Dataset Information

Colorectal cancer susceptibility loci as predictive markers of rectal cancer prognosis after surgery.

ABSTRACT: To understand the molecular mechanism of rectal cancer and develop markers for disease prognostication, we generated and explored a dataset from 243 rectal cancer patients by gene expression microarray analysis of cancer samples and matched controls, and SNP-arrays of germline DNA. We found that two of the loci most strongly linked with colorectal cancer (CRC) risk, 8q24 (upstream of MYC) and 18q21 (in the intron of SMAD7), as well as 20q13 (in the intron of LAMA5), are tightly associated with the prognosis of rectal cancer patients. For SNPs on 18q21 (rs12953717 and rs4464148) and 20q13 (rs4925386), alleles that correlate with higher risk for the development of CRC are associated with shorter disease free survival (DFS). However, for rs6983267 on 8q24, the low risk allele is associated with a higher risk for recurrence and metastasis after surgery, and importantly, is strongly correlated with the resistance of CRC cell lines to chemoradiotherapy (CRT). We also found that although MYC expression is dramatically increased in cancer, patients with higher levels of MYC have a better prognosis. The expression of SMAD7 is weakly correlated with DFS. Notably, the presence of the 8q24 and 18q21 SNP alleles is not correlated with expression levels of MYC and SMAD7. rs4464148, and probably rs6983267 and rs4925386, are linked with overall survival time of patients. In conclusion, we show that several CRC risk SNPs detect subpopulations of rectal cancer patients with poor prognosis, and that rs6983267 probably affects prognosis through interfering with the resistance of cancer cells to CRT.

SUBMITTER: Hu Y

PROVIDER: S-EPMC5778444 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Colorectal cancer susceptibility loci as predictive markers of rectal cancer prognosis after surgery.

Hu Yue Y Gaedcke Jochen J Emons Georg G Beissbarth Tim T Grade Marian M Jo Peter P Yeager Meredith M Chanock Stephen J SJ Wolff Hendrik H Camps Jordi J Ghadimi B Michael BM Ried Thomas T

Genes, chromosomes & cancer 20171128 3

To understand the molecular mechanism of rectal cancer and develop markers for disease prognostication, we generated and explored a dataset from 243 rectal cancer patients by gene expression microarray analysis of cancer samples and matched controls, and SNP-arrays of germline DNA. We found that two of the loci most strongly linked with colorectal cancer (CRC) risk, 8q24 (upstream of MYC) and 18q21 (in the intron of SMAD7), as well as 20q13 (in the intron of LAMA5), are tightly associated with t ...[more]

PMID: 29119627

Similar Datasets

Project description:BackgroundPrevious genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10-8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk.MethodsWe conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10-8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided.ResultsThe discovery GWAS identified 11 variants associated with CRC at P < 5 × 10-8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0.ConclusionsThis study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.

Dataset Information

Colorectal cancer susceptibility loci as predictive markers of rectal cancer prognosis after surgery.

Publications

Colorectal cancer susceptibility loci as predictive markers of rectal cancer prognosis after surgery.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets