Breast cancer genome and transcriptome integration implicates specific mutational signatures with immune cell infiltration (original) (raw)
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Immune Gene Expression Is Associated with Genomic Aberrations in Breast Cancer
Cancer research, 2017
The presence of tumor-infiltrating lymphocytes (TIL) is a favorable prognostic factor in breast cancer, but what drives immune infiltration remains unknown. Here we examine if clonal heterogeneity, total mutation load, neoantigen load, copy number variations (CNV), gene- or pathway-level somatic mutations, or germline polymorphisms (SNP) are associated with immune metagene expression in breast cancer subtypes. Thirteen published immune metagenes correlated separately with genomic metrics in the three major breast cancer subtypes. We analyzed RNA-Seq, DNA copy number, mutation and germline SNP data of 627 ER(+), 207 HER2(+), and 191 triple-negative (TNBC) cancers from The Cancer Genome Atlas. P-values were adjusted for multiple comparisons, and permutation testing was used to assess false discovery rates. Increased immune metagene expression associated significantly with lower clonal heterogeneity estimated by MATH score in all subtypes and with a trend for lower overall mutation, ne...
OncoImmunology, 2017
Cancer immunotherapy is revolutionizing the clinical management of several tumors, but has demonstrated limited activity in breast cancer. The development of more effective treatments is hindered by incomplete knowledge of the genetic determinant of immune responsiveness. To fill this gap, we mined copy number alteration, somatic mutation, and expression data from The Cancer Genome Atlas (TCGA). By using RNA-sequencing data from 1,004 breast cancers, we defined distinct immune phenotypes characterized by progressive expression of transcripts previously associated with immunemediated rejection. The T helper 1 (Th-1) phenotype (ICR4), which also displays upregulation of immuneregulatory transcripts such as PDL1, PD1, FOXP3, IDO1, and CTLA4, was associated with prolonged patients' survival. We validated these findings in an independent meta-cohort of 1,954 breast cancer gene expression data. Chromosome segment 4q21, which includes genes encoding for the Th-1 chemokines CXCL9-11, was significantly amplified only in the immune favorable phenotype (ICR4). The mutation and neoantigen load progressively decreased from ICR4 to ICR1 but could not fully explain immune phenotypic differences. Mutations of TP53 were enriched in the immune favorable phenotype (ICR4). Conversely, the presence of MAP3K1 and MAP2K4 mutations were tightly associated with an immuneunfavorable phenotype (ICR1). Using both the TCGA and the validation dataset, the degree of MAPK deregulation segregates breast tumors according to their immune disposition. These findings suggest that mutation-driven perturbations of MAPK pathways are linked to the negative regulation of intratumoral immune response in breast cancer. Modulations of MAPK pathways could be experimentally tested to enhance breast cancer immune sensitivity.
PLoS medicine, 2016
Immune infiltration of breast tumours is associated with clinical outcome. However, past work has not accounted for the diversity of functionally distinct cell types that make up the immune response. The aim of this study was to determine whether differences in the cellular composition of the immune infiltrate in breast tumours influence survival and treatment response, and whether these effects differ by molecular subtype. We applied an established computational approach (CIBERSORT) to bulk gene expression profiles of almost 11,000 tumours to infer the proportions of 22 subsets of immune cells. We investigated associations between each cell type and survival and response to chemotherapy, modelling cellular proportions as quartiles. We found that tumours with little or no immune infiltration were associated with different survival patterns according to oestrogen receptor (ER) status. In ER-negative disease, tumours lacking immune infiltration were associated with the poorest prognos...
Tumor mutational burden is a determinant of immune-mediated survival in breast cancer
OncoImmunology, 2018
Mounting evidence supports a role for the immune system in breast cancer outcomes. The ability to distinguish highly immunogenic tumors susceptible to anti-tumor immunity from weakly immunogenic or inherently immune-resistant tumors would guide development of therapeutic strategies in breast cancer. Genomic, transcriptomic and clinical data from The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) breast cancer cohorts were used to examine statistical associations between tumor mutational burden (TMB) and the survival of patients whose tumors were assigned to previously-described prognostic immune subclasses reflecting favorable, weak or poor immuneinfiltrate dispositions (FID, WID or PID, respectively). Tumor immune subclasses were associated with survival in patients with high TMB (TMB-Hi, P < 0.001) but not in those with low TMB (TMB-Lo, P = 0.44). This statistical relationship was confirmed in the METABRIC cohort (TMB-Hi, P = 0.047; TMB-Lo, P = 0.39), and also found to hold true in the more-indolent Luminal A tumor subtype (TMB-Hi, P = 0.011; TMB-Lo, P = 0.91). In TMB-Hi tumors, the FID subclass was associated with prolonged survival independent of tumor stage, molecular subtype, age and treatment. Copy number analysis revealed the reproducible, preferential amplification of chromosome 1q immune-regulatory genes in the PID immune subclass. These findings demonstrate a previously unappreciated role for TMB as a determinant of immune-mediated survival of breast cancer patients and identify candidate immune-regulatory mechanisms associated with immunologically cold tumors. Immune subtyping of breast cancers may offer opportunities for therapeutic stratification.
Immune DNA signature of T-cell infiltration in breast tumor exomes
2016
Tumor infiltrating lymphocytes (TILs) have been associated with favorable prognosis in multiple tumor types. The Cancer Genome Atlas (TCGA) represents the largest collection of cancer molecular data, but lacks detailed information about the immune environment. Here, we show that exome reads mapping to the complementarity-determining-region 3 (CDR3) of mature T-cell receptor beta (TCRB) can be used as an immune DNA (iDNA) signature. Specifically, we propose a method to identify CDR3 reads in a breast tumor exome and validate it using deep TCRB sequencing. In 1,078 TCGA breast cancer exomes, the fraction of CDR3 reads was associated with TILs fraction, tumor purity, adaptive immunity gene expression signatures and improved survival in Her2+ patients. Only 2/839 TCRB clonotypes were shared between patients and none associated with a specific HLA allele or somatic driver mutations. The iDNA biomarker enriches the comprehensive dataset collected through TCGA, revealing associations with ...
Journal for ImmunoTherapy of Cancer, 2014
The abundance and functional orientation of tumorinfiltrating effector cells has long been observed to predict for reduced incidence of clinical metastasis and cancer-specific death. Using bioinformatics to mine large breast tumor microarray datasets, we and others have identified prognostic immune gene signatures, or metagenes. Robust evidence indicates that these metagenes are: 1) positively correlated with distant metastasis-free survival (DMFS) of patients, 2) comprised of genes that regulate immune cell-specific biology, and 3) reflective of the relative abundance of discernible populations of tumor infiltrating leukocytes. In recent work we have leveraged the statistical associations between the immune metagenes and the DMFS of breast cancer patients to explore the underlying phenotypes that differ in their ability to potentiate long-term, immunemediated tumor rejection. Using a tumor classification model that combines the prognostic attributes of three distinct immune metagenes, termed the B/P, T/NK and M/D metagenes, we have identified molecular subtypes of breast cancer that either permit or prohibit prognostication by the immune metagenes. On this basis, we have delineated the phenotypic attributes of breast cancer that distinguish two novel immunogenic tumor subtypes, which we have defined as: immune benefit-enabled (IBE) and immune benefit-disabled (IBD). Phenotypically, IBE tumors comprise of Basal-like tumors and highly-proliferative HER2-Enriched and Luminal-B subtypes, while IBD tumors comprise of Claudin-Low, Luminal-A, and low-proliferative HER2-Enriched and Luminal-B tumors. Prognostically, IBE tumors (n = 666) can be stratified by the immune metagene model into prognostic subgroups with high statistical significance (P<0.0001,log-rank test), while IBD tumors cannot (n = 1005, P = 0.3) consistent with the capacity for an innate anti-tumor immunity against IBE tumors, but not IBD tumors, that guards against distant metastasis. Furthermore, these observations were independent of adjuvant treatment, and may owe to differential activation of immunomodulatory pathways. Network analysis revealed that IBE/IBD differentially-expressed genes (q<0.01) underlie highly-significant pathway activation scores for TGF-beta signaling in IBD (p < 0.0001), and Interferon-gamma signaling in IBE (p < 0.0001). Furthermore, 15 of 19 genes comprising the previously described Immunologic Constant of Rejection (Marincola and colleagues) were significantly overexpressed in IBE tumors (P-value range: 0.05-3.5E-14). Thus, we conclude that breast tumors can be dichotomized into two subtypes fundamentally distinct with respect to their potential for metastasis-protective immune responsiveness. These findings indicate new contexts for studying anti-tumor immunity and oncogenic mechanisms of immunosuppression in breast cancer. Whether IBE and IBD subtypes represent clinically-relevant contexts for assessing patient prognosis or evaluating the efficacy of immunotherapeutic treatments warrants further investigation (See .
Molecular cancer therapeutics, 2016
Inflammatory breast cancer (IBC) is a rare and aggressive form of breast cancer that remains poorly understood at the molecular level. Comprehensive tumor profiling was performed to understand clinically actionable alterations in IBC. Targeted-next-generation sequencing and IHC were performed to identify activated pathways in IBC tumor tissues. siRNA studies examined the impact of IBC genomic variants in cellular models. IBC tumor tissues were further characterized for immune infiltration and immune checkpoint expression by IHC. Genomic analysis identified recurrent alterations in core biological pathways including activating and targetable variants in HER/PI3K/mTOR signaling. High rates of activating HER3 point mutations were discovered in IBC tumors. Cell line studies confirmed a role for mutant HER3 in IBC cell proliferation. Immunological analysis revealed a subset of IBC tumors associated with high CD8+/PD-L1+ lymphocyte infiltration. Immune infiltration positively correlated w...
Oncotarget, 2017
The tumor microenvironment is now widely recognized for its role in tumor progression, treatment response, and clinical outcome. The intratumoral immunological landscape, in particular, has been shown to exert both pro-tumorigenic and anti-tumorigenic effects. Identifying immunologically active or silent tumors may be an important indication for administration of therapy, and detecting early infiltration patterns may uncover factors that contribute to early risk. Thus far, direct detailed studies of the cell composition of tumor infiltration have been limited; with some studies giving approximate quantifications using immunohistochemistry and other small studies obtaining detailed measurements by isolating cells from excised tumors and sorting them using flow cytometry. Herein we utilize a machine learning based approach to identify lymphocyte markers with which we can quantify the presence of B cells, cytotoxic T-lymphocytes, T-helper 1, and T-helper 2 cells in any gene expression data set and apply it to studies of breast tissue. By leveraging over 2,100 samples from existing large scale studies, we are able to find an inherent cell heterogeneity in clinically characterized immune infiltrates, a strong link between estrogen receptor activity and infiltration in normal and tumor tissues, changes with genomic complexity, and identify characteristic differences in lymphocyte expression among molecular groupings. With our extendable methodology for capturing cell type specific signal we systematically studied immune infiltration in breast cancer, finding an inverse correlation between beneficial lymphocyte infiltration and estrogen receptor activity in normal breast tissue and reduced infiltration in estrogen receptor negative tumors with high genomic complexity.
Gland Surgery, 2021
Background: Whether tumor mutation burden (TMB) correlated with improved survival outcomes or promotion of immunotherapies remained controversy in various malignancies. We aimed to explore the prognostic value of TMB and the relationship between TMB and immune infiltration in human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC). Methods: We downloaded somatic mutation data and clinical information for 216 HER2+ BC patients from the The Cancer Genome Atlas (TCGA) and cBioPortal databases. Patients were divided into highand low-TMB groups through TMB calculation. Cox regression analysis was used to establish an immuneand mutant-related risk model based on 5-hub genes. The relationship between 5-hub genes mutants and the level of immune infiltration, as well as the relationship between the risk model and the immune microenvironment were analyzed by "TIMER" database. Results: TMB was negatively correlated with overall survival (OS) and disease-free survival (DFS), and high TMB may inhibit immune infiltration in HER2+ BC. Furthermore, risk score classified effectively patients into low-and high-risk groups in training and validation cohorts. The infiltration of CD4 + T cells and NK cells and the levels of immune checkpoint pathway genes were lower in the high-risk group, which indicated a poor prognosis. Conclusions: Higher TMB correlated with poor survival outcomes and might inhibit the immune infiltrates in HER2+ BC. The 5-hub TMB-related signature conferred lower immune cells infiltration which deserved further validation.
Metaplastic breast cancers: Genomic profiling, mutational burden and tumor-infiltrating lymphocytes
The Breast, 2018
Metaplastic breast cancer (MPBC) is a rare subtype that accounts for <1% of all breast cancers. Although these are typically "triple negative," they are relatively chemotherapy-refractory compared to conventional triple negative invasive breast cancers with more aggressive features and an overall poor prognosis. MPBC is a heterogeneous group of tumors that are enriched for TP53 and PIK3CA mutations, and have been found to have high PD-L1 expression though the mechanisms underlying its immunogenicity remain unclear. We perform comprehensive genomic profiling in the largest MPBC dataset (n=192) to date and assess for other potential biomarkers of immune response.