Grant Details
Grant Number: |
5R01CA269589-02 Interpret this number |
Primary Investigator: |
Guo, Xingyi |
Organization: |
Vanderbilt University Medical Center |
Project Title: |
Uncovering Colorectal Cancer Etiology and Biology By Integrating Proteomics with Other Omics Data |
Fiscal Year: |
2024 |
Abstract
PROJECT SUMMARY
Genetic factors play a significant role in the etiology of colorectal cancer (CRC). To date, approximately 180
genetic susceptibility loci have been identified for CRC through genome-wide association studies (GWAS).
However, causal genes for the large majority of these loci remain unknown, hindering the translation of GWAS
findings into disease prevention and treatment. Recently, we and others have identified many putative CRC
susceptibility genes using transcriptome-wide association studies (TWAS) that focus exclusively on mRNAs.
However, it is the proteins not mRNAs that primarily perform cellular functions. Furthermore, cellular proteins
are only moderately correlated with their corresponding mRNAs, and for many proteins, correlation is poor as
many factors affect protein synthesis and post-translation stability. Herein, we propose a well-powered
proteome-wide association study (PWAS) to systematically search the proteome to identify proteins associated
with CRC risk and further characterize their roles in colorectal tumor progression and cellular functions.
Specifically, we propose the following aims. Aim 1: To conduct a well-powered PWAS to identify proteins for
CRC risk. We will generate proteomics (~10,000 proteins) and genomics data in normal colon tissues from 300
subjects to build genetic models to predict protein expression across the proteome. These models will be
applied to the GWAS data of 125,487 individuals (58,131 cases) of European descent to evaluate associations
of genetically predicted proteins with CRC risk. We will integrate PWAS findings, along with results from
GWAS/TWAS to assess inter-relationships of genes, mRNAs and proteins in the pathogenesis of CRC. Aim 2:
To investigate potential roles of PWAS-identified proteins in the adenoma-carcinoma sequence. We will
analyze spatial expression of 30 selected PWAS-identified proteins in FFPE samples from 150 early-, late-
stage adenoma, and invasive carcinoma from white patients (N= 50 for each group) to investigate if these
proteins affect the adenoma-carcinoma sequence. Aim 3: To conduct a nested case-control study to evaluate
associations of CRC risk with promising blood proteins uncovered in Aims 1/2: We will analyze circulating
levels of 21 proteins selected from Aims 1 and 2 in pre-diagnostic blood samples collected from 1,000 and their
matched 1,200 controls of Asian, African and European ancestry. Aim 4: To investigate effects of up to 10
selected PWAS-identified proteins on cellular functions using CRISPRi/a perturbation experiments in multiple
normal colon epithelial, and CRC cell lines. We will also assess their potential roles in regulating known CRC
signaling, and newly identified CRC pathways uncovered from our study by performing RNA-sequencing and
further in vitro verification in both treated and vehicle cells. Given the rigorous study design, the unique
resources, and the methodological strengths, we expect that this proposed study will greatly advance our
understanding of CRC biology to accelerate the translation of genetic findings in CRC prevention and the
development of therapeutic targets.
Publications
Large-scale alternative polyadenylation-wide association studies to identify putative cancer susceptibility genes.
Authors: Guo X.
, Ping J.
, Yang Y.
, Su X.
, Shu X.O.
, Wen W.
, Chen Z.
, Zhang Y.
, Tao R.
, Jia G.
, et al.
.
Source: Cancer Research, 2024-05-17 00:00:00.0; , .
EPub date: 2024-05-17 00:00:00.0.
PMID: 38759092
Related Citations
Racial/Ethnic and Sex Differences in Somatic Cancer Gene Mutations among Patients with Early-Onset Colorectal Cancer.
Authors: Holowatyj A.N.
, Wen W.
, Gibbs T.
, Seagle H.M.
, Keller S.R.
, Edwards D.R.V.
, Washington M.K.
, Eng C.
, Perea J.
, Zheng W.
, et al.
.
Source: Cancer Discovery, 2023-03-01 00:00:00.0; 13(3), p. 570-579.
PMID: 36520636
Related Citations
Author Correction: Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries.
Authors: Fernandez-Rozadilla C.
, Timofeeva M.
, Chen Z.
, Law P.
, Thomas M.
, Schmit S.
, Díez-Obrero V.
, Hsu L.
, Fernandez-Tajes J.
, Palles C.
, et al.
.
Source: Nature Genetics, 2023 Mar; 55(3), p. 519-520.
PMID: 36782065
Related Citations
Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries.
Authors: Fernandez-Rozadilla C.
, Timofeeva M.
, Chen Z.
, Law P.
, Thomas M.
, Schmit S.
, Díez-Obrero V.
, Hsu L.
, Fernandez-Tajes J.
, Palles C.
, et al.
.
Source: Nature Genetics, 2023 Jan; 55(1), p. 89-99.
EPub date: 2022-12-20 00:00:00.0.
PMID: 36539618
Related Citations
Integrating transcription factor occupancy with transcriptome-wide association analysis identifies susceptibility genes in human cancers.
Authors: He J.
, Wen W.
, Beeghly A.
, Chen Z.
, Cao C.
, Shu X.O.
, Zheng W.
, Long Q.
, Guo X.
.
Source: Nature Communications, 2022-11-19 00:00:00.0; 13(1), p. 7118.
EPub date: 2022-11-19 00:00:00.0.
PMID: 36402776
Related Citations
Polygenic Risk Scores Associated with Tumor Immune Infiltration in Common Cancers.
Authors: Choi J.
, Kim J.S.
, Sung H.J.
, Chen Y.W.
, Chen Z.
, Wen W.
, Shu X.O.
, Guo X.
.
Source: Cancers, 2022-11-14 00:00:00.0; 14(22), .
EPub date: 2022-11-14 00:00:00.0.
PMID: 36428664
Related Citations