Our genomes are mostly made up of repetitive 'junk DNA'derived from insertions of sequences through RNA intermediates. Our group has developed methods to identify polymorphic insertions of these understudied sequences, demonstrated they are major sources of structural variation our genome, and found they occur frequently in LD with trait associated SNPs identified by cancer genome wide association study (GWAS). Experiments by others and characterizations of the non-random distribution of mobile DNAs in our genome indicate they have significant potential to effect gene function. The overarching hypothesis of this proposal is that a subset of common mobile DNA insertions predispose to common cancer development. Our three part approach to test this hypothesis will include: (i.) identification of RIPs with potential roles in neoplasia by locating those in the vicnity of regions implicated in disease risk by GWAS;(ii.) determining which of these RIPs may reasonably account for cancer risk by analyses of area linkage and RIP genotype imputing in clinical samples;and (iii.) investigating effects of transposon polymorphisms on transcript expression levels and structure. Hematopoietic malignancies will receive special priority in these studies, and clinical samples from patients with leukemias, lymphomas, and related disordered will be used for a directed RIP discovery effort and for evaluating mechanisms of gene expression effects.

Public Health Relevance

The purpose of the proposed studies is to test the hypothesis that inherited retrotransposon insertion polymorphisms (RIPs) predispose carriers to neoplasias. We will discover potentially relevant RIPs, ascertain which candidates associate with disease risk as appreciated by genome-wide association studies (GWAS), and determine the biologic basis of such effects by gene expression studies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA163705-01A1
Application #
8436682
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Mechanic, Leah E
Project Start
2013-03-04
Project End
2018-02-28
Budget Start
2013-03-04
Budget End
2014-02-28
Support Year
1
Fiscal Year
2013
Total Cost
$336,150
Indirect Cost
$128,650
Name
Johns Hopkins University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Rodi?, Nemanja; Sharma, Reema; Sharma, Rajni et al. (2014) Long interspersed element-1 protein expression is a hallmark of many human cancers. Am J Pathol 184:1280-6
Babatz, Timothy D; Burns, Kathleen H (2013) Functional impact of the human mobilome. Curr Opin Genet Dev 23:264-70