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Grant Details

Grant Number: 5R01CA082282-03 Interpret this number
Primary Investigator: Peltomaki, Paivi
Organization: Ohio State University
Project Title: Predisposing/Modifying Genes in Hereditary Colon Cancer
Fiscal Year: 2001
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Abstract

DESCRIPTION: (Adapted from investigator's abstract) Susceptibility to hereditary nonpolyposis colon cancer (HNPCC) is associated with germline mutations in five genes with DNA mismatch repair function. Previous studies have shown that these genes account for two-thirds of HNPCC kindreds meeting the international diagnostic criteria for the disorder and displaying microsatellite instability as a characteristic abnormality in tumors. The basis for cancer susceptibility is unknown in the remaining one-third of kindreds with microsatellite instability and in most families without this abnormality. Furthermore, in kindreds with detectable mutations and even with shared predispositions, the clinical phenotype varies a lot between and within individual families, the reasons for which are largely unknown. The broad objective of the present study is to identify genes and mechanisms associated with cancer susceptibility and phenotype determination in non-polypotic colon cancer. The detection of such genes is of prime importance given the fact that half the Western population is estimated to develop a colon tumor during their lifetime. Importantly, the progression of those lesions to cancer can be prevented by early intervention, and genetic markers of increased cancer risk are needed to define the cohorts who would be the first to benefit from such preventive measures. The Specific Aim 1 focuses on kindreds with non-polyposis colon cancer in which mutations in the presently known HNPCC-associated DNA mismatch repair genes have been ruled out by sequencing. A genome-wide search is applied with the goal to identify novel genes associated with cancer predisposition in these kindreds. The Specific Aim 2 focuses on a unique series of families with shared predisposing mutations. The observation of clinical variation in the setting shared predisposition suggests the existence of additional phenotype determinants. The aim is to identify genes that might modify the clinical phenotype of HNPCC, taking advantage of association and linkage-based approaches in these genetically homogeneous subsets of HNPCC patients.

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Publications

Lynch syndrome (hereditary nonpolyposis colorectal cancer) diagnostics.
Authors: Lagerstedt Robinson K, Liu T, Vandrovcova J, Halvarsson B, Clendenning M, Frebourg T, Papadopoulos N, Kinzler KW, Vogelstein B, Peltomäki P, Kolodner RD, Nilbert M, Lindblom A
Source: J Natl Cancer Inst, 2007 Feb 21;99(4), p. 291-9.
PMID: 17312306
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Linkage analysis in a large Swedish family supports the presence of a susceptibility locus for adenoma and colorectal cancer on chromosome 9q22.32-31.1.
Authors: Skoglund J, Djureinovic T, Zhou XL, Vandrovcova J, Renkonen E, Iselius L, Bisgaard ML, Peltomäki P, Lindblom A
Source: J Med Genet, 2006 Feb;43(2), p. e7.
PMID: 16467217
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Lynch syndrome genes.
Authors: Peltomäki P
Source: Fam Cancer, 2005;4(3), p. 227-32.
PMID: 16136382
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Restoring mismatch repair does not stop the formation of reciprocal translocations in the colon cancer cell line HCA7 but further destabilizes chromosome number.
Authors: Abdel-Rahman WM, Lohi H, Knuutila S, Peltomäki P
Source: Oncogene, 2005 Jan 20;24(4), p. 706-13.
PMID: 15580308
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Mutations associated with HNPCC predisposition -- Update of ICG-HNPCC/INSiGHT mutation database.
Authors: Peltomäki P, Vasen H
Source: Dis Markers, 2004;20(4-5), p. 269-76.
PMID: 15528792
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Novel splicing associations of hereditary colon cancer related DNA mismatch repair gene mutations.
Authors: Renkonen E, Lohi H, Järvinen HJ, Mecklin JP, Peltomäki P
Source: J Med Genet, 2004 Jul;41(7), p. e95.
PMID: 15235038
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Genotype and phenotype in hereditary nonpolyposis colon cancer: a study of families with different vs. shared predisposing mutations.
Authors: Peltomäki P, Gao X, Mecklin JP
Source: Fam Cancer, 2001;1(1), p. 9-15.
PMID: 14574010
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Altered expression of MLH1, MSH2, and MSH6 in predisposition to hereditary nonpolyposis colorectal cancer.
Authors: Renkonen E, Zhang Y, Lohi H, Salovaara R, Abdel-Rahman WM, Nilbert M, Aittomaki K, Jarvinen HJ, Mecklin JP, Lindblom A, Peltomaki P
Source: J Clin Oncol, 2003 Oct 1;21(19), p. 3629-37.
PMID: 14512394
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Pathogenicity of the hereditary colorectal cancer mutation hMLH1 del616 linked to shortage of the functional protein.
Authors: Raevaara TE, Vaccaro C, Abdel-Rahman WM, Mocetti E, Bala S, Lönnqvist KE, Kariola R, Lynch HT, Peltomäki P, Nyström-Lahti M
Source: Gastroenterology, 2003 Aug;125(2), p. 501-9.
PMID: 12891553
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Role of DNA mismatch repair defects in the pathogenesis of human cancer.
Authors: Peltomäki P
Source: J Clin Oncol, 2003 Mar 15;21(6), p. 1174-9.
PMID: 12637487
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Endometrial and colorectal tumors from patients with hereditary nonpolyposis colon cancer display different patterns of microsatellite instability.
Authors: Kuismanen SA, Moisio AL, Schweizer P, Truninger K, Salovaara R, Arola J, Butzow R, Jiricny J, Nyström-Lahti M, Peltomäki P
Source: Am J Pathol, 2002 Jun;160(6), p. 1953-8.
PMID: 12057899
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Genetic and clinical characterisation of familial adenomatous polyposis: a population based study.
Authors: Moisio AL, Järvinen H, Peltomäki P
Source: Gut, 2002 Jun;50(6), p. 845-50.
PMID: 12010888
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Distinct PTEN mutational spectra in hereditary non-polyposis colon cancer syndrome-related endometrial carcinomas compared to sporadic microsatellite unstable tumors.
Authors: Zhou XP, Kuismanen S, Nystrom-Lahti M, Peltomaki P, Eng C
Source: Hum Mol Genet, 2002 Feb 15;11(4), p. 445-50.
PMID: 11854177
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CYCLIN D1 as a genetic modifier in hereditary nonpolyposis colorectal cancer.
Authors: Bala S, Peltomäki P
Source: Cancer Res, 2001 Aug 15;61(16), p. 6042-5.
PMID: 11507050
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Lack of MSH2 and MSH6 characterizes endometrial but not colon carcinomas in hereditary nonpolyposis colorectal cancer.
Authors: Schweizer P, Moisio AL, Kuismanen SA, Truninger K, Vierumäki R, Salovaara R, Arola J, Butzow R, Jiricny J, Peltomäki P, Nyström-Lahti M
Source: Cancer Res, 2001 Apr 1;61(7), p. 2813-5.
PMID: 11306449
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Deficient DNA mismatch repair: a common etiologic factor for colon cancer.
Authors: Peltomäki P
Source: Hum Mol Genet, 2001 Apr;10(7), p. 735-40.
PMID: 11257106
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MSH6 and MSH3 are rarely involved in genetic predisposition to nonpolypotic colon cancer.
Authors: Huang J, Kuismanen SA, Liu T, Chadwick RB, Johnson CK, Stevens MW, Richards SK, Meek JE, Gao X, Wright FA, Mecklin JP, Järvinen HJ, Grönberg H, Bisgaard ML, Lindblom A, Peltomäki P
Source: Cancer Res, 2001 Feb 15;61(4), p. 1619-23.
PMID: 11245474
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Hereditary colorectal cancer: risk assessment and management.
Authors: Hampel H, Peltomaki P
Source: Clin Genet, 2000 Aug;58(2), p. 89-97.
PMID: 11005140
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Nuclear and mitochondrial genome instability in human breast cancer.
Authors: Richard SM, Bailliet G, Páez GL, Bianchi MS, Peltomäki P, Bianchi NO
Source: Cancer Res, 2000 Aug 1;60(15), p. 4231-7.
PMID: 10945635
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Candidate tumor suppressor RIZ is frequently involved in colorectal carcinogenesis.
Authors: Chadwick RB, Jiang GL, Bennington GA, Yuan B, Johnson CK, Stevens MW, Niemann TH, Peltomaki P, Huang S, de la Chapelle A
Source: Proc Natl Acad Sci U S A, 2000 Mar 14;97(6), p. 2662-7.
PMID: 10688904
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