DF/HCC Program Affiliation

Cancer Genetics
Gastrointestinal Malignancies

Research Abstract

We are involved in generating mouse models for human cancer and studying the roles of genes implicated in cancer initiation and progression. We use gene targeting to generate genetically modified mice. We have made mice with mutations in Apc, Mcc, N-ras, Smad2, Smad4, Msh2, Msh3, Msh4, Msh5, Msh6 and Mlh1. Many of these mice are predisposed to develop cancer at a number of anatomical sites, most frequently in the gastrointestinal tract. Some of these mice individually or in combinations are excellent models for familial adenomatous polyposis (FAP) and hereditary non-polyposis colon cancer (HNPCC). We are currently examining the role of a number of other genes in the initiation and progression of a number of cancers with emphasis on gastrointestinal cancer.

Publications

• Kucherlapati M, Nguyen A, Kuraguchi M, Yang K, Fan K, Bronson R, Wei K, Lipkin M, Edelmann W, Kucherlapati R.Tumor progression in Apc(1638N) mice with Exo1 and Fen1 deficiencies.Oncogene 2007 Apr 23.
  17452984
• Kratz CP, Niemeyer CM, Thomas C, Bauhuber S, Matejas V, Bergstrasser E, Flotho C, Flores NJ, Haas O, Hasle H, van den Heuvel-Eibrink MM, Kucherlapati RS, Lang P, Roberts AE, Stary J, Strahm B, Swanson KD, Trebo M, Zecca M, Neel B, Locatelli F, Loh ML, Zen
  17315019
• Roberts AE, Araki T, Swanson KD, Montgomery KT, Schiripo TA, Joshi VA, Li L, Yassin Y, Tamburino AM, Neel BG, Kucherlapati RS.Germline gain-of-function mutations in SOS1 cause Noonan syndrome.Nat Genet 2007 Jan;39(1):70-4.
  17143285
• Joshi VA, Kucherlapati R.Lung cancer genetics and pharmacogenomics.Cytogenet Genome Res 2006;115(3-4):298-302.
  17124413
• Dumstorf CA, Clark AB, Lin Q, Kissling GE, Yuan T, Kucherlapati R, McGregor WG, Kunkel TA.Participation of mouse DNA polymerase iota in strand-biased mutagenic bypass of UV photoproducts and suppression of skin cancer.Proc Natl Acad Sci U S A 2006 Nov 28;
  17114294
• Kuraguchi M, Wang XP, Bronson RT, Rothenberg R, Ohene-Baah NY, Lund JJ, Kucherlapati M, Maas RL, Kucherlapati R.Adenomatous polyposis coli (APC) is required for normal development of skin and thymus.PLoS Genet 2006 Sep 15;2(9):e146.
  17002498
• Scherer SE, Muzny DM, Buhay CJ, Chen R, Cree A, Ding Y, Dugan-Rocha S, Gill R, Gunaratne P, Harris RA, Hawes AC, Hernandez J, Hodgson AV, Hume J, Jackson A, Khan ZM, Kovar-Smith C, Lewis LR, Lozado RJ, Metzker ML, Milosavljevic A, Miner GR, Montgomery KT,
  16541075
• Moran JL, Bolton AD, Tran PV, Brown A, Dwyer ND, Manning DK, Bjork BC, Li C, Montgomery K, Siepka SM, Vitaterna MH, Takahashi JS, Wiltshire T, Kwiatkowski DJ, Kucherlapati R, Beier DR.Utilization of a whole genome SNP panel for efficient genetic mapping i
  16461637
• Klein J, Ju W, Heyer J, Wittek B, Haneke T, Knaus P, Kucherlapati R, Böttinger EP, Nitschke L, Kneitz B.B cell-specific deficiency for Smad2 in vivo leads to defects in TGF-beta-directed IgA switching and changes in B cell fate.J Immunol 2006 Feb 15;176(4
  16455997
• Lin DP, Wang Y, Scherer SJ, Clark AB, Yang K, Avdievich E, Jin B, Werling U, Parris T, Kurihara N, Umar A, Kucherlapati R, Lipkin M, Kunkel TA, Edelmann W.An Msh2 point mutation uncouples DNA mismatch repair and apoptosis.Cancer Res 2004 Jan 15;64(2):517-
  14744764
• Costa RM, Federov NB, Kogan JH, Murphy GG, Stern J, Ohno M, Kucherlapati R, Jacks T, Silva AJ.Mechanism for the learning deficits in a mouse model of neurofibromatosis type 1.Nature 2002 Jan 31;415(6871):526-30.
  11793011
• Montgomery KT, Lee E, Miller A, Lau S, Shim C, Decker J, Chiu D, Emerling S, Sekhon M, Kim R, Lenz J, Han J, Ioshikhes I, Renault B, Marondel I, Yoon SJ, Song K, Murty VV, Scherer S, Yonescu R, Kirsch IR, Ried T, McPherson J, Gibbs R, Kucherlapati R.A hig
  11237017
• Merscher S, Funke B, Epstein JA, Heyer J, Puech A, Lu MM, Xavier RJ, Demay MB, Russell RG, Factor S, Tokooya K, Jore BS, Lopez M, Pandita RK, Lia M, Carrion D, Xu H, Schorle H, Kobler JB, Scambler P, Wynshaw-Boris A, Skoultchi AI, Morrow BE, Kucherlapati
  11239417
• Joshi VA, Kucherlapati R.Genetics and genomics in the practice of medicine.Gastroenterology 2008 May;134(5):1284-8.
  18471501
• Montgomery KT, Iartchouck O, Li L, Perera A, Yassin Y, Tamburino A, Loomis S, Kucherlapati R.Mutation detection using automated fluorescence-based sequencing.Curr Protoc Hum Genet 2008 Apr;Chapter 7:Unit7.9.
  18428426
• Busuttil RA, Lin Q, Stambrook PJ, Kucherlapati R, Vijg J.Mutation frequencies and spectra in DNA polymerase eta-deficient mice.Cancer Res 2008 Apr 1;68(7):2081-4.
  18381412
• Avdievich E, Reiss C, Scherer SJ, Zhang Y, Maier SM, Jin B, Hou H Jr, Rosenwald A, Riedmiller H, Kucherlapati R, Cohen PE, Edelmann W, Kneitz B.Distinct effects of the recurrent Mlh1G67R mutation on MMR functions, cancer, and meiosis.Proc Natl Acad Sci U
  18337503
• Swanson KD, Winter JM, Reis M, Bentires-Alj M, Greulich H, Grewal R, Hruban RH, Yeo CJ, Yassin Y, Iartchouk O, Montgomery K, Whitman SP, Caligiuri MA, Loh ML, Gilliland DG, Look AT, Kucherlapati R, Kern SE, Meyerson M, Neel BG.SOS1 mutations are rare in h
  18064648
• Martin ES, Tonon G, Sinha R, Xiao Y, Feng B, Kimmelman AC, Protopopov A, Ivanova E, Brennan C, Montgomery K, Kucherlapati R, Bailey G, Redston M, Chin L, DePinho RA.Common and distinct genomic events in sporadic colorectal cancer and diverse cancer types.
  18006816
• Joshi VA, Kucherlapati R.Pharmacogenomics of lung cancer: with a view to address EGFR-targeted therapies.Pharmacogenomics 2007 Sep;8(9):1211-20.
  17924836
• Sequist LV, Joshi VA, Jänne PA, Muzikansky A, Fidias P, Meyerson M, Haber DA, Kucherlapati R, Johnson BE, Lynch TJ.Response to treatment and survival of patients with non-small cell lung cancer undergoing somatic EGFR mutation testing.Oncologist 2007 Jan;
  17285735
• Hung KE, Kho AT, Sarracino D, Richard LG, Krastins B, Forrester S, Haab BB, Kohane IS, Kucherlapati R.Mass spectrometry-based study of the plasma proteome in a mouse intestinal tumor model.J Proteome Res 2006 Aug;5(8):1866-78.
  16889408
• Sequist LV, Joshi VA, Jänne PA, Bell DW, Fidias P, Lindeman NI, Louis DN, Lee JC, Mark EJ, Longtine J, Verlander P, Kucherlapati R, Meyerson M, Haber DA, Johnson BE, Lynch TJ.Epidermal growth factor receptor mutation testing in the care of lung cancer pat
  16857818
• Kucherlapati MH, Nguyen AA, Bronson RT, Kucherlapati RS.Inactivation of conditional Rb by Villin-Cre leads to aggressive tumors outside the gastrointestinal tract.Cancer Res 2006 Apr 1;66(7):3576-83.
  16585182
• Hagendoorn J, Tong R, Fukumura D, Lin Q, Lobo J, Padera TP, Xu L, Kucherlapati R, Jain RK.Onset of abnormal blood and lymphatic vessel function and interstitial hypertension in early stages of carcinogenesis.Cancer Res 2006 Apr 1;66(7):3360-4.
  16585153
• Lin Q, Clark AB, McCulloch SD, Yuan T, Bronson RT, Kunkel TA, Kucherlapati R.Increased susceptibility to UV-induced skin carcinogenesis in polymerase eta-deficient mice.Cancer Res 2006 Jan 1;66(1):87-94.
  16397220
• Ju W, Ogawa A, Heyer J, Nierhof D, Yu L, Kucherlapati R, Shafritz DA, Böttinger EP.Deletion of Smad2 in mouse liver reveals novel functions in hepatocyte growth and differentiation.Mol Cell Biol 2006 Jan;26(2):654-67.
  16382155
• Wang Y, Putnam CD, Kane MF, Zhang W, Edelmann L, Russell R, Carrión DV, Chin L, Kucherlapati R, Kolodner RD, Edelmann W.Mutation in Rpa1 results in defective DNA double-strand break repair, chromosomal instability and cancer in mice.Nat Genet 2005 Jul;37(
  15965476
• Yang K, Fan KH, Lamprecht SA, Edelmann W, Kopelovich L, Kucherlapati R, Lipkin M.Peroxisome proliferator-activated receptor gamma agonist troglitazone induces colon tumors in normal C57BL/6J mice and enhances colonic carcinogenesis in Apc1638 N/+ Mlh1+/-
  15818612
• Shao C, Deng L, Chen Y, Kucherlapati R, Stambrook PJ, Tischfield JA.Mlh1 mediates tissue-specific regulation of mitotic recombination.Oncogene 2004 Dec 2;23(56):9017-24.
  15480418
• Kabbarah O, Mallon MA, Pfeifer JD, Edelmann W, Kucherlapati R, Goodfellow PJ.A panel of repeat markers for detection of microsatellite instability in murine tumors.Mol Carcinog 2003 Dec;38(4):155-9.
  14639654
• Young LC, Peters AC, Maeda T, Edelmann W, Kucherlapati R, Andrew SE, Tron VA.DNA mismatch repair protein Msh6 is required for optimal levels of ultraviolet-B-induced apoptosis in primary mouse fibroblasts.J Invest Dermatol 2003 Oct;121(4):876-80.
  14632208
• Pretlow TP, Edelmann W, Kucherlapati R, Pretlow TG, Augenlicht LH.Spontaneous aberrant crypt foci in Apc1638N mice with a mutant Apc allele.Am J Pathol 2003 Nov;163(5):1757-63.
  14578176
• Yang YC, Piek E, Zavadil J, Liang D, Xie D, Heyer J, Pavlidis P, Kucherlapati R, Roberts AB, Böttinger EP.Hierarchical model of gene regulation by transforming growth factor beta.Proc Natl Acad Sci U S A 2003 Sep 2;100(18):10269-74.
  12930890
• Shinozaki H, Yang K, Fan K, Edelmann W, Kucherlapati R, Weinstein IB, Lipkin M.Cyclin D1 expression in the intestinal mucosa and tumors of Apc1638N mice.Anticancer Res 2003 May-Jun;23(3B):2217-26.
  12894495
• Takahashi C, Bronson RT, Socolovsky M, Contreras B, Lee KY, Jacks T, Noda M, Kucherlapati R, Ewen ME.Rb and N-ras function together to control differentiation in the mouse.Mol Cell Biol 2003 Aug;23(15):5256-68.
  12861012
• Supavekin S, Zhang W, Kucherlapati R, Kaskel FJ, Moore LC, Devarajan P.Differential gene expression following early renal ischemia/reperfusion.Kidney Int 2003 May;63(5):1714-24.
  12675847
• Yang K, Fan K, Kurihara N, Shinozaki H, Rigas B, Augenlicht L, Kopelovich L, Edelmann W, Kucherlapati R, Lipkin M.Regional response leading to tumorigenesis after sulindac in small and large intestine of mice with Apc mutations.Carcinogenesis 2003 Mar;24(
  12663524
• Waterston RH, Lindblad-Toh K, Birney E, Rogers J, Abril JF, Agarwal P, Agarwala R, Ainscough R, Alexandersson M, An P, Antonarakis SE, Attwood J, Baertsch R, Bailey J, Barlow K, Beck S, Berry E, Birren B, Bloom T, Bork P, Botcherby M, Bray N, Brent MR, Br
  12466850
• Bourdon V, Naef F, Rao PH, Reuter V, Mok SC, Bosl GJ, Koul S, Murty VV, Kucherlapati RS, Chaganti RS.Genomic and expression analysis of the 12p11-p12 amplicon using EST arrays identifies two novel amplified and overexpressed genes.Cancer Res 2002 Nov 1;62
  12414650
• Girnun GD, Smith WM, Drori S, Sarraf P, Mueller E, Eng C, Nambiar P, Rosenberg DW, Bronson RT, Edelmann W, Kucherlapati R, Gonzalez FJ, Spiegelman BM.APC-dependent suppression of colon carcinogenesis by PPARgamma.Proc Natl Acad Sci U S A 2002 Oct 15;99(21
  12370429
• Kucherlapati M, Yang K, Kuraguchi M, Zhao J, Lia M, Heyer J, Kane MF, Fan K, Russell R, Brown AM, Kneitz B, Edelmann W, Kolodner RD, Lipkin M, Kucherlapati R.Haploinsufficiency of Flap endonuclease (Fen1) leads to rapid tumor progression.Proc Natl Acad Sc
  12119409
• Velcich A, Yang W, Heyer J, Fragale A, Nicholas C, Viani S, Kucherlapati R, Lipkin M, Yang K, Augenlicht L.Colorectal cancer in mice genetically deficient in the mucin Muc2.Science 2002 Mar 1;295(5560):1726-9.
  11872843
• Hörig H, Wainstein A, Long L, Kahn D, Soni S, Marcus A, Edelmann W, Kucherlapati R, Kaufman HL.A new mouse model for evaluating the immunotherapy of human colorectal cancer.Cancer Res 2001 Dec 1;61(23):8520-6.
  11731437
• Kuraguchi M, Yang K, Wong E, Avdievich E, Fan K, Kolodner RD, Lipkin M, Brown AM, Kucherlapati R, Edelmann W.The distinct spectra of tumor-associated Apc mutations in mismatch repair-deficient Apc1638N mice define the roles of MSH3 and MSH6 in DNA repair
  11691815
• Yang W, Velcich A, Mariadason J, Nicholas C, Corner G, Houston M, Edelmann W, Kucherlapati R, Holt PR, Augenlicht LH.p21(WAF1/cip1) is an important determinant of intestinal cell response to sulindac in vitro and in vivo.Cancer Res 2001 Aug 15;61(16):6297
  11507085
• Kucherlapati R, DePinho RA.Cancer. Telomerase meets its mismatch.Nature 2001 Jun 7;411(6838):647-8.
  11395749
• Puech A, Saint-Jore B, Merscher S, Russell RG, Cherif D, Sirotkin H, Xu H, Factor S, Kucherlapati R, Skoultchi AI.Normal cardiovascular development in mice deficient for 16 genes in 550 kb of the velocardiofacial/DiGeorge syndrome region.Proc Natl Acad Sc
  10963672
• Kneitz B, Cohen PE, Avdievich E, Zhu L, Kane MF, Hou H, Kolodner RD, Kucherlapati R, Pollard JW, Edelmann W.MutS homolog 4 localization to meiotic chromosomes is required for chromosome pairing during meiosis in male and female mice.Genes Dev 2000 May 1;1
  10809667
• Pellegata NS, Dieguez-Lucena JL, Joensuu T, Lau S, Montgomery KT, Krahe R, Kivelä T, Kucherlapati R, Forsius H, de la Chapelle A.Mutations in KERA, encoding keratocan, cause cornea plana.Nat Genet 2000 May;25(1):91-5.
  10802664
• Wu G, Markowitz GS, Li L, D'Agati VD, Factor SM, Geng L, Tibara S, Tuchman J, Cai Y, Park JH, van Adelsberg J, Hou H, Kucherlapati R, Edelmann W, Somlo S.Cardiac defects and renal failure in mice with targeted mutations in Pkd2.Nat Genet 2000 Jan;24(1):75
  10615132
• Cheung VG, Morley M, Aguilar F, Massimi A, Kucherlapati R, Childs G.Making and reading microarrays.Nat Genet 1999 Jan;21(1 Suppl):15-9.
  9915495
• Edelmann W, Cohen PE, Kneitz B, Winand N, Lia M, Heyer J, Kolodner R, Pollard JW, Kucherlapati R.Mammalian MutS homologue 5 is required for chromosome pairing in meiosis.Nat Genet 1999 Jan;21(1):123-7.
  9916805
• Wu G, D'Agati V, Cai Y, Markowitz G, Park JH, Reynolds DM, Maeda Y, Le TC, Hou H, Kucherlapati R, Edelmann W, Somlo S.Somatic inactivation of Pkd2 results in polycystic kidney disease.Cell 1998 Apr 17;93(2):177-88.
  9568711
• Edelmann W, Yang K, Umar A, Heyer J, Lau K, Fan K, Liedtke W, Cohen PE, Kane MF, Lipford JR, Yu N, Crouse GF, Pollard JW, Kunkel T, Lipkin M, Kolodner R, Kucherlapati R.Mutation in the mismatch repair gene Msh6 causes cancer susceptibility.Cell 1997 Nov 1
  9390556
• Johnson L, Greenbaum D, Cichowski K, Mercer K, Murphy E, Schmitt E, Bronson RT, Umanoff H, Edelmann W, Kucherlapati R, Jacks T.K-ras is an essential gene in the mouse with partial functional overlap with N-ras.Genes Dev 1997 Oct 1;11(19):2468-81.
  9334313
• Basson CT, Bachinsky DR, Lin RC, Levi T, Elkins JA, Soults J, Grayzel D, Kroumpouzou E, Traill TA, Leblanc-Straceski J, Renault B, Kucherlapati R, Seidman JG, Seidman CE.Mutations in human TBX5 [corrected] cause limb and cardiac malformation in Holt-Oram
  8988165
• Liedtke W, Edelmann W, Bieri PL, Chiu FC, Cowan NJ, Kucherlapati R, Raine CS.GFAP is necessary for the integrity of CNS white matter architecture and long-term maintenance of myelination.Neuron 1996 Oct;17(4):607-15.
  8893019
• Edelmann W, Cohen PE, Kane M, Lau K, Morrow B, Bennett S, Umar A, Kunkel T, Cattoretti G, Chaganti R, Pollard JW, Kolodner RD, Kucherlapati R.Meiotic pachytene arrest in MLH1-deficient mice.Cell 1996 Jun 28;85(7):1125-34.
  8674118
• Johnson DW, Berg JN, Baldwin MA, Gallione CJ, Marondel I, Yoon SJ, Stenzel TT, Speer M, Pericak-Vance MA, Diamond A, Guttmacher AE, Jackson CE, Attisano L, Kucherlapati R, Porteous ME, Marchuk DA.Mutations in the activin receptor-like kinase 1 gene in her
  8640225
• Smithies O, Gregg RG, Boggs SS, Koralewski MA, Kucherlapati RS.Insertion of DNA sequences into the human chromosomal beta-globin locus by homologous recombination.Nature 1985 Sep 19-25;317(6034):230-4.
  2995814
• Roginski RS, Skoultchi AI, Henthorn P, Smithies O, Hsiung N, Kucherlapati R.Coordinate modulation of transfected HSV thymidine kinase and human globin genes.Cell 1983 Nov;35(1):149-55.
  6313221
• Davies RL, Fuhrer-Krusi S, Kucherlapati RS.Modulation of transfected gene expression mediated by changes in chromatin structure.Cell 1982 Dec;31(3 Pt 2):521-9.
  6186385
• Kucherlapati R, Shin SI.Genetic control of tumorigenicity in interspecific mammalian cell hybrids.Cell 1979 Mar;16(3):639-48.
  455444