Dataset Information

T cell-inflamed gene expression profile is associated with favorable disease-specific survival in non-hypermutated microsatellite-stable colorectal cancer patients.

ABSTRACT:

Background

The anti-tumor immune response plays a key role in colorectal cancer (CRC) progression and survival. The T cell-inflamed gene expression profile (GEP) is a biomarker predicting response to checkpoint inhibitor immunotherapy across immunogenic cancer types, but the prognostic value in CRC is unknown. We evaluated associations with disease-specific survival, somatic mutations, and examined its differentially expressed genes and pathways among 84 sporadic CRC patients from the Seattle Colon Cancer Family Registry.

Methods

Gene expression profiling was performed using Nanostring's nCounter PanCancer IO 360 panel. Somatic mutations were identified by a targeted DNA sequencing panel.

Results

The T cell-inflamed GEP was positively associated with tumor mutation burden and microsatellite instability high (MSI-H). Higher T cell-inflamed GEP had favorable CRC-specific survival (hazard ratio [HR] per standard deviation unit = 0.50, p = 0.004) regardless of hypermutation or MSI status. Analysis of recurrently mutated genes having at least 10 mutation carriers, suggested that the T cell-inflamed GEP is positively associated with RYR1, and negatively associated with APC. However, these associations were attenuated after adjusting for hypermutation or MSI status. We also found that expression of genes RPL23, EPCAM, AREG and ITGA6, and the Wnt signaling pathway was negatively associated with the T cell-inflamed GEP, which might indicate immune-inhibitory mechanisms.

Conclusions

Our results show that the T cell-inflamed GEP is a prognostic biomarker in non-hypermutated microsatellite-stable CRC. This also suggests that patient stratification for immunotherapy within this CRC subgroup should be explored further. Moreover, reported immune-inhibitory gene expression signals may suggest targets for therapeutic combination with immunotherapy.

SUBMITTER: Yin H

PROVIDER: S-EPMC10067089 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Publications

T cell-inflamed gene expression profile is associated with favorable disease-specific survival in non-hypermutated microsatellite-stable colorectal cancer patients.

Yin Hang H Harrison Tabitha A TA Thomas Sushma S SS Sather Cassie L CL Koehne Amanda L AL Malen Rachel C RC Reedy Adriana M AM Wurscher Michelle A MA Hsu Li L Phipps Amanda I AI Zaidi Syed H E SHE Newcomb Polly A PA Peters Ulrike U Huyghe Jeroen R JR

Cancer medicine 20221107 6

<h4>Background</h4>The anti-tumor immune response plays a key role in colorectal cancer (CRC) progression and survival. The T cell-inflamed gene expression profile (GEP) is a biomarker predicting response to checkpoint inhibitor immunotherapy across immunogenic cancer types, but the prognostic value in CRC is unknown. We evaluated associations with disease-specific survival, somatic mutations, and examined its differentially expressed genes and pathways among 84 sporadic CRC patients from the Se ...[more]

PMID: 36341526

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Project description:BackgroundThe prognostic implication of wild-type APC (APC-WT) in microsatellite stable (MSS) metastatic colorectal cancer (mCRC) is not well defined.Materials and methodsAPC prognostic value was evaluated retrospectively in two independent cohorts of patient with MSS mCRC with a confirmatory analysis from a public data set from Memorial Sloan Kettering Cancer Center (MSKCC).ResultsIn comparison with the APC-mutant (APC-MT) population (n = 255), APC-WT patients (n = 86) tended to be younger (59% of age < 40 vs. 26% of age > 50), right-sided (41.7% vs. 27%), BRAFV600E mutated (23.3% vs. 0.8%), and KRAS wild type (65.1% vs. 49.8%). Alternative WNT pathway alterations, RNF43 and CTNNB1, were over-represented in the APC-WT versus APC-MT population (7% vs. 0.4% and 4.7% vs. 0.4%, respectively). APC-WT patients had a worse overall survival (OS) than APC-MT patients (22.6 vs. 45.6 months, p < .0001). Using a multivariate model correcting for primary tumor location, RAS and BRAF status, APC-WT was predictive of poor survival (APC-MT vs. APC-WT, hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.44-0.86, p = .0037). The prognostic implication of APC-WT on OS was confirmed further in a similar multivariate model of 934 stage IV patients from MSKCC public database (APC-MT vs. APC-WT, HR, 0.63, 95% CI, 0.49-0.81, p < .0001).ConclusionAPC-WT is associated with poor OS in MSS mCRC regardless of RAS and BRAF status. Compared with APC-MT mCRC tumors, APC-WT tumors were associated with other Wnt activating alterations, including RNF43 and CTNBB1. Our data suggest alternative therapy needs to be investigated in APC-WT patients.Implications for practicePatients with microsatellite stable metastatic colorectal cancer with wild-type APC had a worse overall survival than patients with mutated APC regardless of RAS/RAF status. APC status should be considered as a stratification factor in prospective trials, and novel therapeutic strategies need to be developed for this subgroup of patients.

Dataset Information

T cell-inflamed gene expression profile is associated with favorable disease-specific survival in non-hypermutated microsatellite-stable colorectal cancer patients.

Background

Methods

Results

Conclusions

Publications

T cell-inflamed gene expression profile is associated with favorable disease-specific survival in non-hypermutated microsatellite-stable colorectal cancer patients.

Similar Datasets

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