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Lymphovascular invasion in breast cancer is associated with gene expression signatures of cell proliferation but not lymphangiogenesis or immune response

  • Preclinical study
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Background

While the prognostic relevance of lymphovascular invasion (LVI) in breast cancer is well known, its molecular biology is poorly understood. We hypothesized that pathologically determined LVI reflects molecular features of tumors and can be discerned from their genomic and transcriptomic profiles.

Methods

LVI status and Nottingham histological scores of primary breast tumors of The Cancer Genome Atlas (TCGA) project were assessed from pathology reports; other clinical and molecular data were obtained from TCGA data portals and publications. Two independent datasets (GSE5460 and GSE7849) were combined and used for validation.

Results

LVI status was determinable for 639 and 196 cases of the TCGA and validation cohorts, among whom LVI incidence was 37.8% and 37.2%, respectively. LVI was associated with high tumor Ki67 expression, advanced pathologic stage, and high Nottingham scores. LVI-positive cases had worse overall and progression-free survival regardless of cancer subtype. Surprisingly, in both cohorts, LVI was not associated with lymphangiogenesis or lymphatic vessel density as estimated from tumor expression of lymphatic endothelium-associated genes. LVI-positive tumors had higher genome copy number aberrations, aneuploidy, and homologous recombination defects, but not single-nucleotide variations or intra-tumor genome heterogeneity. Tumor immune cell composition and cytolytic activity was not associated with LVI status. On the other hand, expression of cell proliferation-related genes was significantly increased in LVI-positive tumors.

Conclusion

Our study suggests that breast cancer with LVI is a highly proliferative cancer, and it does not correlate with gene expression markers for lymphangiogenesis or immune response.

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Data availability

The GEO datasets used in this study are available at https://www.ncbi.nlm.nih.gov/geo with accession numbers GSE5460 and GSE7849. Clinical, gene-level mapped read counts of RNA sequencing data, and MAF files of TCGA-BRCA cases are available at Genome Data Commons portal of National Cancer Institute, USA at https://gdc.cancer.gov. Information on Nottingham scores and LVI status that was collated from pathology reports of the TCGA cases is in Table S2. Other data used in this study is available from sources cited in the Materials and Methods section.

Abbreviations

CNA:

Copy number alteration

ER:

Estrogen receptor

GSEA:

Gene set enrichment analysis

GSVA:

Gene set variation analysis

HER2:

Human epidermal growth factor receptor 2

HRD:

Homologous recombination defect

LEC:

Lymphatic endothelial cell

LVD:

Lymphatic vessel density

LVI:

Lymphovascular invasion

PR:

Progesterone receptor

S1P:

Sphingosine-1-phosphate

SNV:

Single-nucleotide variation

TCGA:

The Cancer Genome Atlas

TIES:

Text Information Extraction System

TPM:

Transcripts per million

tSNE:

T-distributed stochastic neighbor embedding

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Funding

This study was supported by National Institutes of Health (NIH), USA grants R01CA160688 to K.T. and R25CA181003 to Roswell Park Comprehensive Cancer Center in support of F.Z.'s research internship.

Author information

Authors and Affiliations

  1. Department of Breast Surgery, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA

    Mariko Asaoka & Kazuaki Takabe

  2. Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo, Japan

    Mariko Asaoka, Takashi Ishikawa & Kazuaki Takabe

  3. Department of Thoracic Surgery, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA

    Santosh K. Patnaik

  4. Giesel School of Medicine at Dartmouth, Hanover, NH, USA

    Frank Zhang

  5. Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New York, Buffalo, NY, USA

    Kazuaki Takabe

  6. Department of Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

    Kazuaki Takabe

  7. Department of Surgery, Yokohama City University, Yokohama, Japan

    Kazuaki Takabe

Authors
  1. Mariko Asaoka
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  2. Santosh K. Patnaik
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  3. Frank Zhang
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  4. Takashi Ishikawa
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  5. Kazuaki Takabe
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Correspondence to Kazuaki Takabe.

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Text S1—Details of methods.Table S1—Characteristics of TCGA-BRCA tumors for which LVI status was determinable or not.Table S2—Nottingham histologic scores and LVI status for TCGA-BRCA tumors examined in this study.Table S3—Members of the endothelium-specific 88-gene and xCell gene sets.Table S4—Mutation frequency among LVI-positive and -negative tumors of TCGA-BRCA cohort for ten most commonly mutated genes.Table S5—mSigDb Hallmark and Reactome gene sets with significant enrichment in LVI-positive vs. -negative tumor comparison of TCGA-BRCA cohort by GSVA method.Table S6—mSigDb Hallmark and Reactome gene sets with significant enrichment in LVI-positive vs. -negative tumor comparison of validation cohort by GSVA method.Table S7—Top 20 each of genes whose expression is significantly down- or up-regulated in LVI-positive compared to -negative tumors of TCGA-BRCA cohort.

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Asaoka, M., Patnaik, S.K., Zhang, F. et al. Lymphovascular invasion in breast cancer is associated with gene expression signatures of cell proliferation but not lymphangiogenesis or immune response. Breast Cancer Res Treat 181, 309–322 (2020). https://doi.org/10.1007/s10549-020-05630-5

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  • DOI: https://doi.org/10.1007/s10549-020-05630-5

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