Mariko Asaoka1,2, Santosh K Patnaik3, Frank Zhang4, Takashi Ishikawa2, Kazuaki Takabe5,6,7,8,9. 1. Department of Breast Surgery, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. 2. Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo, Japan. 3. Department of Thoracic Surgery, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. 4. Giesel School of Medicine at Dartmouth, Hanover, NH, USA. 5. Department of Breast Surgery, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. kazuaki.takabe@roswellpark.org. 6. Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo, Japan. kazuaki.takabe@roswellpark.org. 7. Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New York, Buffalo, NY, USA. kazuaki.takabe@roswellpark.org. 8. Department of Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan. kazuaki.takabe@roswellpark.org. 9. Department of Surgery, Yokohama City University, Yokohama, Japan. kazuaki.takabe@roswellpark.org.
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.
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.
Entities:
Keywords:
Breast cancer; Cell proliferation; Lymphatic invasion; Lymphovascular invasion; Transcriptome
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