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Transcriptional dynamics of colorectal cancer risk associated variation at 11q23.1 correlate with tuft cell abundance and marker expression in silico.

ABSTRACT: Colorectal cancer (CRC) is characterised by heritable risk that is not well understood. Heritable, genetic variation at 11q23.1 is associated with increased colorectal cancer (CRC) risk, demonstrating eQTL effects on 3 cis- and 23 trans-eQTL targets. We sought to determine the relationship between 11q23.1 cis- and trans-eQTL target expression and test for potential cell-specificity. scRNAseq from 32,361 healthy colonic epithelial cells was aggregated and subject to weighted gene co-expression network analysis (WGCNA). One module (blue) included 19 trans-eQTL targets and was correlated with POU2AF2 expression only. Following unsupervised clustering of single cells, the expression of 19 trans-eQTL targets was greatest and most variable in cluster number 11, which transcriptionally resembled tuft cells. 14 trans-eQTL targets were found to demarcate this cluster, 11 of which were corroborated in a second dataset. Intra-cluster WGCNA and module preservation analysis then identified twelve 11q23.1 trans-eQTL targets to comprise a network that was specific to cluster 11. Finally, linear modelling and differential abundance testing showed 11q23.1 trans-eQTL target expression was predictive of cluster 11 abundance. Our findings suggest 11q23.1 trans-eQTL targets comprise a POU2AF2-related network that is likely tuft cell-specific and reduced expression of these genes correlates with reduced tuft cell abundance in silico.

SUBMITTER: Harris BT

PROVIDER: S-EPMC9365857 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Transcriptional dynamics of colorectal cancer risk associated variation at 11q23.1 correlate with tuft cell abundance and marker expression in silico.

Harris Bradley T BT Rajasekaran Vidya V Blackmur James P JP O'Callaghan Alan A Donnelly Kevin K Timofeeva Maria M Vaughan-Shaw Peter G PG Din Farhat V N FVN Dunlop Malcolm G MG Farrington Susan M SM

Scientific reports 20220810 1

Colorectal cancer (CRC) is characterised by heritable risk that is not well understood. Heritable, genetic variation at 11q23.1 is associated with increased colorectal cancer (CRC) risk, demonstrating eQTL effects on 3 cis- and 23 trans-eQTL targets. We sought to determine the relationship between 11q23.1 cis- and trans-eQTL target expression and test for potential cell-specificity. scRNAseq from 32,361 healthy colonic epithelial cells was aggregated and subject to weighted gene co-expression ne ...[more]

PMID: 35948568

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Project description:ImportanceThe understanding of the association between KRAS sequence variation status and clinical outcomes in colorectal cancer (CRC) has evolved over time.ObjectiveTo characterize the association of age at onset, tumor sidedness, and KRAS sequence variation with survival among patients diagnosed with CRC.Design, setting, and participantsThis cross-sectional study used data extracted from the Surveillance, Epidemiology, and End Results database. Patients diagnosed with adenocarcinoma of the colon or rectum from 2010 through 2015 were included and were classified as having young-onset (YO) cancer if diagnosed between ages 20 to 49 years and late-onset (LO) cancer if diagnosed at age 50 years or older. Data were analyzed from April 2021 through August 2023.Main outcomes and measuresCRC cause-specific survival (CSS) was summarized using Fine and Gray cumulative incidence and Kaplan-Meier curves. Estimation of subdistribution hazard ratios (sHRs) for the association of KRAS status, age at onset, and tumor location with CRC CSS was conducted using the Fine and Gray competing risk model. Cox proportional hazards regression was used to estimate and compare HRs.ResultsAmong 21 661 patients with KRAS sequence variation status (mean [SD] age at diagnosis, 62.50 [13.78] years; 9784 females [45.2%]), 3842 patients had YO CRC, including 1546 patients with KRAS variants, and 17 819 patients had LO CRC, including 7311 patients with KRAS variants. There was a significant difference in median CSS time between patients with variant vs wild-type KRAS (YO: 3.0 years [95% CI, 2.8-3.3 years] vs 3.5 years [95% CI, 3.3-3.9 years]; P = .02; LO: 2.5 years [95% CI, 2.4-2.7 years] vs 3.4 years [95% CI, 3.3-3.6 years]; P < .001). Tumors with variant compared with wild-type KRAS were associated with higher risk of CRC-related death (YO: sHR, 1.09 [95% CI, 1.01-1.18]; P = .03; LO: sHR, 1.06 [95% CI, 1.02-1.09]; P = .002). Among patients with YO cancer, mortality hazards increased by location, from right (sHR, 1.02 [95% CI, 0.88-1.17) to left (sHR, 1.15 [95% CI, 1.02-1.29) and rectum (sHR, 1.16 [95% CI, 0.99-1.36), but no trend by tumor location was seen for LO cancer.Conclusions and relevanceIn this study of patients diagnosed with CRC, KRAS sequence variation was associated with increased mortality among patients with YO and LO tumors. In YO cancer, variant KRAS-associated mortality risk was higher in distal tumors than proximal tumors.

Dataset Information

Transcriptional dynamics of colorectal cancer risk associated variation at 11q23.1 correlate with tuft cell abundance and marker expression in silico.

Publications

Transcriptional dynamics of colorectal cancer risk associated variation at 11q23.1 correlate with tuft cell abundance and marker expression in silico.

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