Mingyi Xia

This secondary analysis of a nonrandomized clinical trial assesses long-term survival and genomic variants associated with therapeutic resistance in patients receiving maintenance rucaparib with BRCA1 , BRCA2 , or PALB2 germline or somatic pathogenic variants and platinum-sensitive metastatic pancreatic adenocarcinoma.

Carriers of germline BRCA1/2 pathogenic variants (g BRCA1/2 PVs) have elevated young-onset breast cancer risk. To define the pretreatment genomic landscapes of young-onset g BRCA -associated breast cancer, we evaluated 136 treatment-naive tumors diagnosed before age 50 in the prospective POSH study and 66 noncarriers from The Cancer Genome Atlas. Using whole-exome sequencing, we analyzed somatic variation, allele-specific loss of heterozygosity (asLOH), homologous recombination deficiency (HRD), and single-base substitution (SBS) signatures. gBRCA1 and gBRCA2 breast cancers had high rates of asLOH but differed significantly in average HRD scores and median SBS composition of signatures SBS1 (aging-associated), SBS18 (ROS-associated), and SBS3 (HRD-associated). Compared with g BRCA2 tumors, g BRCA1 tumors with asLOH were significantly enriched for alterations in hallmark ROS, DNA repair, and epithelial-mesenchymal transition pathways. In ER-positive, HER2-negative tumors from g BRCA1/2 carriers compared with noncarriers, we found significant enrichment of RB1 , TP53 , FAT1 , and MYC single-nucleotide variants, indels, and copy number variants associated with CDK4/6 inhibitor (CDK4/6i) resistance. Together, these findings demonstrate significant differences between g BRCA1 - and g BRCA2 -associated breast cancers, and preexisting CDK4/6i resistance mechanisms, supporting prospective trials comparing individualized therapy for g BRCA1 versus g BRCA2 carriers and comparing poly(ADP-ribose) polymerase inhibitors versus CDK4/6i for ER-positive g BRCA1/2 -associated breast cancer.

Purpose: g BRCA1/2 pathogenic variant (PV) carriers have elevated young-onset breast cancer risk. Understanding the distinct genomic landscapes of g BRCA1- and g BRCA2 -associated breast cancer, including presence of PARP and CDK4/6 inhibitor (PARPi; CDK4/6i) response-associated alterations, may inform treatment selection for these patients. Patients and methods: We evaluated 136 treatment-naïve primary tumors from POSH study participants diagnosed with breast cancer before age 50 years (92.6% diagnosed ≤40): g BRCA1 86(63.2%), g BRCA2 50(36.8%). We evaluated somatic mutational and copy number variations (CNV), allele-specific loss of heterozygosity (asLOH), homologous recombination deficiency (HRD), and single-base substitution signatures (SBS) from whole exome sequencing. Results: Both g BRCA1 (93%) and g BRCA2 (96%) breast cancers had high rates of asLOH. We found significant differences between g BRCA1 and g BRCA2 tumors in average HRD scores (57.4±1.3 vs 43.7±1.5, pBRCA2 tumors, g BRCA1 tumors with asLOH were significantly enriched for gains of chr6q, and alterations in Hallmark ROS, DNA repair, and epithelial-mesenchymal transition pathways. In ER-positive, HER2-negative tumors from POSH g BRCA1/2 carriers compared to noncarriers from the TCGA, we found significant enrichment of RB1 (OR:6.3, 95%CI:2.8-15.4, p _adj =0.001), TP53 (OR:4.6, 95%CI:1.9-12.1, p _adj =0.017), FAT1 (OR:3.9, 95%CI:1.84-8.7, p _adj =0.013), and MYC (OR:4.0, 95%CI:1.8-9.1, p _adj =0.017) SNV/indels/CNVs, which are associated with CDK4/6i resistance. Conclusion: Our data suggest that PARPi may be preferable over CDK4/6i to treat ER-positive, HER2-negative breast cancer in young-onset g BRCA1/2 -associated breast cancer when both therapies are considered in adjuvant and metastatic settings. Additionally, we identified significant differences between g BRCA1- and g BRCA2 -associated tumors, which may inform therapeutic development.

Categorization is an essential task for sensory perception. Individuals learn category labels using a variety of strategies to ensure that sensory signals, such as sounds or images, can be assigned to proper categories. Categories are often learned on the basis of extreme examples, and the boundary between categories can differ among individuals. The trajectories for learning also differ among individuals, as different individuals rely on different strategies, such as repeating or alternating choices. However, little is understood about the relationship between individual learning trajectories and learned categorization. To study this relationship, we trained mice to categorize auditory stimuli into two categories using a two-alternative forced choice task. Because the mice took several weeks to learn the task, we were able to quantify the time course of individual strategies and how they relate to how mice categorize stimuli around the categorization boundary. Different mice exhibited different trajectories while learning the task. Mice displayed preferences for a specific category, manifested by a choice bias in their responses, but this bias drifted with learning. We found that this drift in choice bias correlated with variability in the category boundary for sounds with ambiguous category membership. Next, we asked how stimulus-independent, individual-specific strategies informed learning. We found that the tendency to repeat choices, which is a form of perseveration, contributed to long-term learning. These results indicate that long-term trends in individual strategies during category learning affect learned category boundaries.

Transposable elements, such as Long INterspersed Elements (LINEs), are DNA sequences that can replicate within genomes. LINEs replicate using an RNA intermediate followed by reverse transcription and are typically a few kilobases in length. LINE activity creates genomic structural variants in human populations and leads to somatic alterations in cancer genomes. Long-read RNA sequencing technologies, including Oxford Nanopore and PacBio, can directly sequence relatively long transcripts, thus providing the opportunity to examine full-length LINE transcripts. This study focuses on the development of a new bioinformatics pipeline for the identification and quantification of active, full-length LINE transcripts in diverse human tissues and cell lines. In our pipeline, we utilized RepeatMasker to identify LINE-1 (L1) transcripts from long-read transcriptome data and incorporated several criteria, such as transcript start position, divergence, and length, to remove likely false positives. Comparisons between cancerous and normal cell lines, as well as human tissue samples, revealed elevated expression levels of young LINEs in cancer, particularly at intact L1 loci. By employing bioinformatics methodologies on long-read transcriptome data, this study demonstrates the landscape of L1 expression in tissues and cell lines.

We developed a flexible “electrode-thread” array for recording dopamine neurochemical activity from a lateral distribution of subcortical targets (up to 16) transverse to the axis of insertion. Ultrathin (∼ 10 µm diameter) carbon fiber (CF) electrode-threads (CFETs) are clustered into a tight bundle to introduce them into the brain from a single entry point. The individual CFETs splay laterally in deep brain tissue during insertion due to their innate flexibility. This spatial redistribution allows navigation of the CFETs towards deep brain targets spreading horizontally from the axis of insertion. Commercial “linear” arrays provide single entry insertion but only allow measurements along the axis of insertion. Horizontally configured neurochemical recording arrays inflict separate penetrations for each individual channel (i.e., electrode). We tested functional performance of our CFET arrays in vivo for recording dopamine neurochemical dynamics and for providing lateral spread to multiple distributed sites in the striatum of rats. Spatial spread was further characterized using agar brain phantoms to measure electrode deflection as a function of insertion depth. We also developed protocols to slice the embedded CFETs within fixed brain tissue using standard histology techniques. This method allowed extraction of the precise spatial coordinates of the implanted CFETs and their recording sites as integrated with immunohistochemical staining for surrounding anatomical, cytological, and protein expression labels. Neurochemical recording operations tested here can be integrated with already widely established capabilities of CF-based electrodes to record single neuron activity and local field potentials, to enable multi-modal recording functions. Our CFET array has the potential to unlock a wide range of applications, from uncovering the role of neuromodulators in synaptic plasticity, to addressing critical safety barriers in clinical translation towards diagnostic and adaptive treatment in Parkinson’s disease and major mood disorders.