Evaluation of basal and luminal subtypes of urothelial carcinoma in African American and non-African American patients.

305 Background: African American (AA) patients with urothelial carcinoma (UC) have been known to have a worse prognosis even when corrected for variables such as tumor stage and grade. Analysis of gene expression of several malignancies has resulted in the discovery of molecular subtypes with well-defined intrinsic biology. Recent studies in high grade (HG), muscle-invasive UC have led to the identification of two intrinsic, molecular subsets termed “luminal” and “basal” with characteristics of stages of urothelial differentiation, and that remarkably reflect the luminal and basal-like molecular subtypes of breast cancer. Patients with basal-like UC have a significantly worse overall survival. Methods: A total of 215 HG muscle-invasive UC tumors from the MDACC (n=75) and TCGA (n=140) were used to make intrinsic subtype calls using gene expression profiling (MDACC: DASL [cDNA-mediated Annealing, Selection, extension, and Ligation] and TCGA: RNA seq). Basal and luminal subtype calls were derived using previously published subtype classifiers (Damrauer et. al. PNAS, 2014 and Choi et. al. Cancer Cell, 2014). Patients were classified into AA and non-AA (white, Hispanic, or Asian) based upon self-reported race. Results: In total there were 16 and 199 tumors from AA and non-AA patients respectively. In non-AA patients, the proportion of tumors that were classified as basal and luminal were approximately equal (93 and 106 respectively), while in AA patients, there was enrichment of basal tumors (12 basal and 4 luminal) (p=0.03735, Fisher’s exact test). Conclusions: AA patients are enriched in the basal molecular subtype of UC. Similar findings have been previously documented in AA women with breast cancer. The enrichment of basal UC in AAs suggests that a biological explanation may in part underlie the poor outcomes seen in AA patients. Future studies will explore the prognostic and predictive implications of basal subtype in AA patients with UC.

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PAX5 expression associates with survival in triple negative breast cancer.

10.31219/osf.io/rh6xb ◽

2021 ◽

Author(s):

Shahan Mamoor

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Cancer Patients ◽

Triple Negative Breast Cancer ◽

Microarray Data ◽

Triple Negative ◽

Molecular Subtype ◽

Breast Cancer Patients ◽

Primary Tumors ◽

Significant Gene

We mined published microarray data (1) to understand the most significant gene expression differences in the tumors of triple negative breast cancer patients based on survival following treatment: dead or alive. We observed significant transcriptome-wide differential expression of paired box 5, encoded by PAX5 when comparing the primary tumors of triple negative breast cancer patients dead or alive. Importantly, PAX5 expression was significantly correlated with overall survival in basal subtype breast cancer, a molecular subtype sharing significant overlap with triple negative breast cancer. PAX5 may be of relevance as a biomarker or as a molecule of interest in understanding the etiology or progression of triple negative breast cancer.

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Predictive and prognostic role of tumour-infiltrating lymphocytes in breast cancer patients with different molecular subtypes: a meta-analysis

BMC Cancer ◽

10.1186/s12885-020-07654-y ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Zhao-hua Gao ◽

Cun-xin Li ◽

Ming Liu ◽

Jia-yuan Jiang

Keyword(s):

Breast Cancer ◽

Neoadjuvant Chemotherapy ◽

Cancer Patients ◽

Predictive Value ◽

Molecular Subtypes ◽

Molecular Subtype ◽

Meta Analysis ◽

Breast Cancer Patients ◽

Tumour Infiltrating Lymphocytes ◽

Infiltrating Lymphocytes

Abstract Background Whether tumour-infiltrating lymphocytes (TILs) play different roles in different molecular subtypes of breast cancer remains unknown. Additionally, their prognostic and predictive value in different molecular subtypes of breast cancer is still controversial. The aim of our meta-analysis was to assess the prognostic and predictive value of TILs in different molecular subtypes of breast cancer by summarizing all relevant studies performing multivariate analysis. Methods PubMed, Embase, EBSCO, ScienceDirect, the Cochrane Database and Web of Science were comprehensively searched (until March 2020). Hazard ratios (HRs), odds ratios (ORs) and their 95% confidence intervals (CIs) were used as effect measures to perform our meta-analysis. A random effect model was used. Stata software, version 15 (2017) (StataCorp, College Station, TX, USA) was used to perform the statistical analysis. Results Thirty-three studies including 18,170 eligible breast cancer patients were analysed. The meta-analysis showed that high TIL expression was significantly associated with increased pathological complete response (pCR) rates after neoadjuvant chemotherapy in patients with the HER2-enriched molecular subtype (OR = 1.137, 95% CI [1.061 ~ 1.218], p < 0.001) and triple-negative breast cancer (TNBC) subtype (OR = 1.120, 95% CI [1.061 ~ 1.182], p < 0.001). However, high TIL expression was not significantly associated with high pCR rates after neoadjuvant chemotherapy in patients with the luminal molecular subtype of breast cancer (OR = 1.154, 95% CI [0.789 ~ 1.690], p = 0.460). We carried out a meta-analysis on the HRs of overall survival (OS) and disease-free survival (DFS) to assess the prognostic value of TILs in breast cancer with different molecular subtypes more deeply. Our meta-analysis confirmed that high TILs were associated with significantly improved DFS in patients with the HER2-enriched molecular subtype [HR = 0.940, 95% CI (0.903 ~ 0.979), p = 0.003] and TNBC molecular subtype [HR = 0.907, 95% CI (0.862 ~ 0.954), p < 0.001]. However, high TILs were not associated with significantly better DFS in patients with the luminal molecular subtype of breast cancer [HR = 0.998, 95% CI (0.977 ~ 1.019), p = 0.840]. Furthermore, the results confirmed that high TILs were significantly related to better OS in patients with the HER2-enriched molecular subtype [HR = 0.910, 95% CI (0.866 ~ 0.957), p < 0.001] and TNBC molecular subtype [HR = 0.869, 95% CI (0.836 ~ 0.904), p < 0.001]. Conversely, the summarized results indicated that high TILs were significantly associated with poor OS in patients with the luminal molecular subtype of breast cancer [HR = 1.077, 95% CI (1.016 ~ 1.141), p = 0.012]. Conclusions Our meta-analysis confirms that high TILs are associated with favourable survival and predicts pCR in breast cancer patients with the TNBC and HER2-enriched molecular subtypes.

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LAX1 expression associates with survival in triple negative breast cancer.

10.31219/osf.io/7mhje ◽

2021 ◽

Author(s):

Shahan Mamoor

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Cancer Patients ◽

Triple Negative Breast Cancer ◽

Microarray Data ◽

Triple Negative ◽

Molecular Subtype ◽

Breast Cancer Patients ◽

Primary Tumors ◽

Significant Gene

We mined published microarray data (1) to understand the most significant gene expression differences in the tumors of triple negative breast cancer patients based on survival at time of analysis: dead or alive. We observed significant transcriptome-wide differential expression of lymphocyte transmembrane adaptor 1, encoded by LAX1 when comparing the primary tumors of triple negative breast cancer patients dead or alive. Importantly, LAX1 expression was significantly correlated with overall survival in basal subtype breast cancer, a molecular subtype sharing significant overlap with triple negative breast cancer. LAX1 may be of relevance as a biomarker or as a molecule of interest in understanding the etiology or progression of triple negative breast cancer.

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SELL expression associates with survival in triple negative breast cancer.

10.31219/osf.io/mjvc9 ◽

2021 ◽

Author(s):

Shahan Mamoor

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Cancer Patients ◽

Triple Negative Breast Cancer ◽

Microarray Data ◽

Triple Negative ◽

Molecular Subtype ◽

Breast Cancer Patients ◽

Primary Tumors ◽

Significant Gene

We mined published microarray data (1) to understand the most significant gene expression differences in the tumors of triple negative breast cancer patients based on survival at time of analysis: dead or alive. We observed significant transcriptome-wide differential expression of selectin L, encoded by SELL, when comparing the primary tumors of triple negative breast cancer patients dead or alive. Importantly, SELL expression was significantly correlated with overall survival in basal subtype breast cancer, a molecular subtype sharing significant overlap with triple negative breast cancer. SELL may be of relevance as a biomarker or as a molecule of interest in understanding the etiology or progression of triple negative breast cancer.

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RASGRP1 expression associates with survival in triple negative breast cancer.

10.31219/osf.io/m2x3j ◽

2021 ◽

Author(s):

Shahan Mamoor

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Cancer Patients ◽

Triple Negative Breast Cancer ◽

Microarray Data ◽

Triple Negative ◽

Molecular Subtype ◽

Breast Cancer Patients ◽

Primary Tumors ◽

Significant Gene

We mined published microarray data (1) to understand the most significant gene expression differences in the tumors of triple negative breast cancer patients based on survival following treatment: dead or alive. We observed significant transcriptome-wide differential expression of RAS guanyl releasing protein 1 (calcium and DAG-regulated), encoded by RASGRP1 when comparing the primary tumors of triple negative breast cancer patients dead or alive. Importantly, RASGRP1 expression was correlated with overall survival in basal subtype breast cancer, a molecular subtype sharing significant overlap with triple negative breast cancer. RASGRP1 may be of relevance as a biomarker or as a molecule of interest in understanding the etiology or progression of triple negative breast cancer.

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TUBA1C expression associates with survival in triple negative breast cancer.

10.31219/osf.io/qytd6 ◽

2021 ◽

Author(s):

Shahan Mamoor

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Cancer Patients ◽

Triple Negative Breast Cancer ◽

Microarray Data ◽

Triple Negative ◽

Molecular Subtype ◽

Breast Cancer Patients ◽

Primary Tumors ◽

Significant Gene

We mined published microarray data (1) to understand the most significant gene expression differences in the tumors of triple negative breast cancer patients based on survival following treatment: dead or alive. We observed significant transcriptome-wide differential expression of tubulin, alpha 1c, encoded by TUBA1C when comparing the primary tumors of triple negative breast cancer patients dead or alive. Importantly, TUBA1C expression was correlated with overall survival in basal subtype breast cancer, a molecular subtype sharing significant overlap with triple negative breast cancer. TUBA1C may be of relevance as a biomarker or as a molecule of interest in understanding the etiology or progression of triple negative breast cancer.

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GSR expression associates with survival in triple negative breast cancer.

10.31219/osf.io/unkvz ◽

2021 ◽

Author(s):

Shahan Mamoor

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Cancer Patients ◽

Triple Negative Breast Cancer ◽

Microarray Data ◽

Triple Negative ◽

Molecular Subtype ◽

Breast Cancer Patients ◽

Primary Tumors ◽

Significant Gene

We mined published microarray data (1) to understand the most significant gene expression differences in the tumors of triple negative breast cancer patients based on survival following treatment: dead or alive. We observed significant transcriptome-wide differential expression of glutathione reductase, encoded by GSR when comparing the primary tumors of triple negative breast cancer patients dead or alive. Importantly, GSR expression was correlated with overall survival in basal subtype breast cancer, a molecular subtype sharing significant overlap with triple negative breast cancer. GSR may be of relevance as a biomarker or as a molecule of interest in understanding the etiology or progression of triple negative breast cancer.

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Single cell transcriptomics reveals molecular subtype and functional heterogeneity in models of breast cancer

10.1101/282079 ◽

2018 ◽

Cited By ~ 1

Author(s):

Daniel L. Roden ◽

Laura A. Baker ◽

Benjamin Elsworth ◽

Chia-Ling Chan ◽

Kate Harvey ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Single Cell ◽

Cell Line ◽

Molecular Subtypes ◽

Molecular Subtype ◽

Cellular Heterogeneity ◽

Breast Cancers ◽

Intrinsic Subtypes ◽

Pdx Model

AbstractBreast cancer has long been classified into a number of molecular subtypes that predict prognosis and therefore influence clinical treatment decisions. Cellular heterogeneity is also evident in breast cancers and plays a key role in the development, evolution and metastatic progression of many cancers. How clinical heterogeneity relates to cellular heterogeneity is poorly understood, so we approached this question using single cell gene expression analysis of well established in vitro and in vivo models of disease.To explore the cellular heterogeneity in breast cancer we first examined a panel of genes that define the PAM50 classifier of molecular subtype. Five breast cancer cell line models (MCF7, BT474, SKBR3, MDA-MB-231, and MDA-MB-468) were selected as representatives of the intrinsic molecular subtypes (luminal A and B, basal-like, and Her2-enriched). Single cell multiplex RT-PCR was used to isolate and quantify the gene expression of single cells from each of these models, and the PAM50 classifier applied. Using this approach, we identified heterogeneity of intrinsic subtypes at single-cell level, indicating that cells with different subtypes exist within a cell line. Using the Chromium 10X system, this study was extended into thousands of cells from the MCF7 cell-line and an ER+ patient derived xenograft (PDX) model and again identified significant intra-tumour heterogeneity of molecular subtype.Estrogen Receptor (ER) is an important driver and therapeutic target in many breast cancers. It is heterogeneously expressed in a proportion of clinical cases but the significance of this to ER activity is unknown. Significant heterogeneity in the transcriptional activation of ER regulated genes was observed within tumours. This differential activation of the ER cistrome aligned with expression of two known transcriptional co-regulatory factors of ER (FOXA1 and PGR).To examine the degree of heterogeneity for other important phenotypic traits, we used an unsupervised clustering approach to identify cellular sub-populations with diverse cancer associated transcriptional properties, such as: proliferation; hypoxia; and treatment resistance. In particular, we show that we can identify two distinct sub-populations of cells that may have denovo resistance to endocrine therapies in a treatment naïve PDX model of ER+ breast cancer. One of these consists of cells with a non-proliferative transcriptional phenotype that is enriched for transcriptional properties of ERBB2 tumours. The other is heavily enriched for components of the primary cilia. Gene regulatory networks were used to identify transcription factor regulons that are active in each cell, leading us to identify potential transcriptional drivers (such as E2F7, MYB and RFX3) of the cilia associated endocrine resistant cells. This rare subpopulation of cells also has a highly heterogenous mix of intrinsic subtypes highlighting a potential role of intra-tumour subtype heterogeneity in endocrine resistance and metastatic potential.Overall, These results suggest a high degree of cellular heterogeneity within breast cancer models, even cell lines, that can be functionally dissected into sub-populations of cells with transcriptional phenotypes of potential clinical relevance.

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Frequent Molecular Subtype Switching and Gene Expression Alterations in Lung and Pleural Metastasis From Luminal A–Type Breast Cancer

JCO Precision Oncology ◽

10.1200/po.19.00337 ◽

2020 ◽

pp. 848-859

Author(s):

Max Klebe ◽

Carlo Fremd ◽

Mark Kriegsmann ◽

Katharina Kriegsmann ◽

Thomas Albrecht ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Cell Cycle ◽

Differential Gene Expression ◽

Molecular Subtypes ◽

Molecular Subtype ◽

Cytoskeletal Proteins ◽

Luminal A ◽

Pleural Metastasis ◽

Differential Gene

PURPOSE Conversion of tumor subtype frequently occurs in the course of metastatic breast cancer but is a poorly understood phenomenon. This study aims to compare molecular subtypes with subsequent lung or pleural metastasis. PATIENTS AND METHODS In a cohort of 57 patients with breast cancer and lung or pleural metastasis (BCLPM), we investigated paired primary and metastatic tissues for differential gene expression of 269 breast cancer genes. The PAM50 classifier was applied to identify intrinsic subtypes, and differential gene expression and cluster analysis were used to further characterize subtypes and tumors with subtype conversion. RESULTS In primary breast cancer, the most frequent molecular subtype was luminal A (lumA; 49.1%); it was luminal B (lumB) in BCLPM (38.6%). Subtype conversion occurred predominantly in lumA breast cancers compared with other molecular subtypes (57.1% v 27.6%). In lumA cancers, 62 genes were identified with differential expression in metastatic versus primary disease, compared with only 10 differentially expressed genes in lumB, human epidermal growth factor receptor 2 (HER2)–enriched, and basal subtypes combined. Gene expression changes in lumA cancers affected not only the repression of the estrogen receptor pathway and cell cycle–related genes but also the WNT pathway, proteinases ( MME, MMP11), and motility-associated cytoskeletal proteins (CK5, CK14, CK17). Subtype-switched lumA cancers were further characterized by cell proliferation and cell cycle checkpoint gene upregulation and dysregulation of the p53 pathway. This involved 83 notable gene expression changes. CONCLUSION Our results indicate that gene expression changes and subsequent subtype conversion occur on a large scale in metastatic luminal A–type breast cancer compared with other molecular subtypes. This underlines the significance of molecular changes in metastatic disease, especially in tumors of initially low aggressive potential.

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Impact of mRNA-Assessed Molecular Subtype Conversion, Intact and Apoptotic Circulating Tumor Cells on Survival of Metastatic Breast Cancer Patients: Proof of Principle

Diagnostics ◽

10.3390/diagnostics10060369 ◽

2020 ◽

Vol 10 (6) ◽

pp. 369

Author(s):

Stefan Stefanovic ◽

Thomas M. Deutsch ◽

Ralph Wirtz ◽

Andreas Hartkopf ◽

Peter Sinn ◽

...

Keyword(s):

Breast Cancer ◽

Overall Survival ◽

Metastatic Breast Cancer ◽

Triple Negative ◽

Molecular Subtype ◽

Metastatic Breast ◽

Intrinsic Subtype ◽

Breast Cancer Patients ◽

Liquid Biopsies ◽

Primary Tumors

Breast cancers (BC) can mutate, allowing metastatic tumors (MT) to sometimes differ to primary tumors (PT) in gene expression. Despite contemporary metastatic breast cancer (MBC) therapy, subtype conversion seems prognostically disadvantageous. We strived to determine the influence of mRNA-assessed intrinsic subtype stability comparing PT and MT biopsies and circulating tumor cell (CTC)-based liquid biopsies on progression free survival (PFS) and overall survival (OS). Additional analyzed prognostic factors were PT subtype, MT subtype and hormone receptor loss. Kaplan-Meier curves and the log rank tests were used to compare PFSs and OSs. The proportions of luminal B and triple negative subtype MTs were increased compared to those observed in PTs. Fifteen patients were found to have tumors that underwent intrinsic subtype conversion and their OS was significantly decreased (p = 0.038). No such difference was observed when it comes to PFS. The majority of these tumors switched to a more aggressive intrinsic subtype. No significant differences in PFSs or OSs were observed between subtype converters with triple negative PTs compared to those with luminal subtype PTs. The same is true of subtype stable patients. Total CTC, iCTC and aCTC counts decreased with therapy, but there were no significant differences between subtype converters and subtype stable patients. Our data confirm a poorer overall survival of the intrinsic subtype converters and emphasize the importance of acquiring biopsies and re-biopsies of all available metastatic lesions alongside with CTC-based liquid biopsies for earlier recognition of patients with poorer prognosis and in need of altered individualized therapy regimens.

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