Immunogenomic pathways associated with cytotoxic lymphocyte infiltration and survival in colorectal cancer
Abstract Background Colorectal cancer (CRC) is the second leading cancer killer in the US today and patients with metastatic disease have only a 14% 5-year survival. One of the most impactful recent advances in cancer therapy, immune checkpoint inhibition, has not been shown to be effective for the...
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| Format: | Article |
| Language: | English |
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BMC
2020-02-01
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| Series: | BMC Cancer |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12885-020-6513-4 |
| _version_ | 1819179652201054208 |
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| author | Yuanyuan Shen Yue Guan Justin J. Hummel Chi-Ren Shyu Jonathan B. Mitchem |
| author_facet | Yuanyuan Shen Yue Guan Justin J. Hummel Chi-Ren Shyu Jonathan B. Mitchem |
| author_sort | Yuanyuan Shen |
| collection | DOAJ |
| description | Abstract Background Colorectal cancer (CRC) is the second leading cancer killer in the US today and patients with metastatic disease have only a 14% 5-year survival. One of the most impactful recent advances in cancer therapy, immune checkpoint inhibition, has not been shown to be effective for the majority of these patients. In this study, we use The Cancer Genome Atlas (TCGA) and recently developed informatic-based tools to identify targets for immune based therapy in colorectal cancer patients. Methods Open access, pre-processed (level 3) mRNA data and clinical data from colorectal patients from the TCGA was downloaded from FireCloud. Using the Microenvironment Cell Populations-Counter method (MCP-Counter), cytotoxic lymphocyte scores were calculated for all patients. Patients were then grouped by cytotoxic lymphocyte score (High vs Low), pathologic stage, and location to identify differentially expressed genes. Pathway enrichment analysis was performed using Reactome to determine differentially expressed genes associated with immune pathways. Survival analysis was performed with identified differentially expressed genes. Results In the TCGA dataset, there are 461 colon and 172 rectal cancer patients. After stratifying patients by cytotoxic lymphocyte score, anatomical location, and stage, we found a significant number of differentially expressed genes. We identified one pathway, “immunoregulatory interactions between a lymphoid and non-lymphoid cell”, that was highly enriched and included in all tumor locations and stages. Survival analysis performed with differentially expressed genes in this pathway identified 21 different genes associated with survival and cytotoxic lymphocyte infiltration, with ~ 70% of these genes occurring in the metastatic right-sided CRC group. Specifically, all genes associated with survival in the metastatic right-sided colorectal cancer group with low cytotoxic lymphocyte scores positively impacted survival. Conclusions Utilizing the TCGA, a publicly available dataset, and informatics-based analyses, we identified potential targets to improve immune based therapy in colorectal cancer. Additionally, we note the most targets in metastatic right-sided CRC patients, the patient group with the worst predicted survival. The results from this study demonstrate the ability of informatics-based analytic techniques to identify new therapeutic targets as well as improve patient selection for intervention, helping us to achieve the goals of precision-based oncology. |
| first_indexed | 2024-12-22T22:01:51Z |
| format | Article |
| id | doaj.art-0ae303ac63e64e8ab6276dfd46b202e5 |
| institution | Directory Open Access Journal |
| issn | 1471-2407 |
| language | English |
| last_indexed | 2024-12-22T22:01:51Z |
| publishDate | 2020-02-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Cancer |
| spelling | doaj.art-0ae303ac63e64e8ab6276dfd46b202e52022-12-21T18:11:05ZengBMCBMC Cancer1471-24072020-02-0120111010.1186/s12885-020-6513-4Immunogenomic pathways associated with cytotoxic lymphocyte infiltration and survival in colorectal cancerYuanyuan Shen0Yue Guan1Justin J. Hummel2Chi-Ren Shyu3Jonathan B. Mitchem4Institute for Data Science and Informatics, University of MissouriDepartment of Surgery, University of Missouri School of MedicineInstitute for Data Science and Informatics, University of MissouriInstitute for Data Science and Informatics, University of MissouriHarry S. Truman Memorial Veterans’ HospitalAbstract Background Colorectal cancer (CRC) is the second leading cancer killer in the US today and patients with metastatic disease have only a 14% 5-year survival. One of the most impactful recent advances in cancer therapy, immune checkpoint inhibition, has not been shown to be effective for the majority of these patients. In this study, we use The Cancer Genome Atlas (TCGA) and recently developed informatic-based tools to identify targets for immune based therapy in colorectal cancer patients. Methods Open access, pre-processed (level 3) mRNA data and clinical data from colorectal patients from the TCGA was downloaded from FireCloud. Using the Microenvironment Cell Populations-Counter method (MCP-Counter), cytotoxic lymphocyte scores were calculated for all patients. Patients were then grouped by cytotoxic lymphocyte score (High vs Low), pathologic stage, and location to identify differentially expressed genes. Pathway enrichment analysis was performed using Reactome to determine differentially expressed genes associated with immune pathways. Survival analysis was performed with identified differentially expressed genes. Results In the TCGA dataset, there are 461 colon and 172 rectal cancer patients. After stratifying patients by cytotoxic lymphocyte score, anatomical location, and stage, we found a significant number of differentially expressed genes. We identified one pathway, “immunoregulatory interactions between a lymphoid and non-lymphoid cell”, that was highly enriched and included in all tumor locations and stages. Survival analysis performed with differentially expressed genes in this pathway identified 21 different genes associated with survival and cytotoxic lymphocyte infiltration, with ~ 70% of these genes occurring in the metastatic right-sided CRC group. Specifically, all genes associated with survival in the metastatic right-sided colorectal cancer group with low cytotoxic lymphocyte scores positively impacted survival. Conclusions Utilizing the TCGA, a publicly available dataset, and informatics-based analyses, we identified potential targets to improve immune based therapy in colorectal cancer. Additionally, we note the most targets in metastatic right-sided CRC patients, the patient group with the worst predicted survival. The results from this study demonstrate the ability of informatics-based analytic techniques to identify new therapeutic targets as well as improve patient selection for intervention, helping us to achieve the goals of precision-based oncology.https://doi.org/10.1186/s12885-020-6513-4Colorectal cancerColonRectumImmunotherapyImmunogenomicsImmuno-oncology |
| spellingShingle | Yuanyuan Shen Yue Guan Justin J. Hummel Chi-Ren Shyu Jonathan B. Mitchem Immunogenomic pathways associated with cytotoxic lymphocyte infiltration and survival in colorectal cancer BMC Cancer Colorectal cancer Colon Rectum Immunotherapy Immunogenomics Immuno-oncology |
| title | Immunogenomic pathways associated with cytotoxic lymphocyte infiltration and survival in colorectal cancer |
| title_full | Immunogenomic pathways associated with cytotoxic lymphocyte infiltration and survival in colorectal cancer |
| title_fullStr | Immunogenomic pathways associated with cytotoxic lymphocyte infiltration and survival in colorectal cancer |
| title_full_unstemmed | Immunogenomic pathways associated with cytotoxic lymphocyte infiltration and survival in colorectal cancer |
| title_short | Immunogenomic pathways associated with cytotoxic lymphocyte infiltration and survival in colorectal cancer |
| title_sort | immunogenomic pathways associated with cytotoxic lymphocyte infiltration and survival in colorectal cancer |
| topic | Colorectal cancer Colon Rectum Immunotherapy Immunogenomics Immuno-oncology |
| url | https://doi.org/10.1186/s12885-020-6513-4 |
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