell carcinomas of the kidney. , 2000, Cancer research.

[35]  M. Dizdaroglu,et al.  Effect of single mutations in the OGG1 gene found in human tumors on the substrate specificity of the Ogg1 protein. , 2000, Nucleic acids research.

[36]  Y. Yuasa.  [Hereditary nonpolyposis colorectal cancer]. , 2000, Nihon rinsho. Japanese journal of clinical medicine.

[37]  P. Beaune,et al.  Frequent allelic loss at chromosome 3p distinct from genetic alterations of the 8‐oxoguanine DNA glycosylase 1 gene in head and neck cancer , 1999, Molecular carcinogenesis.

[38]  T. Caldés,et al.  Denaturing gradient gel electrophoresis-based analysis of loss of heterozygosity distinguishes nonobvious, deleterious BRCA1 variants from nonpathogenic polymorphisms. , 1999, Clinical chemistry.

[39]  A. de la Chapelle,et al.  Genetic susceptibility to non-polyposis colorectal cancer , 1999, Journal of medical genetics.

[40]  Jeffrey H. Miller,et al.  Functional Expression of hMYH, a Human Homolog of the Escherichia coli MutY Protein , 1999, Journal of bacteriology.

[41]  H T Lynch,et al.  New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. , 1999, Gastroenterology.

[42]  J. Radicella,et al.  Base excision repair of 8-hydroxyguanine protects DNA from endogenous oxidative stress. , 1999, Biochimie.

[43]  S Srivastava,et al.  A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. , 1998, Cancer research.

[44]  J. Yokota,et al.  Genetic polymorphisms and alternative splicing of the hOGG1 gene, that is involved in the repair of 8-hydroxyguanine in damaged DNA , 1998, Oncogene.

[45]  J. Eshleman,et al.  Increased transversions in a novel mutator colon cancer cell line , 1998, Oncogene.

[46]  J. Yokota,et al.  Cloning of a human homolog of the yeast OGG1 gene that is involved in the repair of oxidative DNA damage , 1997, Oncogene.

[47]  H. Lynch,et al.  Overview of natural history, pathology, molecular genetics and management of HNPCC (Lynch syndrome) , 1996, International journal of cancer.

[48]  K. Maruyama,et al.  Polymorphisms and probable lack of mutation in a human mutT homolog, hMTH1, in hereditary nonpoliposis colorectal cancer. , 1995, Biochemical and biophysical research communications.

[49]  T. Lindahl.  Instability and decay of the primary structure of DNA , 1993, Nature.

[50]  H. Lynch,et al.  Extracolonic cancer in hereditary nonpolyposis colorectal cancer. , 1993, Cancer.

[51]  J. Mecklin,et al.  The International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC) , 1991, Diseases of the colon and rectum.

[52]  A. Grollman,et al.  Insertion of specific bases during DNA synthesis past the oxidation-damaged base 8-oxodG , 1991, Nature.

[53]  Shirley A. Miller,et al.  A simple salting out procedure for extracting DNA from human nucleated cells. , 1988, Nucleic acids research.

[54]  S. Nishimura,et al.  Hydroxylation of deoxyguanosine at the C-8 position by ascorbic acid and other reducing agents. , 1984, Nucleic acids research.