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• Chromatin remodeler CHD7 regulates the stem cell identity of human neural progenitors

  Multiple congenital disorders often present complex phenotypes, but how the mutation of individual genetic factors can lead to multiple defects remains poorly understood. In the present study, we used human neuroepithelial (NE) cells and CHARGE patient-derived cells as an in vitro model system to identify the function of chromodomain helicase DNA-binding 7 (CHD7) in NE?neural crest bifurcation, thus revealing an etiological link between the central nervous system (CNS) and craniofacial anomalies observed in CHARGE syndrome. We found that CHD7 is required for epigenetic activation of superenhancers and CNS-specific enhancers, which support the maintenance of the NE and CNS lineage identities. Furthermore, we found that BRN2 and SOX21 are downstream effectors of CHD7, which shapes cellular identities by enhancing a CNS-specific cellular program and indirectly repressing non- CNS-specific cellular programs. Based on our results, CHD7, through its interactions with superenhancer elements, acts as a regulatory hub in the orchestration of the spatiotemporal dynamics of transcription factors to regulate NE and CNS lineage identities.

  Study JGAS000131

• Single cell RNA seq of breast cancer stem cells

  RNA sequences of breast cancer have been investigated for many patients. Recently it has been shown that there are intra-heterogeneity in tumor tissues. When the tumor cells were sequenced in bulk condition, only the major populations' mRNA will be detected. With respect to breast cancer, it has been also reported that cancer cells can sub-gropued into cancer stem cells and non-cancer stem cells. Although the mRNA expressions' difference between this two groups has been profoundly investigated, whether each group is composed by unique cell or not is yet to be elucidated. Since cancer stem cells are the thought to be the major contributor of metastasis and/or recurrence, we focused on cancer stem cells in this study. We separated cancer cells into cancer stem cells and non-cancer stem cells exploiting cancer stem cell specific surface markers. Thereafter, we sequenced mRNA of cancer stem cells in single cell resolution. From this result, we examined whether these cells can be sub-grouped or not.

  Study JGAS000305

• Impact of germline pathogenic variants in 27 cancer-predisposing genes on the risk of lymphoma

  The application of advanced molecular technology has significantly expanded lymphoma classification, allowing risk stratification and treatment optimization. Limited evidence suggests the presence of a genetic predisposition in lymphoma, indicating the potential for better individualized clinical management based on a novel lymphoma classification. Herein, we examined the impact of germline pathogenic variants in 27 cancer-predisposing genes with lymphoma risk and explored the clinical characteristics of pathogenic variant carriers. This study included 2,066 lymphoma patients and 38,153 cancer-free controls from the Japanese population. Following quality control of sequencing data, samples from 1,982 lymphoma patients and 37,592 controls were further analyzed. Sequencing data of controls were obtained from JGAD000721. Germline pathogenic variants in some cancer-predisposing genes were associated with a high risk of lymphoma. Furthermore, germline pathogenic variants in these genes were especially associated with the higher risk of a certain subtype. These results would provide novel insights concerning monogenic form into lymphoma classification. Some lymphoma patients may benefit from surveillance and targeted treatment like other neoplasms.

  Study JGAS000347

• Non-invasive human skin transcriptome analysis using mRNA in skin surface lipids

  Non-invasive acquisition of mRNA data from the skin can be extremely useful for understanding skin physiology and diseases. Inspired by the holocrine process, in which the sebaceous glands secrete cell contents into the sebum, we focused on the possible presence of mRNAs in skin surface lipids (SSLs). We found that measurable levels of human mRNAs exist in SSLs, where the sebum protects them from degradation by RNases. The AmpliSeq transcriptome analysis was modified to measure SSL-RNA levels, and our results revealed that the SSL-RNAs predominantly comprised mRNAs derived from sebaceous glands, the epidermis, and hair follicles. Analysis of SSL-RNAs non-invasively collected from patients with atopic dermatitis revealed significantly increased expression of inflammation-related genes and decreased expression of terminal-differentiation���related genes, consistent with the results of previous reports. Further, we found that lipid-synthesis���related genes were downregulated in the sebaceous glands of patients with atopic dermatitis. These results indicate that the analysis of SSL-RNAs is a promising strategy to understand the pathophysiology of skin diseases.

  Study JGAS000418

• Non-invasive human skin transcriptome analysis using mRNA in skin surface lipids

  Non-invasive acquisition of mRNA data from the skin can be extremely useful for understanding skin physiology and diseases. Inspired by the holocrine process, in which the sebaceous glands secrete cell contents into the sebum, we focused on the possible presence of mRNAs in skin surface lipids (SSLs). We found that measurable levels of human mRNAs exist in SSLs, where the sebum protects them from degradation by RNases. The AmpliSeq transcriptome analysis was modified to measure SSL-RNA levels, and our results revealed that the SSL-RNAs predominantly comprised mRNAs derived from sebaceous glands, the epidermis, and hair follicles. Analysis of SSL-RNAs non-invasively collected from patients with atopic dermatitis revealed significantly increased expression of inflammation-related genes and decreased expression of terminal-differentiation���related genes, consistent with the results of previous reports. Further, we found that lipid-synthesis���related genes were downregulated in the sebaceous glands of patients with atopic dermatitis. These results indicate that the analysis of SSL-RNAs is a promising strategy to understand the pathophysiology of skin diseases.

  Study JGAS000417

• Myasthenia gravis-specific aberrant neuromuscular gene expression by medullary thymic epithelial cells in thymoma

  Myasthenia gravis (MG) is a neurological disease caused by autoantibodies against neuromuscular-associated proteins. While MG is frequently developed in thymoma patients, the etiologic factors for MG are not well understood. Here, by constructing a comprehensive atlas of thymoma using bulk and single-cell RNA-seq, we identified ectopic expression of neuromuscular molecules in MG-associated thymoma (MG-thymoma). These molecules were originated from a distinct subpopulation of medullary thymic epithelial cells (mTECs), which we named neuromuscular mTECs (nmTECs). MG-thymoma also exhibited microenvironments dedicated to autoantibody production, including ectopic germinal center formation, T follicular helper cell accumulation, and type 2 conventional dendritic cell migration. Cell-cell interaction analysis also predicted the interaction between nmTECs and T/B cells via CXCL12-CXCR4. The enrichment of nmTECs presenting neuromuscular molecules within MG-thymoma was further confirmed by immunohistochemically and by cellular composition estimation from MG-thymoma transcriptome. Altogether, this study suggests that nmTECs play a significant role in MG pathogenesis via ectopic expression of neuromuscular molecules.

  Study JGAS000482

• High MAPK Activity Leading to Reduced WNT Signaling Drives Metastasis in Colorectal Cancer

  Colorectal cancer, a leading cause of cancer-related mortality due to distant metastases, is driven by activating mutations in the Wnt and MAPK pathways. Understanding the interplay between these crucial pathways during metastatic progression is essential for developing effective treatments. Here we developed an immunocompetent mouse model of metastatic colorectal cancer using in vivo orthotopic passaging. We demonstrate that highly metastatic tumor cells exhibit chromosomal amplifications in MAPK pathway genes, leading to increased MAPK activity, which in turn suppresses Wnt-associated transcriptional programs, including stem cell-associated genes. Inhibiting mutant KrasG12D effectively reversed this metastatic transcriptional state, reducing MAPK-driven gene expression and restoring Wnt activity. Notably, this treatment significantly curtailed lung metastases and reduced liver metastases during early seeding stages. Analysis of CRC patient data revealed that high MAPK activity and the associated metastatic gene signature correlated with poorer survival outcomes. These findings underscore that the plasticity of metastasis-initiating cells in CRC arises from the opposing roles of MAPK and Wnt signaling, despite their synergistic importance in colon tumor initiation.

  Study EGAS50000001231

• Distinct genomic profiles and clinical outcomes in constitutional mismatch repair deficiency-associated high-grade gliomas: insights into mutational signatures and clonal evolution

  Constitutional mismatch repair deficiency (CMMRD) is a rare cancer-predisposition syndrome, yet the mutational processes and clonal evolution of CMMRD-associated high-grade gliomas (HGGs) remain incompletely understood. In this study, mutational signatures and tumor evolution were analyzed in 25 CMMRD-associated HGGs. Germline biallelic mutations were most frequently identified in MSH6 (56.0%), followed by PMS2 (36.0%) and MLH1 (8.0%). Affected patients showed very early disease onset (mean 5.8 years) and poor clinical outcomes, with a mean progression-free survival of 16 months. Distinct genomic and clinical differences were observed between MSH6- and PMS2-associated tumors. MSH6-deficient HGGs were enriched for SBS6, whereas PMS2-deficient tumors showed predominance of SBS21, and these mutational signatures were correlated with prognosis. Clonal evolution analyses revealed early involvement of POLE/POLD1 mutations and persistence of the founding clone at recurrence. Overall, the study highlights the importance of mutational signatures and clonal evolution in shaping tumor behavior and clinical outcomes in CMMRD-associated HGGs.

  Study EGAS50000001506

• TGF-β signaling mediates microglial resilience to spatiotemporally restricted myelin degeneration

  Microglia survey and regulate central nervous system myelination during embryonic development and adult homeostasis. However, whether microglia-myelin interactions are spatiotemporally regulated remains unexplored. By examining spinal cord white matter tracts, we found that myelin degeneration was particularly prominent in the dorsal column (DC) during normal aging. This was accompanied by molecular and functional changes in DC microglia as well as an upregulation of TGF-β signaling. Disrupting TGF-β signaling in microglia led to unchecked microglial responses and myelin loss in the DC, accompanied by neurological deficits exacerbated with aging. snRNA-seq revealed the emergence of a TGF-β signaling-sensitive microglial subset and a disease-associated oligodendrocyte subset, both spatially restricted to the DC. We further discovered that microglia rely on a TGFβ autocrine mechanism to prevent damage of myelin in the DC. These findings demonstrate that TGF-β signaling is indispensable for maintaining microglial resilience to myelin degeneration in the DC during the aging process. This highlights a previously unresolved checkpoint mechanism of TGF-β signaling with regional specificity and spatially restricted microglia-oligodendrocyte interactions.

  Study EGAS50000001413

• Whole Genome Sequencing of Gingivo-buccal Cancer: ICGC-India Project_YR03

  As a part of the ICGC, India has undertaken genomic studies on gingivobuccal cancer of the oral cavity, which is the most prevalent form of cancer among men in India. There are various known environmental (life-style) correlates of this cancer, the most important of which are tobacco chewing and HPV infection. Whole genome sequencing of paired DNA samples – isolated from the tumor tissue and from the blood of twenty five patients – have been performed to catalog germline and somatic mutations. Association between each observed genomic alteration and exposure to environmental risk factors is being explored. Detailed clinical characterization of the patients, collection of data on demographic and environmental exposures, and isolation of DNA samples from blood and tumor tissues collected from each patient are being done at the Advanced Centre for Research, Treatment and Education on Cancer, Mumbai. Whole genome sequencing is being performed at the National Institute of Biomedical Genomics, Kalyani. We have completed whole genome sequencing of paired blood and tumor DNA samples using Illumina HiSeq-2000 and 2500.

  Study EGAS00001001901