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• RNA Sequencing Analysis of Patient-Derived Xenograft Tissue PIM-084 Treated with L-NMMA+Alpelisib vs Vehicle Control

  This dataset contains RNA-seq analysis of vehicle control compared to L-NMMA+alpelisib treated metaplastic breast cancer PDX PIM084 tumors (RNA sequencing and analysis performed by Novogene). The submitted data contains the gene ID, gene name, normalized read counts from all samples from control group and combination treatment group, log2-fold change derived from DESeq2 R/EdgeR package, p-value, adjusted p-value, read counts from each group, and gene FPKM from the each sample in the group. Due to patient privacy, we are submitting only the processed and desensitized RNA sequencing analysis to this repository.

  Study phs003814

• Copy-choice recombination during mitochondrial L-strand synthesis causes DNA deletions

  Mitochondrial DNA (mtDNA) deletions are associated with mitochondrial disease, and also accumulate during normal human ageing. The mechanisms underlying mtDNA deletions remain unknown although several models have been proposed. Here we use deep sequencing to characterize abundant mtDNA deletions in patients with mutations in POLG, the gene encoding mitochondrial DNA polymerase, and show that these have distinct directionality and repeat characteristics. Furthermore, we recreate the deletion formation process in vitro using only purified mitochondrial proteins and defined DNA templates. Based on our in vivo and in vitro findings, we conclude that mtDNA deletion formation involves copy-choice recombination during replication of the mtDNA light strand.

  Study EGAS00001003148

• Predictive value of genomic, transcriptomic and epigenetic biomarkers in patients with recurrent and/or metastatic HNSC treated with PD-1/PD-L1 inhibitors

  Immune checkpoint inhibitors have improved survival in several solid tumors, including head and neck squamous cell carcinoma (HNSCC). However, current use of PD-1/PD-L1 inhibitors relies on PD-L1 expression, which does not reliably predict patient response. Therefore, better predictive biomarkers are needed to identify which patients benefit from immunotherapy. Previous studies suggest that genomic and transcriptomic features may help predict treatment response. This study aims to integrate genomic, transcriptomic, and methylomic data from 31 patients with recurrent/metastatic HNSCC to identify new biomarkers of resistance to anti-PD-1/PD-L1 therapy.

  Study EGAS50000001746

• Scalable Whole-Exome Sequencing of Cell-Free DNA Reveals High Concordance with Metastatic Tumors

  We performed whole genome sequencing and whole-exome sequencing of cell-free DNA (cfDNA) and whole-exome sequencing of matched tumor biopsies and germline DNA from patients with metastatic cancer. Using ichorCNA, a software tool that quantifies tumor content in ultra-low pass whole genome sequencing (~0.1x) of cfDNA without prior genomic characterization of the tumor, we show genome-wide concordance between cfDNA and tumor biopsies and detectability of high tumor fractions (>0.1) in the cfDNA of many patients with metastatic cancer. We then established that whole-exome sequencing of cfDNA can enable comprehensive profiling of tumors from blood, with high tumor-content cfDNA samples demonstrating concordance of clonal somatic mutations, copy number alterations, mutational signatures, and neoantigens with matched tumor biopsies. This study introduces a new method to identify patients that could be eligible for tumor profiling from cfDNA and sheds light on the concordance between metastatic tissue and blood biopsies.

  Study phs001417

• Functional Dynamics of the Elderly Gut Microbiome During Probiotic Consumption

  A mechanistic understanding of the health benefits conferred by consumption of probiotic bacteria has been limited by our knowledge of the resident gut microbiota and its interaction with the host. We used fecal samples from a study of twelve healthy individuals aged 65-80 to characterize the structure and functional dynamics of the gut microbiota associated with consumption of the single-organism probiotic, Lactobacillus rhamnosus GG ATCC 53103 (LGG). Samples were collected prior to probiotic consumption (day 0), on day 28 immediately after consuming 10^10 CFU of LGG twice daily for 28 days and day 56, one month after stopping LGG consumption. Our integrative approach incorporated bacterial 16S rRNA gene sequencing, whole-community expression profiling using RNA-seq, and metagenomic sequencing. We highlight the value of combinatorial 'omics methods and concomitant high-resolution informatics to probe the role that probiotics may play on the structure and function of the resident microbiota.

  Study phs000896

• Cellular Dynamics Upon Immune Checkpoint Inhibition

  Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, yet most patients experience limited or no clinical benefit. To elucidate the mechanisms of response and resistance, we analyzed single-cell RNA-sequencing data from 141 patients across multiple cancer types and ICI treatment modalities, with longitudinally paired samples. Using a robust, integration-free deep phenotyping framework, we annotated 876,410 cells into 80 granular states. We identified consistent compositional changes in 17 cell subtypes following ICI treatment, including enhanced adaptive immune responses and reduced interferon-responsive cells. Co-regulated cell communities within the tumor microenvironment (TME) highlighted coordinated interplay between immune and non-immune components. Importantly, we discovered two distinct patient groups with divergent TME dynamics post-treatment: responders showed expansion of naive lymphocytes, while non-responders exhibited increased immune-experienced/suppressive cells. This dichotomy offers a potential predictive biomarker for patient stratification. Our comprehensive analysis of TME dynamics during ICI treatment advances understanding of response mechanisms and personalized cancer immunotherapy.

  Study EGAS50000000459

• Divergence between high metastatic tumor burden and low circulating tumor DNA concentration in metastasized breast cancer

  Circulating tumor DNA (ctDNA) was reported to represent a highly sensitive biomarker of metastatic cancer disease directly reflecting tumor burden and dynamics. Here we investigated the role of ctDNA in patients with metastatic breast cancer. In an index patient with more than 100,000 circulating tumor cells (CTCs) in serial blood analyses, whole genome, exome, or targeted deep sequencing of the primary tumor, metastases, and 551 CTCs were consistent with a genetically homogeneous cancer. However, the allele fractions (AFs) of ctDNA were only 2-3% in each analysis, which did neither reflect the tumor burden nor the dynamics of this progressive disease by far. Indeed, plasma analyses of 71 further patients demonstrated highly variable AFs of mutant fragments, which frequently did not correspond to the tumor burden. These results provide insights into mechanisms involved in CTC and ctDNA release into the circulation and have important implications for diagnostic tests based on liquid biopsies.

  Study EGAS00001000625

• Whole exome sequencing of long-term, never relapse exceptional responders of trastuzumab-treated HER2+ metastatic breast cancer

  Trastuzumab has significantly improved the overall survival of patients with HER2+ metastatic breast cancer (MBC). However, outcomes can vary, with patients progressing within 1-year of treatment or exceptional cases of complete response to trastuzumab for ≥ 10 years. Identification of the underlying genomic aberrations of “exceptional responders (ExRs)” compared to “rapid non-responders (NR)” increases our understanding of the mechanisms involved in MBC progression and identification of biomarkers of trastuzumab response and resistance. Whole exome sequencing was performed on six ExRs compared to five NR. The overall fraction of genome copy number alteration (CNA) burden was higher in NR patients (P=0.07), while more significantly pronounced in copy number gains (P=0.03) in NR compared to ExRs. Delineation of the distribution of CNA burden across the genome identified a greater degree of CNA burden in NR within chr8 (P=0.02) and in chr17 (P=0.06) and conferred a statistically significant benefit in overall survival.

  Study EGAS00001004486

• Latency and interval therapy affect the evolution in metastatic colorectal cancer

  While comparison of primary tumor and metastases has highlighted genomic heterogeneity in colorectal cancer (CRC), previous studies have focused on a single metastatic site or limited genomic testing. Combining data from whole exome and ultra-deep targeted sequencing, we explored possible evolutionary trajectories beyond the status of these mutations, particularly among patient-matched metastatic tumors. Our findings confirm the persistence of known clinically-relevant mutations (e.g. those of RAS family of oncogenes) in CRC primary and metastases, yet reveal that latency and interval systemic therapy affect the course of evolutionary events within metastatic lesions. Specifically, our analysis of patient-matched primary and multiple metastatic lesions, developed over time, showed a similar genetic composition for liver metastatic tumors, which were 21-months apart. This genetic makeup was different from those identified in lung metastases developed before manifestation of the second liver metastasis. These results underscore the role of dormancy in the evolutionary path of metastatic CRC.

  Study EGAS00001003646

• Familial adult myoclonic epilepsy in Sri Lankan and Indian families

  Familial adult myoclonic epilepsy 1 (FAME1), first recognised in Japanese families, was recently shown to be caused by a TTTCA repeat insertion in intron 4 of SAMD12 on chromosome 8. We performed whole genome sequencing on two families with FAME, one of Sri Lankan origin and the other of Indian origin, and identified a TTTCA repeat insertion in SAMD12 in both families. Haplotype analysis revealed that both families shared the same core ancestral haplotype reported in Japanese and Chinese families with FAME1. Mutation dating, based on the length of shared haplotypes, estimated the age of the ancestral haplotype to be approximately 670 generations, or 17,000 years old. Our data extend the geographic range of this repeat expansion to Southern Asia and potentially implicate an even broader regional distribution given the age of the variant. This finding suggests patients of Asian ancestry with suspected FAME should be screened for the SAMD12 TTTCA expansion.

  Study EGAS00001004012