The identification of novel germline modifiers of aggressive prostate cancer development
Principal Investigator
Name
Nigel Crawford
Institution
NHGRI, DIR, GMBB
Position Title
Investigator
Email
About this CDAS Project
Study
PLCO
(Learn more about this study)
Project ID
PLCO-72
Initial CDAS Request Approval
Mar 25, 2014
Title
The identification of novel germline modifiers of aggressive prostate cancer development
Summary
The goal of this work is to use human prostate cancer GWAS datasets to confirm or refute the role of novel germline modifiers of aggressive prostate cancer that have been identified in a mouse model of prostate tumorigenesis. Specifically, we have used a quantitative trait locus (QTL) mapping approach to identify prostate metastasis modifier loci mapping using the C57BL/6-Tg(TRAMP)8247Ng/J (TRAMP) mouse model of aggressive prostate carcinoma. We hypothesize that germline variation influences metastasis in prostate cancer.
The effect of germline variation in TRAMP mice was investigated by crossing it to different inbred mouse strains and quantifying metastasis in transgene-positive F1 males. Strains with the greatest phenotypic variation from the wildtype TRAMP C57BL6/J mice were chosen for modifier mapping using an F2 intercross approach. F2 mice were genotyped using a linkage panel of 1,449 SNPs and modifier loci were analyzed using a java-based QTL mapping package (j/QTL). The greatest number of loci achieving genome-wide significance were observed in the TRAMPxNOD/ShiLtJ F2 cross (n=232). Modifier loci associated with metastasis were observed on chromosomes 1, 6 and 11. We performed microarray analysis of primary tumors derived from the TRAMPxNOD/ShiLtJ F2 cross (n=122) and correlated metastasis with the expression of all transcripts within the three metastasis susceptibility loci on chromosomes 1, 6 and 11. These analyses allowed for the identification of 22 novel metastasis susceptibility candidate genes.
We have therefore identified multiple novel metastasis susceptibility candidate genes using both QTL mapping and tumor expression profiling. We wish to confirm the importance of these 22 genes, as well as genes identified as being associated with other aggressive prostate cancer traits in our QTL mapping studies, in a human prostate cancer GWAS cohort. To this end, we wish to be granted access to the PLCO prostate cancer cohort.
The effect of germline variation in TRAMP mice was investigated by crossing it to different inbred mouse strains and quantifying metastasis in transgene-positive F1 males. Strains with the greatest phenotypic variation from the wildtype TRAMP C57BL6/J mice were chosen for modifier mapping using an F2 intercross approach. F2 mice were genotyped using a linkage panel of 1,449 SNPs and modifier loci were analyzed using a java-based QTL mapping package (j/QTL). The greatest number of loci achieving genome-wide significance were observed in the TRAMPxNOD/ShiLtJ F2 cross (n=232). Modifier loci associated with metastasis were observed on chromosomes 1, 6 and 11. We performed microarray analysis of primary tumors derived from the TRAMPxNOD/ShiLtJ F2 cross (n=122) and correlated metastasis with the expression of all transcripts within the three metastasis susceptibility loci on chromosomes 1, 6 and 11. These analyses allowed for the identification of 22 novel metastasis susceptibility candidate genes.
We have therefore identified multiple novel metastasis susceptibility candidate genes using both QTL mapping and tumor expression profiling. We wish to confirm the importance of these 22 genes, as well as genes identified as being associated with other aggressive prostate cancer traits in our QTL mapping studies, in a human prostate cancer GWAS cohort. To this end, we wish to be granted access to the PLCO prostate cancer cohort.
Aims
We aim to examine the frequencies of SNPs and haplotypes in the human orthologs of genes identified through our mouse mapping studies. We will focus on SNP/haplotype associations with disease aggrssiveness markers such as tumor grade and clinical stage
Collaborators
Ying Hu, NCI