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• Single Cell RNA-Seq Reveals Malignant and Stromal Programs Associated with Metastasis in Head and Neck Cancer

  This study of head and neck cancer aimed to profile individual malignant, stromal, and immune cells in treatment-naive oral cavity squamous cell carcinoma, with or without matched metastatic cervical lymph nodes. Clinical and pathologic information was collected on all patients, in addition to a fresh biopsy sample from the primary tumor and/or metastatic lymph node at the time of initial surgery. Biopsy specimens were processed for single cell RNA-seq (scRNA-seq) and/or whole exome sequencing (WES). A total of ~6,000 single cells from 18 participants were included in the final dataset. Stromal and immune cells had consistent expression programs across patients. Conversely, malignant cells varied within and between tumors in their expression of signatures related to cell cycle, stress, hypoxia, epithelial differentiation, and partial epithelial-to-mesenchymal transition (p-EMT). One of the top scoring genes in this program was TGFβ-induced (TGFBI), implicating the classic EMT regulator TGFβ. Cells expressing the p-EMT program spatially localized to the leading edge of primary tumors. By integrating single-cell transcriptomes with bulk expression profiles for hundreds of tumors, we refined Head and Neck Squamous Cell Carcinoma (HNSCC) subtypes by their malignant and stromal composition, and established p-EMT as an independent predictor of nodal metastasis, grade, and adverse pathologic features. Our results provide insight into the HNSCC ecosystem and define stromal interactions and a p-EMT program associated with metastasis.

  Study phs001474

• Tumor-reactive heterotypic CD8 T cell clusters from clinical samples

  Emerging evidence suggests a correlation between CD8+ T cell-tumor cell proximity and anti-tumor immune response. However, it remains unknown whether these cells exist as functional clusters that can be isolated from clinical samples. By conventional and imaging flow cytometry, we show here that from 21/21 human melanoma metastases, we could isolate heterotypic clusters, comprising CD8+ T cells interacting with one or more tumor cells and/or antigen-presenting cells (APCs). Single-cell RNA-sequencing revealed that T cells from clusters were enriched for gene signatures associated with tumor reactivity and exhaustion. Clustered T cells exhibited increased TCR clonality indicative of expansion, while TCR-matched T cells showed more exhaustion and co-modulation when conjugated to APCs than to tumor cells. T cells that were expanded from clusters ex vivo exerted on average 9-fold increased killing activity towards autologous melanomas, which was accompanied by enhanced cytokine production. Upon adoptive cell transfer into mice, T cells from clusters showed improved patient-derived melanoma control, which was associated with increased T cell infiltration and activation. Together, these results demonstrate that tumor-reactive CD8+ T cells are enriched in functional clusters with tumor cells and/or APCs and that they can be isolated and expanded from clinical samples. Typically excluded by single cell gating in flow cytometry, these distinct heterotypic T cell clusters serve as a valuable source to decipher functional tumor-immune cell interactions, while they may also be therapeutically explored.

  Study EGAS50000000785

• Whole Tumor spatial heterogeneity in metastatic melanoma

  Heterogeneous inter-tumoral responses, sustained periods of apparent clinical benefit despite lack of objective response to various therapies, and even spontaneous remission are well known within a subpopulation of advanced melanoma patients. The molecular and cellular dynamics facilitating long-term survival remain poorly defined, particularly in the current era ofexposure to multiple potentially active therapies. We studied an exceptional case of long-term survival in a patient with non-responding metastatic melanoma in order to characterize the clonal and microenvironmental factors.We performed immunogenomic analysis of 3 metachronous tumors, and of 67 intratumor sub-regions of one metastatic lesion, usingwhole exome sequencing, RNA-sequencing, immunohistochemistry, and T cell receptor sequencing. Longitudinal analysesidentified mutations in severalknownresistance genes affecting distinctmetastases. Intra-tumoral immune signatures revealed spatially-distinct pockets of immune activation and suppression throughout the metastasis. A specific T cell VBeta CDR3 rearrangement was identified as both dominant and recurrent not only across multiple spatial points within a single tumor mass, but also across metachronous tumors spanning the patient’s disease course. Immunophenotyping of this T cell population with single-cell sequencingsuggestedrepeatedT-cell priming events leading to the persistence of both activated and exhausted T cells bearing this same TCR-Beta at any given time.Our findings highlight genomic and immune heterogeneityin metastatic disease, extending to the intra-tumoral leveland provide a rationale for integrative spatiotemporal analysis of metastatic lesions in the context of immune checkpoint blockade.

  Study EGAS00001003292

• Persistent STAG2 mutation in recurrent pediatric glioblastoma

  Similar to their adult counterparts, the prognosis for pediatric patients with high-grade gliomas remains poor. At time of recurrence, treatment options are limited and remain without consensus. This report describes the genetic findings, obtained from whole exome sequencing of a pediatric patient with glioblastoma who underwent multiple surgical resections and treatment with standard chemoradiation, as well as a novel recombinant poliovirus vaccine therapy. Strikingly, despite the variety of treatments, there was persistence of a tumor clone, characterized by a deleterious STAG2 mutation, whose deficiency in pre-clinical studies can cause aneuploidy and aberrant mitotic progression, but remains understudied in the clinical setting. There was near elimination of an EGFR mutated and amplified tumor clone after gross total resection, standard chemoradiation, and poliovirus therapy, followed by the emergence of a persistently STAG2 mutated clone, with rare mutations in PTPN11 and BRAF, the latter composed of a novel deleterious mutation previously not reported in pediatric glioblastoma (p.D594G). This was accompanied by a mutation signature shift towards one characterized by increased DNA damage repair defects, consistent with the known underlying STAG2 deficiency. As such, this case represents a novel report following the clinical and genetic progression of a STAG2 mutated glioblastoma, including treatment with a novel and emerging immunotherapy. Although STAG2 deficiency comprises only a small subset of gliomas, this case adds clinical evidence to existing pre-clinical data supporting a role for STAG2 mutations in tumor formation and resistance to standard therapies.

  Study EGAS00001004340

• Targeted sequencing of candidate regions on chromosome 22q predisposing to multiple schwannomas

  Constitutional LZTR1 or SMARCB1 pathogenic variants have been found in ~86% of familial and ~40% of sporadic schwannomatosis cases. Hence, we performed massively parallel sequencing of the entire LZTR1, SMARCB1 and NF2 genomic loci in 35 individuals with schwannomas negative for constitutional first-hit pathogenic variants in the LZTR1/SMARCB1/NF2 coding sequences, however with 22q deletion and/or a different NF2 pathogenic variant in each tumor, including six cases with only one tumor available. Furthermore, we verified whether any other LZTR1/SMARCB1/NF2 (likely) pathogenic variant(s) could be found in 16 cases carrying a SMARCB1 constitutional variant in the 3’ untranslated region (3’-UTR) c.*17C>T, c.*70C>T or c.*82C>T. As no additional variants were found, functional studies were performed to clarify the effect of these 3’-UTR variants on the transcript. The 3’-UTR variants c.*17C>T and c.*82C>T showed pathogenicity by negatively affecting SMARCB1 transcript level. Two novel deep intronic SMARCB1 variants, c.500+883T>G and c.500+887G>A, resulting in out-of-frame missplicing of intron 4, were identified in two unrelated individuals. Further resequencing of the entire repeat - masked genomics sequences of chromosome 22q in individuals negative for pathogenic variants in the SMARCB1/LZTR1/NF2 coding- and non-coding regions revealed five potential schwannomatosis-predisposing candidate genes, i.e. MYO18B, NEFH, SGSM1, SGSM3 and SBF1, pending further verification.

  Study EGAS00001005680

• Whole exome sequencing data for paired non-serous endometrial and ovarian carcinomas from 27 patients with concurrent tumours.

  Introduction: Concurrent non-serous endometrial and ovarian tumours are often managed clinically as two separate primary tumours, but almost all exhibit evidence of a genomic relationship. Methodology: This study investigates the extent of relatedness using whole exome sequencing, which was performed on paired non-serous endometrial and ovarian carcinomas from 27 patients with concurrent tumours in a cohort with detailed clinicopathological annotation. Four whole exome sequencing-derived parameters (mutation, mutational burden, mutational signatures and mutant allele tumour heterogeneity scores) were used to develop a novel unsupervised model for the assessment of genomic similarity to infer genomic relatedness of paired tumours. Results: This novel model demonstrated genomic relatedness across all four parameters in all tumour pairs. Mutations in PTEN, ARID1A, CTNNB1, KMT2D and PIK3CA occurred most frequently and 24 of 27 (89 %) tumour pairs shared identical mutations in at least one of these genes, with all pairs sharing mutations in a number of other genes. Ovarian endometriosis, CTNNB1 exon 3 mutation, and progression and death from disease were present across the similarity ranking. Mismatch repair deficiency was associated with less genomically similar pairs. Discussion: Although there was diversity across the cohort, the presence of genomic similarity in all paired tumours supports the hypothesis that concurrent non-serous endometrial and ovarian carcinomas are genomically related and may have arisen from a common origin. Keywords: Co-existing; Concurrent; Endometrial carcinoma; Genomics; Mutation; Ovarian carcinoma; Paired tumours; Tumour mutational burden.

  Study EGAS00001008259

• Preclinical Pediatric Molecular Analysis for Therapy Choice (MATCH)

  Purpose: Pediatric solid tumors arise from diverse tissues during development and exhibit a wide range of molecular, cellular and genetic features. This diversity, combined with the low incidence of pediatric cancer makes it increasingly difficult to personalize therapy for individual patients based on the unique features of their tumors. Therefore, well-credentialed preclinical models that capture the diversity and heterogeneity of pediatric solid tumors are essential for identifying molecular targeted therapeutics for precision medicine. Experimental Design: Here, we report 281 orthotopic patient derived xenografts (O-PDXs) from 224 patients representing 24 different types of pediatric solid tumors. We have performed genomic characterization of the O-PDXs and compared them to their corresponding patient tumors. To demonstrate the feasibility and utility of using such a diverse collection of O-PDXs in preclinical studies, we performed a preclinical pediatric precision medicine trial based on the NCI-COG Pediatric MATCH trial enrollment criteria. We also tested molecular targeted therapy for a novel oncogenic fusion recently reported in pediatric melanoma and precision drug delivery using nano-liposomal irinotecan. Results: In the preclinical match study, we identified one specific single agent response to LY3023414 in an osteosarcoma model with a TSC2 variant of unknown significance. Combinations of nano-liposomal irinotecan were effective in treating both Ewing sarcoma and rhabdomyosarcoma xenografts. Conclusion: Our studies demonstrate the value of large, well-credentialed preclinical models for future precision medicine in pediatric oncology using single agents, drug combinations and novel drug formulations.

  Study EGAS00001008011

• Extrachromosomal DNA Amplification Contributes to Small Cell Lung Cancer Heterogeneity and is Associated with Worse Outcomes

  Small-cell lung cancer (SCLC) is a very aggressive neuroendocrine lung cancer often associated with oncogenic MYC amplifications, which are known to drive SCLC heterogeneity marked by neuroendocrine (NE) and non-neuroendocrine (non-NE) cell states. The genetic mechanisms of MYC amplification and phenotypic plasticity between cell states is not known. Using data from cell-lines and a few patient-derived samples along with integrated whole-genome sequencing, long-range optical mapping, single-cell DNA sequencing, and fluorescence in situ hybridization, we have attempted to successfully characterize extrachromosomal DNA (ecDNA) as the primary source of MYC amplifications and driver fusions in SCLC.

  Study phs003190

• Genetic Studies of Chronic Kidney Disease (CKD)

  The Genetic Studies of Chronic Kidney Disease (CKD) is an ongoing genetic research and biobanking protocol which aims to elucidate the genetic basis CKD. The study recruits patients seen at the Columbia University Medical Center (CUMC) Nephrology Division for the evaluation and care of CKD. All patients clinically diagnosed with CKD are eligible to participate; there are no inclusion or exclusion criteria related to age, sex/gender, and/or race/ethnicity. In addition to office visits, patients are recruited in contexts including perinatal care and nonprofit events for patients with various forms of CKD; recruitment tools include bilingual informational brochures, flyers, and consent forms. All individuals provide informed consent; for minors, signature of the parent/guardian is required. Consent includes: use of biosamples given for genetic studies, and the request to be re-contacted if medically actionable genetic findings are identified. In the case of the latter, such research-level findings are first validated in a clinically certified (CLIA) laboratory environment, using a second sample given by the individual at the time of re-contact; following CLIA validation, the individual is once again re-contacted, and, assuming he or she still desires return of these results, they can then be returned. Following the above consent process to participate in the study, individuals provide a single biosample (generally, a venous blood sample), from which DNA is extracted using standard protocols and used for genetic studies, such as exome sequencing. Basic clinical and demographic data, including sex/gender, age, and race/ethnicity are also collected. All data collected is stored in a secure computerized database, with patient samples anonymized using numerical identifiers; the relation of this identifier to patients' names is kept in a locked computer file in a centralized database. Electronic data complies with all HIPAA and other privacy and security regulations, and resides on a firewall server maintained by the CUMC IT department.

  Study phs001828

• Multicenter International Lymphangioleiomyomatosis Efficacy of Sirolimus Trial (The MILES Trial)

  Lymphangioleiomyomatosis (LAM) is an uncommon, progressive, cystic lung disease that predominantly affects young women. It is believed to be caused by defects within cellular pathways that regulate nutrient uptake, cell size, cell migration, and cell proliferation. The disease is caused by mutations in tuberous sclerosis complex (TSC) genes. Individuals with Lymphangioleiomyomatosis (LAM) often experience pneumothorax and chylothorax, as well progressive loss of lung function. Lymphangioleiomyomatosis (LAM) is frequently fatal and existing therapies for the disease have not proven effective. Lung transplantation can be considered as a last option, but alternative treatments are needed. Sirolimus is an immunosuppressive drug that is often used in people who have had kidney transplants. It directly affects the genetic pathway that causes Lymphangioleiomyomatosis (LAM). This study will evaluate the safety and effectiveness of sirolimus in stabilizing or improving lung function in people with Lymphangioleiomyomatosis (LAM). Individuals interested in participating in this 2-year, double-blind study will first report to the study sites for pulmonary function testing to determine their eligibility for participation. Participants deemed eligible will be randomly assigned to receive either sirolimus or placebo for 1 year. Sirolimus or placebo will be administered in 2 tablet doses (2 mg for sirolimus) for the duration of the study. Study visits will occur at baseline, Week 3, every 3 months for 12 months, and Months 18 and 24. Study visits will include a physical exam, questionnaires, a pregnancy test, blood and urine collection, and functional lung tests. A 6-minute walk test will occur at most study visits; a chest x-ray will be taken at baseline and Month 24; and a volumetric computed tomography scan will occur at baseline Month 12, and Month 24. Adverse events, medication side effects, and lung function will be assessed at each visit.

  Study phs000605