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Grant Details

Grant Number: 5R03CA103500-02 Interpret this number
Primary Investigator: Ellis, Nathan
Organization: Sloan-Kettering Inst Can Research
Project Title: Mechanisms of Carcinogenesis By Crc-Susceptibility Genes
Fiscal Year: 2004
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Abstract

DESCRIPTION (provided by applicant): We are developing a repository of specimens consisting of genomic DNA samples from over 1,500 consecutive Ashkenazi Jewish colorectal cancer (CRC) cases. This repository will be linked to essential clinico-pathological parameters and to the tumor specimens themselves. A major application of the repository is the identification of CRC-susceptibility genes that are present in the cases are at greater frequency compared to the same number of healthy, age- and sex- matched Ashkenazi Jewish controls. One such CRC-susceptibility gene is the blmAsh mutation, which is protein-terminating mutation in the DNA-repair protein BLM, that confers a three fold increased risk of developing colorectal cancer. We propose here a pilot project to utilize the tumor specimens accessible through the repository to investigate mechanism(s) of colorectal carcinogenesis in blmAsh carriers. The blmAsh mutation causes a >95 percent reduction of BLM protein expression from the mutant allele. Two mechanisms are hypothesized: 1) cancer susceptibility is caused by haploinsufficiency of BLM, generating a constitutive risk of transformation of all colon cells and 2) somatic oss of BLM is an early step in carcinogenesis. To test these hypotheses, we will investigate whether BLM protein expression is detectable in the tumor ceils of blmAsh carriers compared to noncarriers by immunohistochemistry using BLM antibodies and whether or not the normal BLM allele is lost genetically by loss of heterozygosity studies. In addition, we will investigate the effect of blmAsh on known mechanisms of colorectal carcinogenesis. By comparison of paired tumor-normal material from blmAsh carriers and from noncarriers, we will test i) mutational status of the APC gene by protein truncation test, ii) microsatellite instability, including the A9 run in BLM itself, iii) MLH1 and MSH2 immunohistochemistry, iv) mutational status of TP53 by direct DNA sequencing and immunohistochemistry, v) mutational status of RAS by direct sequencing and vi) DCC by immunohistochemistry. This application describes the design of the DNA repository and associated database, methods we will use for the identification of mutation carders, and the procedures for testing mechanisms of carcinogenesis.

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Publications

Single-amplicon MSH2 A636P mutation testing in Ashkenazi Jewish patients with colorectal cancer: role in presurgical management.
Authors: Guillem J.G. , Glogowski E. , Moore H.G. , Nafa K. , Markowitz A.J. , Shia J. , Offit K. , Ellis N.A. .
Source: Annals of surgery, 2007 Apr; 245(4), p. 560-5.
PMID: 17414604
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Increased frequency of disease-causing MYH mutations in colon cancer families.
Authors: Peterlongo P. , Mitra N. , Sanchez de Abajo A. , de la Hoya M. , Bassi C. , Bertario L. , Radice P. , Glogowski E. , Nafa K. , Caldes T. , et al. .
Source: Carcinogenesis, 2006 Nov; 27(11), p. 2243-9.
EPub date: 2006-06-14.
PMID: 16774938
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Prediction of germline mutations and cancer risk in the Lynch syndrome.
Authors: Chen S. , Wang W. , Lee S. , Nafa K. , Lee J. , Romans K. , Watson P. , Gruber S.B. , Euhus D. , Kinzler K.W. , et al. .
Source: JAMA, 2006-09-27; 296(12), p. 1479-87.
PMID: 17003396
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Localization of breast cancer susceptibility loci by genome-wide SNP linkage disequilibrium mapping.
Authors: Ellis N.A. , Kirchhoff T. , Mitra N. , Ye T.Z. , Chuai S. , Huang H. , Nafa K. , Norton L. , Neuhausen S. , Gordon D. , et al. .
Source: Genetic epidemiology, 2006 Jan; 30(1), p. 48-61.
PMID: 16206141
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TGFBR1*6A may contribute to hereditary colorectal cancer.
Authors: Bian Y. , Caldes T. , Wijnen J. , Franken P. , Vasen H. , Kaklamani V. , Nafa K. , Peterlongo P. , Ellis N. , Baron J.A. , et al. .
Source: Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2005-05-01; 23(13), p. 3074-8.
PMID: 15860866
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Germline mutations of AXIN2 are not associated with nonsyndromic colorectal cancer.
Authors: Peterlongo P. , Howe L.R. , Radice P. , Sala P. , Hong Y.J. , Hong S.I. , Mitra N. , Offit K. , Ellis N.A. .
Source: Human mutation, 2005 May; 25(5), p. 498-500.
PMID: 15841489
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Colorectal cancer risk in individuals with biallelic or monoallelic mutations of MYH.
Authors: Peterlongo P. , Mitra N. , Chuai S. , Kirchhoff T. , Palmer C. , Huang H. , Nafa K. , Offit K. , Ellis N.A. .
Source: International journal of cancer, 2005-04-10; 114(3), p. 505-7.
PMID: 15578699
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Value of immunohistochemical detection of DNA mismatch repair proteins in predicting germline mutation in hereditary colorectal neoplasms.
Authors: Shia J. , Klimstra D.S. , Nafa K. , Offit K. , Guillem J.G. , Markowitz A.J. , Gerald W.L. , Ellis N.A. .
Source: The American journal of surgical pathology, 2005 Jan; 29(1), p. 96-104.
PMID: 15613860
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Localization of cancer susceptibility genes by genome-wide single-nucleotide polymorphism linkage-disequilibrium mapping.
Authors: Mitra N. , Ye T.Z. , Smith A. , Chuai S. , Kirchhoff T. , Peterlongo P. , Nafa K. , Phillips M.S. , Offit K. , Ellis N.A. .
Source: Cancer research, 2004-11-01; 64(21), p. 8116-25.
PMID: 15520224
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The utility of immunohistochemical detection of DNA mismatch repair gene proteins.
Authors: Shia J. , Ellis N.A. , Klimstra D.S. .
Source: Virchows Archiv : an international journal of pathology, 2004 Nov; 445(5), p. 431-41.
EPub date: 2004-09-29.
PMID: 15455227
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