Steven M. LipkinAssociate Professor, Medicine Associate Professor, Biological Chemistry Associate Professor, Epidemiology |
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Research Interests |
DNA mismatch repair, Molecular epidemiology of colorectal cancer | |
| URLs | www.ucihs.uci.edu/biochem/faculty/LIPKIN.html | |
| Dept. of Epidemiology - School of Medicine | ||
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Academic Distinctions |
Phi Beta Kappa, Sigma Xi (1986) Summa Cum Laude (1986) NIH Medical Scientist Training Program Fellowship Awardee (1986-89,1993-1995) American Cancer Society Research Scholar (2003) |
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Research Abstract |
DNA mismatch repair (MMR) is critical for maintaining both mitotic and meiotic genomic integrity. MMR malfunction causes cancer through both a mutator phenotype called microsatellite instability (MSI) and the inability to respond to DNA damage by apoptosis. Mutations in four MMR genes (MLH1, MSH2, MSH6, and PMS2) cause cancer susceptibility. Including both Hereditary Non-Polyposis Colon Cancer (HNPCC) and sporadic cases, ~17-20% of Colorectal (CRC) and ~15-25% of endometrial cancer are attributable to MMR defects. MMR is also critical for mammalian meiosis. Mice null for MMR genes Msh4, Msh5 or Mlh1 are infertile for both sexes. Similarly, male Pms2-/- mice are sterile. As a postdoc I cloned MLH3, the last uncharacterized MMR gene encoded in the human genome. MLH3 has higher amino-acid identity with homologues in S. cerevisiae, Arabidopsis, and C. elegans than to any other human protein. This conser-vation suggests it may perform unique functions in mammalian MMR. My previous studies revealed strong associations between MLH3 and both human and mouse cancer susceptibility loci. I have recently generated a mouse Mlh3 knock out and propose to test three hypotheses: (1) Mlh3 deficiency causes MSI. These data will define the tumor MSI subtype (High, Low or Stable) associated with MLH3 deficiency, and is anticipated to help molecular stratification of patient tumor subtypes in future clinical CRC therapy trials. (2) Mlh3 deficiency causes inherited cancer susceptibility. These data will help define the cancer spectrum of MLH3 deficiency and help my lab prioritize different patients for MLH3 mutation analyses. (3) Mlh3 is required for meiosis. This study will define whether MLH3 participates in meiotic checkpoint recognition and is a plausible candidate gene for mutation analyses in idiopathic human infertility or genetic aneuploidy disorders such as Down or Turner Syndromes. Additionally, I propose to use a custom Affymetrix high-density array I designed that resequences all MLH1, MSH2 and MSH6 exons and splice donor/acceptors (HNPCC DNA Chip) to examine whether MMR single nucleotide polymorphisms (SNPs) contribute to CRC susceptibility. Previously, an APC SNP (APC I1307K) was identified among CRC patients that is attributable for ~20% of CRC in Ashkenazi Jews with a CRC family history. Because of the association between MMR and HNPCC, I propose the following studies: To perform high-throughput SNP discovery for MLH1, MSH2 and MSH6 coding and splice-junction sequences in Molecular Epidemiology of Colon Cancer (MECC) Study CRC patients with an affected first degree relative using the HNPCC DNA Chip. SNPdiscovery is important at present in that recent studies suggest only ~2-12% of all human cSNPs are represented in public domain databases. To perform a case-control study to determine if there exists any SNP(s) associated with altered CRC risk. To validate SNP association with CRC risk in a replication set of MECC matched CRC cases and controls distinct from those samples analyzed in (B). The discovery of MMR gene CRC susceptibility alleles as proposed in this study would help enable more precisely the identification of individuals at higher risk than the general population for targeted intensive screening before CRC initiation and/or metastasis. Furthermore, the ability to genotype CRC cases for the presence of different susceptibility alleles is anticipated in future randomized CRC therapeutic trials to allow stratification and identification of patient subpopulations with distinct tumor responses and clinical outcomes that might otherwise not be recognized without this type of patient stratification. |
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| Publications |
Lipkin, SM, Wang, V., Jacoby, R., Basu, S., Baxevanis, A., Lynch, H., Elliott, R., and Collins, F. "MLH3: A novel DNA mismatch repair gene associated with mammalian microsatellite instability and a colon cancer susceptibility locus in the mouse." Nature Genetics (Article)2000 Jan 24(1):27-35. Lipkin SM, Wang V, Stoler DL, Anderson GR, Kirsch I, Hadley D, Lynch HT, Collins FS. "Germline and somatic mutation analyses in the DNA mismatch repair gene MLH3: Evidence for somatic mutation in colorectal cancers." Hum Mutat 2001 May;17(5):389-96 Stella A, Wagner A, Shito K, Lipkin SM, Watson P, Guanti G, Lynch HT, Fodde R, Liu B. "A nonsense mutation in MLH1 causes exon skipping in three unrelated HNPCC families."> Cancer Research 2001 Oct 1;61(19):7020-4 Lipkin, SM, Moens PB,, Wang, V., Lenzi, M.,Shanmugarajah, D.,Gilgeous, A., Thomas, J. Cheng, J., Touchman, J. Green, E., Schwartzberg, P,.Collins, FS, & Paula E. Cohen "Meiotic arrest and aneuploidy in MLH3 deficient mice Nature Genetics (August,2002) p104-107. Lynch HT, Weisenburger, D., Quinn-Laquer, B. Snyder, C., Lynch JF, D., Lipkin, SM, and Sanger, W.G."Family with acute myelogenous leukemia, breast, ovarian and gastrointestinal cancer. Cancer Genetics and Cytogenetics, 2002 Aug; 137(1):8-14 Kudryavtseva, E., Sugihara, T., Wang, N., Lasso, R., Gudnason, J., Lipkin, SM and Andersen, B.A."Identification and characterization of Grainyhead-like Epithelial Transactivator (GET-1), a novel mammalian grainyhead-like factor." Developmental Dynamics, (April, 2002) 226(4):604-17 Lipkin SM, Chen, J., Hacia, J., Fodor, S., Rennert, G. and Gruber, S. "Novel DNA Mismatch Repair Gene Variants Associated With Microsatellite Stable Population Based Colorectal Cancer." Nature Genetics (July, 2004). Domcheck, S., Rebbeck, T., Lipkin S.M and Tucker, M. "Risk Modifiers in Hereditary Cancer Syndromes." Am Soc Clin Oncol Supplement 89-97, 2005 Shin, BY, Rozek, L., Paxton, L., Peel, D., Anton-Culver, H., Rennert, G., Goodfellow, P., Gruber, S.,Lipkin SM. "Low Allele Frequency of MLH1 D132H in American Colorectal and Endometrial Cancer Patients" Dis. of the Colon and Rectum Jun 27, 2005. Rozek, L., Lipkin, SM, Fearon E., Hanash, S., Giordano T., Greenson J., Kuick R., Misek, D., Taylor J., Douglas, J., Rennert, G., and Gruber S. "CDX2 Polymorphisms, RNA Expression, and Risk of Colorectal Cancer" Cancer Research 2005 65(13):5488-92. Chen, J., Kuriaguchi, M., Reichow, D., Dudley, S., Arnheim. N., Liskay, RM and Lipkin SM. "Contributions by MutL Homologues Mlh3 and Pms2 to DNA Mismatch Repair and Tumor Suppression in the Mouse." Cancer Research 2005 65(19):8662-7065. Kolas, N., Svetlanov, A, Lenzi, M., Macaluso, F., Lipkin, S.M., Liskay, R.M, Greally, J., Edelmann, W. and Cohen, P. "Localization of MMR proteins on meiotic chromosomes in mice indicates distinct functions during prophase I."J. Cell Biology 2005 Nov 7;171(3):447-58 J. L. Velasquez and S. M. Lipkin" "What Are SNPs and Haplotypes and How Will They Help Us Manage the Prevention of Adult Cancer?" Curr Oncol Rep 7 (6) 475-9 (2005). Cannavo, E., Marra, G., Sabatés-Bellver, J., Menigatti, M., Lipkin, S.M. Fischer, S., Cejka, P., and Jiricny, J. "Expression of the MutL homologue hMLH3 in human cells and its role in DNA mismatch repair." Cancer Research 2005 65(23):10759-66. Wu, X., Tsai, C., Patam, M., Zan, H., Chen, J., Lipkin, S.M. and Casali, P. "A role for the MutL mismatch repair Mlh3 protein in immunoglobulin class switch DNA recombination and somatic hypermutation." Journal of Immunology (in press). S.A. Frank, Chen, J., and Lipkin, S.M. "Kinetics of cancer: a method to test hypotheses of genetic causation" BMC Cancer 2005 Dec 21;5:163 . Chao, L. and Lipkin, SM. "Molecular Models for the Tissue Specificity of DNA Mismatch Repair Deficient Carcinogenesis." Nucleic Acids Research 2006 Feb 6;34(3):840-52. Nguyen, H., Tran, A., Lipkin S.M. and John P. Fruehauf "Pharmacogenomics of Colorectal Cancer Prevention and Treatment." Cancer Investigation 2006 6:24 (in press). Lipkin, SM, Boman, B. and Offit, K. "Hereditary Colorectal Cancer: New Advances and the Integration of Molecular Testing into Clinical Practice."Am Soc Clin Oncol Supplement (in press). |
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| Zell, JA, Rhee,JM, Ziogas, A, Lipkin,SM and Anton-Culver, H. “Race, Socioeconomic Status, Treatment, and Survival Time among Pancreatic Cancer Cases in California.” Cancer Epidemiol Biomarkers Prev 2007;16(3). March 2007 | ||
| Le, H, Ziogas, A, Lipkin,SM and Zell, J. “Race, Socioeconomic Status, Treatment, and Survival among Colorectal Cancer Cases in California.” Cancer Epidemiol Biomarkers Prev 2007;16(3). In press | ||
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Chao, E, Velasquez, J, Ng, P, Peel, D, Anton-Culver, H, Gruber, SB and Lipkin, SM. “MAPP-MMR: A Novel in silico Approach to Distinguish Deleterious MLH1/MSH2 Missense Mutations from Benign Polymorphisms.” Human Mutation March 27 2008 Epub. |
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| Grants | National Cancer Institute 9/2006-9/2008 N01-CN-35160 “Inhibiting EGF Receptor Signaling in Aberrant Crypt Foci of the Colon” Role: Principal Investigator The major goal of this Phase IIa trial is to test whether Tarceva (Erlotinib) can decrease molecular biomarkers of activated EGFR in aberrant crypt foci of the colon (Funded but pending final FDA and NCI and UCI IRB approval of Protocol) | |
| National Cancer Institute 9/2006-9/2008 N01-CN-35160 “Phase IIA Trial testing Erlotinib as an Intervention against Intraductal Pancreatic Mucinous Neoplasms” Role: Principal Investigator The major goal of this Phase IIa trial is to test whether Tarceva (Erlotinib) can prevent pancreatic cancer by decreasing molecular biomarkers in the pre-neoplastic precursor lesion Intraductal Pancreatic Mucinous Neoplasms. | ||
| National Cancer Institute 09/2007-10/2009 NCI Minority Training Branch Fellowship attached to R01 CA098626 to Mavee Witherspoon in Lipkin Lab Role: Principal Investigator | ||
| National Cancer Institute 10/2004-9/2009 R01 CA098626 Cancer Susceptibility in Mlh3 Null Mice Role: Principal Investigator The major goal of this project is to identify the mechanisms of cancer susceptibility in Mlh3 and Mlh3 Pms2 null mouse models. | ||
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Professional Societies |
American Society for Clinical Oncology NCI Colorectal Cancer Family Registry Network American Association for Cancer Research |
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| Graduate Programs |
Epidemiology |
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| Research Center | UCI Genetic Epidemiology Research Institute | |
| Link to this profile | http://www.faculty.uci.edu/profile.cfm?faculty_id=4707 | |
| Last updated | 07/09/2008 | |
| (This faculty member is (or was) affiliated with UCI, but does not currently have an active appointment with UCI.) | ||