A genome-wide search for determinants of survival in 1926 patients with advanced colorectal cancer with follow-up in over 22,000 patients

Wills, Christopher; He, Yazhou; Summers, Matthew G.; Lin, Yi; Phipps, Amanda I.; Watts, Katie; Law, Philip; Al-Tassan, Nada A.; Maughan, Tim; Kaplan, Richard; Houlston, Richard S.; Peters, Ulrike; Newcomb, Polly A.; Chan, Andrew T.; Buchanan, Daniel D.; Gallinger, Steve; Marchand, Loı̈c Le; Pai, Rish K.; Alberts, Steven R.; Gray, Victoria; West, Hannah; Escott‐Price, Valentina; Dunlop, Malcolm; Cheadle, Jeremy P.

doi:10.1016/j.ejca.2021.09.047

Cited by 9 publications

(15 citation statements)

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“…A single nucleotide polymorphism (SNP) on gene ERBB4 was previously described as the most significant SNP associated with overall survival (HR = 1.24, 95%CI = 1.16-1.32, P = 1.9 × 10-7) (Wills et al ., 2021). We therefore further wanted to understand whether this gene showed some effect in our dataset by sex.…”

Section: Resultsmentioning

confidence: 99%

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Exploring the association between Body Mass Index, Sex and Gene Expression in human colorectal epithelium

Lemler

Donnelly

Tomlinson

et al. 2022

Preprint

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Introduction Colorectal cancer (CRC) is the second most common cause of cancer death globally. Genome-wide association studies have established that cancer risk mediated through common genetic variants can be linked to variation in gene expression. Since obesity and male sex impart substantially elevated CRC risk, we studied transcriptional profiles of normal colorectal mucosa using RNA sequencing to better understand the relationship of these risk factors with gene expression levels. Methods Normal colorectal mucosa was sampled from 365 participants (208 males, 157 females) either during surgery (n=103) or through endoscopic biopsy (n=262) from cancer patients and patients with other unrelated conditions. In total, 238 samples were used for our discovery dataset and 380 samples were obtained for the validation of our findings. The transcription analysis was done using paired-end total RNA sequencing. Data processing and gene filtering followed the Genotype-Tissue Expression (GTEx) Project pipeline v8. Differential Expression Analysis (DEA) was performed on normalised counts to evaluate effects of sex and body mass index on the total gene expression, as well as possible confounding effects of cancer presence on the gene expression in normal colorectal tissue. Results Following filtering, there were 15,465 genes available for analysis. DEA identified two genes that were significantly associated with sex and five associated with body mass index. However, whilst these nominal signals are of interest, none of the genes associated with sex remained significant in a replication dataset. Due to the missing BMI information, replication of DEA by BMI was not possible. Conclusion We found no systematic differences in gene expression in normal colorectal epithelium between males and females, nor did we find a strong association between gene expression and BMI. Although sample size may limit our analysis, the results suggest no or limited confounding effects of BMI and sex on gene expression in normal colorectal mucosa samples.

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Section: Resultsmentioning

confidence: 99%

“…) (Wills et al, 2021). We therefore further wanted to understand whether this gene showed some effect in our dataset by sex.…”

Section: Association Between Sex and Gene Expressionmentioning

confidence: 99%

Exploring the association between Body Mass Index, Sex and Gene Expression in human colorectal epithelium

Lemler

Donnelly

Tomlinson

et al. 2022

Preprint

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“…We previously identified clinicopathological factors associated with survival in patients from COIN and COIN‐B 22 . Due to the number of covariates added to the regression models, dimensionality reduction was performed using PCA to reduce the risk of overfitting.…”

Section: Methodsmentioning

confidence: 99%

“…In total, 2671 unrelated patients with metastatic or locally advanced CRC were recruited into the MRC clinical trials COIN (NCT00182715) 20 and COIN‐B (NCT00640081) 21 and treated with oxaliplatin and fluoropyrimidine chemotherapy, with or without cetuximab. Patients were combined for survival analyses since there was no evidence of heterogeneity in overall survival (OS; time from trial randomization to death or end of trial) between patients when analyzed by trial, trial arm, type of chemotherapy received, or cetuximab use 22 . Assessment of response was performed at 12 weeks; response was defined as complete or partial response using RECIST 1.0 guidelines and no response was defined as stable or progressive disease.…”

Section: Methodsmentioning

confidence: 99%

Germline variation in RASAL2 may predict survival in patients with RAS‐activated colorectal cancer

Wills

Watts

Maughan

et al. 2023

Genes Chromosomes & Cancer

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Background: Therapeutic agents that specifically target patients with RAS mutant colorectal cancer (CRC) are needed. We sought potential drug targets by relating genome-wide association study and survival data in patients with advanced CRC profiled for mitogen-activated protein kinase (MAPK) pathway mutations.Methods: In total, 694 patients from the clinical trials COIN and COIN-B had MAPKactivated CRCs (assigned as KRAS, NRAS, or BRAF mutant). Genome-wide single nucleotide polymorphism (SNP), gene, and gene-set analyses were performed to identify determinants of survival. For rs12028023 in RAS protein activator-like 2 (RASAL2), we studied its effect by MAPK pathway activation status (by comparing to 760 patients without MAPK-activated CRCs), MAPK gene mutation status, surface area of the primary tumor (as a marker of proliferation), and expression on RASAL2.Results: In MAGMA genome-wide analyses, RASAL2 was the most significant gene associated with survival (p = 2.0 Â 10 À5 ). Patients carrying the minor (A) allele in the lead SNP, rs12028023 in intron 1 of RASAL2, had a median increase in survival of 167 days as compared with patients carrying the major allele. rs12028023 was predictive for survival by MAPK-activation status (p Z-test = 2.1 Â 10 À3 ). Furthermore, rs12028023 improved survival in patients with RAS mutant (hazard ratio[HR] = 0.62, 95% confidence intervals [CI] = 0.5-0.8, p = 3.4 Â 10 À5 ) but not BRAF mutant (p = 0.87) CRCs. The rs12028023 A-allele was associated with reduced surface area of the primary tumor (Beta = À0.037, standard error [SE] = 0.017, p = 3.2 Â 10 À2 ) and reduced RASAL2 expression in cultured fibroblasts (p = 1.6 Â 10 À11 ). Conclusion:Our data demonstrate a prognostic role for RASAL2 in patients with MAPK-activated CRCs, with potential as a therapeutic target.

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“…Very recently, in a bioinformatics analysis, Wills et al conducted a whole genome-wide association study (GWAS) in a very large cohort of patients and reported an association with overall survival and rs79612564 in the receptor tyrosine kinase ERBB4. Patients with high ERBB4 expression in colon tumours showed worse survival; both the rs79612564 variant and ERBB4 were proposed as predictive biomarkers of survival [114]. Next generation sequencing (NGS), in addition to demonstrating that mutations are common in advanced colon tumours, has proven that tumours located in the right colon have more genetic aberrations than in the left colon.…”

Section: Genomicsmentioning

confidence: 99%

Use of Omics Technologies for the Detection of Colorectal Cancer Biomarkers

Alorda-Clara

Torrens‐Mas

Morla-Barcelo

et al. 2022

Cancers

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Colorectal cancer (CRC) is one of the most frequently diagnosed cancers with high mortality rates, especially when detected at later stages. Early detection of CRC can substantially raise the 5-year survival rate of patients, and different efforts are being put into developing enhanced CRC screening programs. Currently, the faecal immunochemical test with a follow-up colonoscopy is being implemented for CRC screening. However, there is still a medical need to describe biomarkers that help with CRC detection and monitor CRC patients. The use of omics techniques holds promise to detect new biomarkers for CRC. In this review, we discuss the use of omics in different types of samples, including breath, urine, stool, blood, bowel lavage fluid, or tumour tissue, and highlight some of the biomarkers that have been recently described with omics data. Finally, we also review the use of extracellular vesicles as an improved and promising instrument for biomarker detection.

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A genome-wide search for determinants of survival in 1926 patients with advanced colorectal cancer with follow-up in over 22,000 patients

Cited by 9 publications

References 50 publications

Exploring the association between Body Mass Index, Sex and Gene Expression in human colorectal epithelium

Exploring the association between Body Mass Index, Sex and Gene Expression in human colorectal epithelium

Germline variation in RASAL2 may predict survival in patients with RAS‐activated colorectal cancer

Use of Omics Technologies for the Detection of Colorectal Cancer Biomarkers

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