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.

Peer Review #3 of "Prognostic implications of metabolism-associated gene signatures in colorectal cancer (v0.2)"

“…The R-package "survival ROC" drew the Receiver Operating Characteristic (ROC) curve, which was used to investigate the sensitivity and specificity of the survival prediction by the gene marker risk score (Le et al 2019 Manuscript to be reviewed conducted clinical correlation an analysis using the R-package "beeswarm". The prognostic metabolismrelated gene was verified in the independent colorectal cancer cohort of GEO (GSE39582, GSE87211) (Hu et al 2018;Marisa et al 2013).…”

“…The Marisa cohort consisted of patients (GSE39582), including 566 with stage I-IV colon adenocarcinoma and 19 colon mucosa samples (Marisa et al 2013). The Hu cohort included 363 patients (GSE87211), consisting of 203 rectal tumors and 160 rectal mucosa samples (Hu et al 2018). A total of 948 patients were obtained after merging the two sets of data.…”

Identification of Autophagy-Associated Biomarkers and Corresponding Regulatory Factors in the Progression of Colorectal Cancer

“…Gene and miRNA expression data, methylation data, and the clinical data of CRC patients were downloaded from TCGA 1 (Cancer Genome Atlas Research Network, 2008 (Barretina et al, 2012). Additionally, a cohort of 177 COAD patients and 196 READ patients from the GEO database (GSE17536 and GSE87211) (Smith et al, 2010;Hu et al, 2018) was used as an independent external test set.…”

A metagene of NRF2 expression is a prognostic biomarker in all stage colorectal cancer

“…The datasets were divided into a training set, GSE17536 [27] and validation sets. Validation was carried out using datasets representative of non-metastatic, stage I-III disease (GSE14333 and GSE39582) [28,29], metastatic disease (MRC FOCUS trial) [30] and rectal only cancer (GSE87211) [31]. As part of the MRC Stratification in Colorectal cancer (S:CORT) consortium, we had access to the MRC FOCUS trial data including the RNA expression profiles generated by S:CORT (See supplementary information).…”