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Methylation patterns of circulating cell-free DNA (cfDNA) contain rich information about recent cell death events in the body. Here, we present an approach for unbiased determination of the tissue origins of cfDNA, using a reference methylation atlas of 25 human tissues and cell types. The method is validated using in silico simulations as well as in vitro mixes of DNA from different tissue sources at known proportions. We show that plasma cfDNA of healthy donors originates from white blood cells (55%), erythrocyte progenitors (30%), vascular endothelial cells (10%) and hepatocytes (1%). Deconvolution of cfDNA from patients reveals tissue contributions that agree with clinical findings in sepsis, islet transplantation, cancer of the colon, lung, breast and prostate, and cancer of unknown primary. We propose a procedure which can be easily adapted to study the cellular contributors to cfDNA in many settings, opening a broad window into healthy and pathologic human tissue dynamics. The methylation status of circulating cell-free DNA (cfDNA) can be informative about recent cell death events. Here the authors present an approach to determine the tissue origins of cfDNA, using a reference methylation atlas of 25 human tissues and cell types, and find that cfDNA from patients reveals tissue contributions that agree with clinical findings.

The Oxford Nanopore (ONT) platform provides portable and rapid genome sequencing, and its ability to natively profile DNA methylation without complex sample processing is attractive for point-of-care real-time sequencing. We recently demonstrated ONT shallow whole-genome sequencing to detect copy number alterations (CNAs) from the circulating tumor DNA (ctDNA) of cancer patients. Here, we show that cell type and cancer-specific methylation changes can also be detected, as well as cancer-associated fragmentation signatures. This feasibility study suggests that ONT shallow WGS could be a powerful tool for liquid biopsy. Graphical Abstract

Cell-free DNA (cfDNA) in human plasma provides access to molecular information about the pathological processes in the organs or tumors from which it originates. These DNA fragments are derived from fragmented chromatin in dying cells and retain some of the cell-of-origin histone modifications. In this study, we applied chromatin immunoprecipitation of cell-free nucleosomes carrying active chromatin modifications followed by sequencing (cfChIP-seq) to 268 human samples. In healthy donors, we identified bone marrow megakaryocytes, but not erythroblasts, as major contributors to the cfDNA pool. In patients with a range of liver diseases, we showed that we can identify pathology-related changes in hepatocyte transcriptional programs. In patients with metastatic colorectal carcinoma, we detected clinically relevant and patient-specific information, including transcriptionally active human epidermal growth factor receptor 2 (HER2) amplifications. Altogether, cfChIP-seq, using low sequencing depth, provides systemic and genome-wide information and can inform diagnosis and facilitate interrogation of physiological and pathological processes using blood samples. Circulating cell-free DNA from patients is analyzed by ChIP-seq to reconstruct gene expression in human organs and tumors.

Radiotherapy has an important role in the treatment of brain metastases but carries risk of short and/or long-term toxicity, termed radiation-induced brain injury (RBI). As the diagnosis of RBI is crucial for correct patient management, there is an unmet need for reliable biomarkers for RBI. The aim of this proof-of concept study is to determine the utility of brain-derived circulating free DNA (BncfDNA), identified by specific methylation patterns for neurons, astrocytes, and oligodendrocytes, as biomarkers brain injury induced by radiotherapy. Twenty-four patients with brain metastases were monitored clinically and radiologically before, during and after brain radiotherapy, and blood for BncfDNA analysis (98 samples) was concurrently collected. Sixteen patients were treated with whole brain radiotherapy and eight patients with stereotactic radiosurgery. During follow-up nine RBI events were detected, and all correlated with significant increase in BncfDNA levels compared to baseline. Additionally, resolution of RBI correlated with a decrease in BncfDNA. Changes in BncfDNA were independent of tumor response. Elevated BncfDNA levels reflects brain cell injury incurred by radiotherapy. further research is needed to establish BncfDNA as a novel plasma-based biomarker for brain injury induced by radiotherapy.

Background Inequalities among the western population, combined with the introduction of new treatment options for cancer, have challenged endeavors to provide equal care to patients with cancer. Israel’s highly developed healthcare system and mandatory National Health Insurance afforded an opportunity to study geographic variation over time in mortality following cancer diagnosis. Methods This historical prospective cohort study included a nationally representative cohort that was assessed by the Israeli Central Bureau of Statistics 1995 census and followed until 2011. The cancer incidence (1995–2009) was ascertained by the Israel National Cancer Registry. We analyzed the effect on patient outcome of living in a given district, according to the Israeli Central Bureau of Statistics classification. Patients were stratified by the year of diagnosis (1995–1997, 1998–2000, etc.), and associations were adjusted for age, ethnicity, and districts. We excluded patients with malignancies associated with screening program (breast, prostate, colon, and cervical cancers). Results This study included 26,173 patients living in 13 residential districts. During the last years (2007–2009) of the study, the hazard ratio (HR) for risk of death was high in 8/13 districts (61.5%), compared to 4/13 (30.7%) during 2004–2006, and 0/13 (0%) during 2001–2003. Districts that were less likely to be associated with increased risk of death were located in the center of Israel and in metropolitan areas, compared to the peripheral regions. Furthermore, HRs were substantially higher in the last years of the study (2007–2009, HRs rose to 1.69, 95%CI: 1.38–2.08) compared to the earlier years (2004–2006, HRs rose to 1.35, 95%CI: 1.13–1.62). Conclusion Our findings suggested that geographic variation for mortality following cancer diagnosis have increased over time. Our results provide policy makers with vital information regarding the need for targeted interventions, mainly in peripheral regions.

A Correction to this paper has been published: https://doi.org/10.1038/s41587-021-00831-9.

A Correction to this paper has been published: https://doi.org/10.1038/s41587-021-00853-3.

ERBB2 amplification is a prognostic marker for aggressive tumors and a predictive marker for prolonged survival following treatment with HER2 inhibitors. We attempt to sub-group HER2+ tumors based on amplicon structures and co-amplified genes. We examined five HER2+ cell lines, three HER2+ xenographs and 57 HER2+ tumor tissues. ERBB2 amplification was analyzed using digital droplet PCR and low coverage whole genome sequencing. In some HER2+ tumors PPM1D , that encodes WIP1, is co-amplified. Cell lines were treated with HER2 and WIP1 inhibitors. We find that inverted duplication is the amplicon structure in the majority of HER2+ tumors. In patients suffering from an early stage disease the ERBB2 amplicon is composed of a single segment while in patients suffering from advanced cancer the amplicon is composed of several different segments. We find robust WIP1 inhibition in some HER2+ PPM1D amplified cell lines. Sub-grouping HER2+ tumors using low coverage whole genome sequencing identifies inverted duplications as the main amplicon structure and based on the number of segments, differentiates between local and advanced tumors. In addition, we found that we could determine if a tumor is a recurrent tumor or second primary tumor and identify co-amplified oncogenes that may serve as targets for therapy.

Abstract Small round cell sarcoma is a group of undifferentiated malignancies arising in the bone and soft tissue, notable for Ewing sarcoma. Recently, a new World Health Organization classification has been introduced, including an additional subset of these sarcomas, named CIC-rearranged sarcoma. Within this group, CIC-FOXO4 translocation is an exceedingly rare fusion that has been reported only 4 times in the literature. Herein, we report in-depth the pathological, clinical, and molecular features of a CIC-FOXO4 translocation-driven tumor in a 46-year-old woman.