Delineation of Pathogenomic Insights of Breast Cancer in Young Women

Abstract

The prognosis of breast cancer (BC) in young women (BCYW) aged ≤40 years tends to be poorer than that in older patients due to aggressive phenotypes, late diagnosis, distinct biologic, and poorly understood genomic features of BCYW. Considering the estimated predisposition of only approximately 15% of the BC population to BC-promoting genes, the underlying reasons for an increased occurrence of BCYW, at large, cannot be completely explained based on general risk factors for BC. This underscores the need for the development of next-generation of tissue- and body fluid-based prognostic and predictive biomarkers for BCYW. Here, we identified the genes associated with BCYW with a particular focus on the age, intrinsic BC subtypes, matched normal or normal breast tissues, and BC laterality. In young women with BC, we observed dysregulation of age-associated cancer-relevant gene sets in both cancer and normal breast tissues, sub-sets of which substantially affected the overall survival (OS) or relapse-free survival (RFS) of patients with BC and exhibited statically significant correlations with several gene modules associated with cellular processes such as the stroma, immune responses, mitotic progression, early response, and steroid responses. For example, high expression of COL1A2, COL5A2, COL5A1, NPY1R, and KIAA1644 mRNAs in the BC and normal breast tissues from young women correlated with a substantial reduction in the OS and RFS of BC patients with increased levels of these exemplified genes. Many of the genes upregulated in BCYW were overexpressed or underexpressed in normal breast tissues, which might provide clues regarding the potential involvement of such genes in the development of BC later in life. Many of BCYW-associated gene products were also found in the extracellular microvesicles/exosomes secreted from breast and other cancer cell-types as well as in body fluids such as urine, saliva, breast milk, and plasma, raising the possibility of using such approaches in the development of non-invasive, predictive and prognostic biomarkers. In conclusion, the findings of this study delineated the pathogenomics of BCYW, providing clues for future exploration of the potential predictive and prognostic importance of candidate BCYW molecules and research strategies as well as a rationale to undertake a prospective clinical study to examine some of testable hypotheses presented here. In addition, the results presented here provide a framework to bring out the importance of geographical disparities, to overcome the current bottlenecks in BCYW, and to make the next quantum leap for sporadic BCYW research and treatment.

Extracellular Microenvironment Alterations in Ductal Carcinoma In Situ and Invasive Breast Cancer Pathologies by Multiplexed Spatial Proteomics

“…While other tryptic peptides such as m/z 1550.809 from the collagen α2(I) chain and m/z 1797.841 from the collagen α1(III) chain were localized primarily to regions outside the DCIS and IDC lesions ( Figure 6 H and Figure S9 ). In contemporary literature, a transcriptional signature including COL1A2 was associated with reduced overall survival in breast cancer [ 41 ]. Similarly, COL3A1 has been reported to have an important role in breast cancer progression as knockdown studies in triple-negative breast cancer cell lines have been linked to reduced invasion and proliferation [ 42 ].…”

Influence of age as a continuous variable on the prognosis of patients with pT1-2N1 breast cancer

“…It is possible that age-related differences reside at the molecular level or by gene expression [ 23 ]. A recent study based on breast cancer genomic datasets revealed a dysregulation of age-associated cancer-relevant gene sets in both cancer and normal breast tissues, and sub-sets of which adversely affect the survival in young women with breast cancer [ 24 ]. Further studies are warranted to identify a biological or molecular explanation for the higher relapse rate of breast cancer in younger patients.…”

Unveiling Collagen’s Role in Breast Cancer: Insights into Expression Patterns, Functions and Clinical Implications

“…Although less studied in breast cancer compared to COL1A1, COL1A2 is identified as a hub gene associated with the survival outcomes of human epidermal growth factor receptor 2 (HER2)-positive patients by constructing the protein–protein interaction (PPI) network. 54 Upregulated in breast cancer tissues, COL1A2 is correlated with reduced overall and recurrence-free survival, 55 and its expression is elevated by radiation. 28 Research on its mechanism in breast cancer is ongoing, with previous studies indicating potent induction of COL1A2 transcription by TGF-β, involving Smad family proteins or Smad-binding elements.…”