Single-Cell Transcriptomic Analysis of T Cells in Cancer-free BRCA1 Mutation Carriers and Age-Matched Controls
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Breast cancer is a multifactorial disease caused by the interaction of inherited abnormalities, hormonal and reproductive history, lifestyle, and environmental exposure. Among the genetic factors, BRCA1 and BRCA2 are the most frequently mutated high-penetrance genes in hereditary breast cancer. Although carriers of a single mutated allele exhibit no apparent phenotypic abnormalities, inherited mutations in the BRCA1 gene increase breast cancer risk to 55-72%, and for BRCA2, to 45-69%, compared with an approximate 13% lifetime risk in the general population.BRCA1 is essential for maintaining genome integrity through its roles in DSB repair by homologous recombination (HR), in protecting replication forks under stress from nucleolytic degradation, and in transcriptional regulation. Recently, research has focused on answering why BRCA1 mutations confer a predilection for breast and ovarian cancers and whether other components of the tissue-specific microenvironment also contribute to tumorigenesis. Haploinsufficiency for these genome integrity functions has been detected in breast epithelial cells and stroma prior to tumor emergence, contributing to tumorigenesis and a sign that the neoplastic process begins long before it becomes clinically apparent. These findings show that the pro-tumorigenic consequences of BRCA1 germline haploinsufficiency extend to other cell populations in this complex microenvironment, including stroma and potentially the immune cell population. The ubiquitous expression of BRCA1 germline mutation, which means that immune cells also carry it, raises the critical question of whether immune surveillance, the process by which the immune system monitors the body and detects and eliminates emerging pre-malignant or malignant cells, may be compromised before tumor development. Wu et al. (2023) proposed a ‘dual impact’ model in which germline BRCA1 mutations both increase epithelial cell tumorigenicity and compromise adaptive antitumor immunity, providing a key functional precedent for the present thesis, which aims to better understand how germline BRCA1 mutations affect T cells and shape the immune landscape in healthy, cancer-free carriers, potentially contributing to tumorigenesis. In this study, pan-T cells isolated from PBMCs of 10 BRCA1 mutation carriers and 10 age-matched controls were analyzed using scRNA-seq. Cluster annotation revealed conventional (CD4+ and CD8+ T cells) and unconventional T cell subsets. The compositional analysis revealed a significantly higher cell frequency in γδT (Vδ1) cells and a trend toward increased SOX4+ naïve T cell frequency and decreased T reg cell frequency in BRCA1 mutation carriers. SOX4+ naïve T cells and Treg trends in the compositional analysis were consistent with the trajectory analysis, in which the progression test indicated a possible shift of CD4+ T cells towards a SOX4+ naïve-like cell state. While no significant compositional pattern was found in CD8+T cells, trajectory analysis implied a shift towards the most terminally differentiated cells. Together, these findings suggest an association between BRCA1 mutation status and shifts in differentiation toward the extremes of the maturation axis, away from functional effector states.
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