Familial and Early Onset Colorectal Cancer

Information

  • Research Project
  • 9535869
  • ApplicationId
    9535869
  • Core Project Number
    R01CA072851
  • Full Project Number
    5R01CA072851-22
  • Serial Number
    072851
  • FOA Number
    PA-13-302
  • Sub Project Id
  • Project Start Date
    5/10/1996 - 28 years ago
  • Project End Date
    7/31/2020 - 3 years ago
  • Program Officer Name
    THURIN, MAGDALENA
  • Budget Start Date
    8/1/2018 - 5 years ago
  • Budget End Date
    7/31/2019 - 4 years ago
  • Fiscal Year
    2018
  • Support Year
    22
  • Suffix
  • Award Notice Date
    7/27/2018 - 5 years ago

Familial and Early Onset Colorectal Cancer

DESCRIPTION (provided by applicant): In spite of all we have learned about the genetic basis of colorectal cancer (CRC) over the past 25 years, a large proportion of patients with some form of familial CRC (FCC) cannot be characterized in a way that the family can be rationally counseled. This proposal is a dual-principal investigator renewal application for a highly productive program that has been ongoing for 18 years. Over the past 5 years, we have made progress in our understanding of how methylation-based silencing of the DNA mismatch repair (MMR) genes play a role in the genesis of CRC; our work has characterized early-onset CRCs that occur in the absence of FCC, and we found that genetic and epigenetic alterations in the tumor tissues of these patients are similar to that of non- Lynch syndrome FCC (or, FCC-type X). We characterized how alterations in expression of the MSH3 gene are involved in the genesis of sporadic CRCs. We have provided insights into the role of epigenetics in the genesis and clinical behavior of CRCs. The overarching goal of this program is to move toward a more complete personalization of the concepts used in the classification of familiality in CRC. We have four specific aims. Based upon our work on the somatic inactivation of MSH3 in CRCs, we propose to test the hypothesis that germline mutations in the MSH3 gene cause a previously unidentified disease - Lynch syndrome-MSH3 type, which would have a phenotype that would be systematically overlooked because of how we currently screen for Lynch syndrome. Second, we plan to develop an approach for finding balanced inversions in the Lynch syndrome-associated MMR genes to resolve the uncertainty in families where the anticipated germline mutations cannot be identified. Third, we propose that FCC-type X is associated with a unique tumor phenotype that will lead us to the germline basis of that disease. Finally, we propose to use whole genome sequencing techniques to test the hypothesis that the serrated polyposis syndrome (SPS) is a rare recessive disease caused by biallelic mutations in a gene involved in the methylator pathway of colorectal tumorigenesis. If successful, this work will fill several remaining gaps in the FCC problem, and is likely to have a substantial impact on patient care.

IC Name
NATIONAL CANCER INSTITUTE
  • Activity
    R01
  • Administering IC
    CA
  • Application Type
    5
  • Direct Cost Amount
    237500
  • Indirect Cost Amount
    134900
  • Total Cost
    372400
  • Sub Project Total Cost
  • ARRA Funded
    False
  • CFDA Code
    394
  • Ed Inst. Type
  • Funding ICs
    NCI:372400\
  • Funding Mechanism
    Non-SBIR/STTR RPGs
  • Study Section
    ZRG1
  • Study Section Name
    Special Emphasis Panel
  • Organization Name
    BAYLOR RESEARCH INSTITUTE
  • Organization Department
  • Organization DUNS
    145745022
  • Organization City
    DALLAS
  • Organization State
    TX
  • Organization Country
    UNITED STATES
  • Organization Zip Code
    75201
  • Organization District
    UNITED STATES