Comprehensive Analysis of the Immunogenomics of Triple-Negative Breast Cancer Brain Metastases From LCCC1419
BackgroundTriple negative breast cancer (TNBC) is an aggressive variant of breast cancer that lacks the expression of estrogen and progesterone receptors (ER and PR) and HER2. Nearly 50% of patients with advanced TNBC will develop brain metastases (BrM), commonly with progressive extracranial diseas...
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Frontiers Media S.A.
2022-07-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2022.818693/full |
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| author | Eric D. Routh Amanda E. D. Van Swearingen Maria J. Sambade Steven Vensko Marni B. McClure Marni B. McClure Mark G. Woodcock Mark G. Woodcock Shengjie Chai Shengjie Chai Luz A. Cuaboy Amy Wheless Amy Garrett Lisa A. Carey Lisa A. Carey Alan P. Hoyle Joel S. Parker Joel S. Parker Benjamin G. Vincent Benjamin G. Vincent Benjamin G. Vincent Benjamin G. Vincent Benjamin G. Vincent Carey K. Anders Carey K. Anders |
| author_facet | Eric D. Routh Amanda E. D. Van Swearingen Maria J. Sambade Steven Vensko Marni B. McClure Marni B. McClure Mark G. Woodcock Mark G. Woodcock Shengjie Chai Shengjie Chai Luz A. Cuaboy Amy Wheless Amy Garrett Lisa A. Carey Lisa A. Carey Alan P. Hoyle Joel S. Parker Joel S. Parker Benjamin G. Vincent Benjamin G. Vincent Benjamin G. Vincent Benjamin G. Vincent Benjamin G. Vincent Carey K. Anders Carey K. Anders |
| author_sort | Eric D. Routh |
| collection | DOAJ |
| description | BackgroundTriple negative breast cancer (TNBC) is an aggressive variant of breast cancer that lacks the expression of estrogen and progesterone receptors (ER and PR) and HER2. Nearly 50% of patients with advanced TNBC will develop brain metastases (BrM), commonly with progressive extracranial disease. Immunotherapy has shown promise in the treatment of advanced TNBC; however, the immune contexture of BrM remains largely unknown. We conducted a comprehensive analysis of TNBC BrM and matched primary tumors to characterize the genomic and immune landscape of TNBC BrM to inform the development of immunotherapy strategies in this aggressive disease.MethodsWhole-exome sequencing (WES) and RNA sequencing were conducted on formalin-fixed, paraffin-embedded samples of BrM and primary tumors of patients with clinical TNBC (n = 25, n = 9 matched pairs) from the LCCC1419 biobank at UNC—Chapel Hill. Matched blood was analyzed by DNA sequencing as a comparison for tumor WES for the identification of somatic variants. A comprehensive genomics assessment, including mutational and copy number alteration analyses, neoantigen prediction, and transcriptomic analysis of the tumor immune microenvironment were performed.ResultsPrimary and BrM tissues were confirmed as TNBC (23/25 primaries, 16/17 BrM) by immunohistochemistry and of the basal intrinsic subtype (13/15 primaries and 16/19 BrM) by PAM50. Compared to primary tumors, BrM demonstrated a higher tumor mutational burden. TP53 was the most frequently mutated gene and was altered in 50% of the samples. Neoantigen prediction showed elevated cancer testis antigen- and endogenous retrovirus-derived MHC class I-binding peptides in both primary tumors and BrM and predicted that single-nucleotide variant (SNV)-derived peptides were significantly higher in BrM. BrM demonstrated a reduced immune gene signature expression, although a signature associated with fibroblast-associated wound healing was elevated in BrM. Metrics of T and B cell receptor diversity were also reduced in BrM.ConclusionsBrM harbored higher mutational burden and SNV-derived neoantigen expression along with reduced immune gene signature expression relative to primary TNBC. Immune signatures correlated with improved survival, including T cell signatures. Further research will expand these findings to other breast cancer subtypes in the same biobank. Exploration of immunomodulatory approaches including vaccine applications and immune checkpoint inhibition to enhance anti-tumor immunity in TNBC BrM is warranted. |
| first_indexed | 2024-12-10T17:25:09Z |
| format | Article |
| id | doaj.art-15f0d0e7c2c44235bb8dc96191eb0af9 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-10T17:25:09Z |
| publishDate | 2022-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-15f0d0e7c2c44235bb8dc96191eb0af92022-12-22T01:39:51ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2022-07-011210.3389/fonc.2022.818693818693Comprehensive Analysis of the Immunogenomics of Triple-Negative Breast Cancer Brain Metastases From LCCC1419Eric D. Routh0Amanda E. D. Van Swearingen1Maria J. Sambade2Steven Vensko3Marni B. McClure4Marni B. McClure5Mark G. Woodcock6Mark G. Woodcock7Shengjie Chai8Shengjie Chai9Luz A. Cuaboy10Amy Wheless11Amy Garrett12Lisa A. Carey13Lisa A. Carey14Alan P. Hoyle15Joel S. Parker16Joel S. Parker17Benjamin G. Vincent18Benjamin G. Vincent19Benjamin G. Vincent20Benjamin G. Vincent21Benjamin G. Vincent22Carey K. Anders23Carey K. Anders24Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United StatesLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United StatesLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United StatesLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United StatesLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United StatesNational Cancer Center Research Institute, Tokyo, JapanLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United StatesDepartment of Medicine, Division of Medical Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United StatesLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United StatesCurriculum in Bioinformatics and Computational Biology, UNC School of Medicine, Chapel Hill, NC, United StatesLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United StatesLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United StatesLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United StatesLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United StatesDepartment of Medicine, Division of Medical Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United StatesLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United StatesLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United StatesDepartment of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, United StatesLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United StatesDepartment of Medicine, Division of Medical Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United StatesCurriculum in Bioinformatics and Computational Biology, UNC School of Medicine, Chapel Hill, NC, United StatesDepartment of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United StatesDivision of Hematology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United StatesLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United StatesDepartment of Medicine, Division of Medical Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United StatesBackgroundTriple negative breast cancer (TNBC) is an aggressive variant of breast cancer that lacks the expression of estrogen and progesterone receptors (ER and PR) and HER2. Nearly 50% of patients with advanced TNBC will develop brain metastases (BrM), commonly with progressive extracranial disease. Immunotherapy has shown promise in the treatment of advanced TNBC; however, the immune contexture of BrM remains largely unknown. We conducted a comprehensive analysis of TNBC BrM and matched primary tumors to characterize the genomic and immune landscape of TNBC BrM to inform the development of immunotherapy strategies in this aggressive disease.MethodsWhole-exome sequencing (WES) and RNA sequencing were conducted on formalin-fixed, paraffin-embedded samples of BrM and primary tumors of patients with clinical TNBC (n = 25, n = 9 matched pairs) from the LCCC1419 biobank at UNC—Chapel Hill. Matched blood was analyzed by DNA sequencing as a comparison for tumor WES for the identification of somatic variants. A comprehensive genomics assessment, including mutational and copy number alteration analyses, neoantigen prediction, and transcriptomic analysis of the tumor immune microenvironment were performed.ResultsPrimary and BrM tissues were confirmed as TNBC (23/25 primaries, 16/17 BrM) by immunohistochemistry and of the basal intrinsic subtype (13/15 primaries and 16/19 BrM) by PAM50. Compared to primary tumors, BrM demonstrated a higher tumor mutational burden. TP53 was the most frequently mutated gene and was altered in 50% of the samples. Neoantigen prediction showed elevated cancer testis antigen- and endogenous retrovirus-derived MHC class I-binding peptides in both primary tumors and BrM and predicted that single-nucleotide variant (SNV)-derived peptides were significantly higher in BrM. BrM demonstrated a reduced immune gene signature expression, although a signature associated with fibroblast-associated wound healing was elevated in BrM. Metrics of T and B cell receptor diversity were also reduced in BrM.ConclusionsBrM harbored higher mutational burden and SNV-derived neoantigen expression along with reduced immune gene signature expression relative to primary TNBC. Immune signatures correlated with improved survival, including T cell signatures. Further research will expand these findings to other breast cancer subtypes in the same biobank. Exploration of immunomodulatory approaches including vaccine applications and immune checkpoint inhibition to enhance anti-tumor immunity in TNBC BrM is warranted.https://www.frontiersin.org/articles/10.3389/fonc.2022.818693/fulltriple-negative breast cancerbrain metastasesimmunogenomicswhole-exome sequencingmRNA sequencingbiobank |
| spellingShingle | Eric D. Routh Amanda E. D. Van Swearingen Maria J. Sambade Steven Vensko Marni B. McClure Marni B. McClure Mark G. Woodcock Mark G. Woodcock Shengjie Chai Shengjie Chai Luz A. Cuaboy Amy Wheless Amy Garrett Lisa A. Carey Lisa A. Carey Alan P. Hoyle Joel S. Parker Joel S. Parker Benjamin G. Vincent Benjamin G. Vincent Benjamin G. Vincent Benjamin G. Vincent Benjamin G. Vincent Carey K. Anders Carey K. Anders Comprehensive Analysis of the Immunogenomics of Triple-Negative Breast Cancer Brain Metastases From LCCC1419 Frontiers in Oncology triple-negative breast cancer brain metastases immunogenomics whole-exome sequencing mRNA sequencing biobank |
| title | Comprehensive Analysis of the Immunogenomics of Triple-Negative Breast Cancer Brain Metastases From LCCC1419 |
| title_full | Comprehensive Analysis of the Immunogenomics of Triple-Negative Breast Cancer Brain Metastases From LCCC1419 |
| title_fullStr | Comprehensive Analysis of the Immunogenomics of Triple-Negative Breast Cancer Brain Metastases From LCCC1419 |
| title_full_unstemmed | Comprehensive Analysis of the Immunogenomics of Triple-Negative Breast Cancer Brain Metastases From LCCC1419 |
| title_short | Comprehensive Analysis of the Immunogenomics of Triple-Negative Breast Cancer Brain Metastases From LCCC1419 |
| title_sort | comprehensive analysis of the immunogenomics of triple negative breast cancer brain metastases from lccc1419 |
| topic | triple-negative breast cancer brain metastases immunogenomics whole-exome sequencing mRNA sequencing biobank |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2022.818693/full |
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