Biology subjects

Karaayvaz, M.

Publications and source records attributed to Karaayvaz, M..

3 recordsLinked to original sources

bioRxiv2026

Integrated Collagen Architecture and Composition Improve Risk Stratification in Triple-Negative Breast Cancer

PurposeTriple-negative breast cancer (TNBC) exhibits substantial clinical heterogeneity, with some patients experiencing early recurrence and poor survival despite similar clinicopathologic features. We sought to determine whether quantitative measures of intratumoral collagen architecture and composition derived from standard histopathologic specimens can identify patients at risk of recurrence and adverse survival outcomes. Experimental DesignWe analyzed a retrospective cohort of 79 TNBC tumors assembled into a tissue microarray using a multimodal computational pathology framework integrating Massons Trichrome staining with COL1 and COL3 immunohistochemistry. Collagen architecture was quantified using fiber-based image analysis and unsupervised clustering, while collagen composition was assessed using a normalized COL3:COL1 ratio. Associations with recurrence-free interval (RFI) and overall survival (OS) were evaluated using Kaplan-Meier analysis, restricted mean survival time (RMST), and Cox proportional hazards modeling. ResultsUnsupervised analysis identified four distinct collagen architectural states, which were consolidated into low-risk and high-risk groups based on recurrence patterns. High-risk collagen architecture was associated with significantly worse long-term RFI (log-rank p=0.025; RMST difference 10.1 months). Independently, a higher COL3:COL1 ratio was associated with improved OS (log-rank p=0.042; RMST difference 9.4 months). Integration of architectural and compositional biomarkers further refined risk stratification, identifying a subgroup with high-risk architecture and low COL3:COL1 ratio that exhibited the poorest survival outcomes. Notably, collagen-based stratification identified patients with divergent outcomes not readily predicted from tumor stage alone. ConclusionsQuantitative assessment of intratumoral collagen architecture and composition provides clinically meaningful prognostic information in TNBC and enables stratification of recurrence and survival risk. These findings support extracellular matrix phenotyping as a practical and scalable computational pathology approach for refining risk assessment in TNBC. Translational RelevanceTriple-negative breast cancer (TNBC) remains clinically challenging due to heterogeneous outcomes that are not fully captured by standard clinicopathologic variables. In this study, we demonstrate that quantitative features of intratumoral collagen architecture and composition, derived from routine pathology specimens, provide clinically meaningful prognostic information. Collagen-based biomarkers, including distinct collagen architectural phenotypes and the COL3:COL1 ratio, identify patient subgroups with distinct recurrence and survival outcomes, particularly among individuals whose risk is not adequately predicted by conventional staging. Importantly, these features can be extracted from widely available histological stains and immunohistochemistry, supporting the potential integration into existing pathology workflows. These findings support the tumor microenvironment as an underutilized source of biomarkers and suggest that extracellular matrix-based phenotyping may improve risk stratification and inform clinical decision-making in TNBC.

cancer biology↗

bioRxiv2023

Alterations in the preneoplastic breast microenvironment of BRCA1/2 mutation carriers revealed by spatial transcriptomics

Breast cancer is the most common cancer in females, affecting one in every eight women and accounting for the majority of cancer-related deaths in women worldwide. Germline mutations in the BRCA1 and BRCA2 genes are significant risk factors for specific subtypes of breast cancer. BRCA1 mutations are associated with basal-like breast cancers, whereas BRCA2 mutations are associated with luminal-like disease. There are currently few chemoprevention strategies available for BRCA1/2 mutation carriers, and irreversible prophylactic mastectomy is the primary option. Designing chemo-preventive strategies requires an in-depth understanding of the physiological processes underlying tumor initiation. Here, we employ spatial transcriptomics to investigate defects in mammary epithelial cell differentiation accompanied by distinct microenvironmental alterations in preneoplastic breast tissues from BRCA1/2 mutation carriers and normal breast tissues from non-carrier controls. We uncovered spatially defined receptor-ligand interactions in these tissues for the investigation of autocrine and paracrine signaling. We discovered that {beta}1-integrin-mediated autocrine signaling in BRCA2-deficient mammary epithelial cells differs from BRCA1-deficient mammary epithelial cells. In addition, we found that the epithelial-to-stromal paracrine signaling in the breast tissues of BRCA1/2 mutation carriers is greater than in control tissues. More integrin-ligand pairs were differentially correlated in BRCA1/2-mutant breast tissues than non-carrier breast tissues with more integrin receptor-expressing stromal cells. These results reveal alterations in the communication between mammary epithelial cells and the microenvironment in BRCA1 and BRCA2 mutation carriers, laying the foundation for designing innovative breast cancer chemo-prevention strategies for high-risk patients.

cancer biology↗

bioRxiv2019

Aneuploidy and deregulated DNA damage response define haploinsufficiency in breast tissues of BRCA2 mutation carriers

Women harboring heterozygous germline mutations of BRCA2 have a 50-80% risk of developing breast cancer, yet the early pathogenesis of these cancers is poorly understood. We sought to reveal early steps in BRCA2-associated carcinogenesis through analysis of sorted cell populations from freshly-isolated, non-cancerous breast tissues among a cohort of BRCA2 mutation carriers and matched controls. Single-cell whole-genome sequencing demonstrates that >25% of BRCA2 carrier (BRCA2mut/+) luminal progenitor (LP) cells exhibit sub-chromosomal copy number variations (CNVs), which are rarely observed in non-carriers. Correspondingly, primary BRCA2mut/+ breast epithelia exhibit spontaneous and replication stress-induced DNA damage together with attenuated replication checkpoint and apoptotic responses, associated with an age-associated expansion of the LP compartment in human carrier tissues. These phenotypes are not associated with loss of wild-type BRCA2. Collectively, these findings provide evidence for BRCA2 haploinsufficiency and associated DNA damage in vivo that precede histologic abnormalities. These results provide unanticipated opportunities for new cancer risk assessment and prevention strategies in high-risk patients.

cancer biology↗