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Immunogenomic analysis of human brain metastases reveals diverse immune landscapes across genetically distinct tumors.

ABSTRACT: Brain metastases (BrMs) are the most common form of brain tumors in adults and frequently originate from lung and breast primary cancers. BrMs are associated with high mortality, emphasizing the need for more effective therapies. Genetic profiling of primary tumors is increasingly used as part of the effort to guide targeted therapies against BrMs, and immune-based strategies for the treatment of metastatic cancer are gaining momentum. However, the tumor immune microenvironment (TIME) of BrM is extremely heterogeneous, and whether specific genetic profiles are associated with distinct immune states remains unknown. Here, we perform an extensive characterization of the immunogenomic landscape of human BrMs by combining whole-exome/whole-genome sequencing, RNA sequencing of immune cell populations, flow cytometry, immunofluorescence staining, and tissue imaging analyses. This revealed unique TIME phenotypes in genetically distinct lung- and breast-BrMs, thereby enabling the development of personalized immunotherapies tailored by the genetic makeup of the tumors.

SUBMITTER: Alvarez-Prado AF

PROVIDER: S-EPMC9873981 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Immunogenomic analysis of human brain metastases reveals diverse immune landscapes across genetically distinct tumors.

Álvarez-Prado Ángel F ÁF Maas Roeltje R RR Soukup Klara K Klemm Florian F Kornete Mara M Krebs Fanny S FS Zoete Vincent V Berezowska Sabina S Brouland Jean-Philippe JP Hottinger Andreas F AF Daniel Roy T RT Hegi Monika E ME Joyce Johanna A JA

Cell reports. Medicine 20230101 1

Brain metastases (BrMs) are the most common form of brain tumors in adults and frequently originate from lung and breast primary cancers. BrMs are associated with high mortality, emphasizing the need for more effective therapies. Genetic profiling of primary tumors is increasingly used as part of the effort to guide targeted therapies against BrMs, and immune-based strategies for the treatment of metastatic cancer are gaining momentum. However, the tumor immune microenvironment (TIME) of BrM is ...[more]

PMID: 36652909

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Project description:ImportanceMerkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine carcinoma. In rare cases, the development of an additional cutaneous MCC tumor is clinically consistent with a second primary MCC tumor rather than a cutaneous metastasis, which has important treatment and prognostic implications.ObjectiveTo evaluate genetic relatedness in 4 cases with the clinical diagnosis of multiple primary MCCs.Design, setting, and participantsIn this case series, 7 cases of clinically designated multiple primary MCC were identified; 4 cases met inclusion criteria for next-generation sequencing (NGS) analysis. Mutations, copy number alterations, and Merkel cell polyomavirus (MCPyV) sequence were analyzed and compared between clinically designated multiple primary tumors to characterize genetic relatedness and hence assess clonality. Patients with clinically designated multiple primary MCC were identified from the multidisciplinary MCC Program at the University of Michigan, a tertiary care center.Main outcomes and measuresFour cases of clinically designated multiple primary MCC were characterized by tumor sequencing and targeted MCPyV sequencing to distinguish independent primary tumors from related metastases.ResultsOverall, 4 patients in their 70s or 80s were included and analyzed. Cases 1 and 4 were verified as genetically distinct primary tumors and did not harbor similar copy number alterations or demonstrate significant mutational overlap. Cases 2 and 3 were designated as clonally related based on overlapping copy number alterations. In clonally related tumors, chromosomal copy number changes were more reliable than mutations for demonstrating clonality. Regardless of clonality, we found that MCPyV status was concordant for all tumor pairs and MCPyV positive tumors harbored predominatly subclonal mutations.Conclusions and relevanceOur findings suggest that patients with MCC may develop a second genetically distinct primary tumor; in this case, the subsequent tumor is likely to develop through similar mechanisms of pathogenesis, either MCPyV-mediated or ultraviolet light-mediated. Next-generation sequencing analysis of chromosomal copy number changes and mutations is useful in distinguishing multiple primary MCCs from progression of MCC clinically resembling multiple primaries, allowing appropriate staging of the patient.

Dataset Information

Immunogenomic analysis of human brain metastases reveals diverse immune landscapes across genetically distinct tumors.

Publications

Immunogenomic analysis of human brain metastases reveals diverse immune landscapes across genetically distinct tumors.

Similar Datasets

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