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Ion channels, transporters, and other ion-permeating proteins, collectively comprising the ion permeome (IP), are common drug targets. However, their roles in cancer are understudied. Our integrative pan-cancer analysis shows that IP genes display highly-elevated expression patterns in subsets of cancer samples significantly more often than expected transcriptome-wide. To enable target identification, we identified 410 survival-associated IP genes in 29 cancer types using a machine learning approach. Notably,GJB2andSCN9Ashow prominent expression in neoplastic cells and associate with poor prognosis in glioblastoma (GBM), the most common and aggressive brain cancer.GJB2orSCN9Aknockdown in patient-derived GBM cells induces transcriptome-wide changes involving neural projection and proliferation pathways, impairs cell viability and tumor sphere formation, mitigates tunneling nanotube formation, and extends the survival of GBM-bearing mice. Thus, aberrant activation of IP genes appears as a pan-cancer feature of tumor heterogeneity that can be exploited for mechanistic insights and therapy development.

Malignant peripheral nerve sheath tumor (MPNST)-like melanoma is a rare malignancy with overlapping characteristics of both neural sarcoma and melanoma. Although the genomics of cutaneous melanoma has been extensively studied, those of MPNST-like melanoma have not. To characterize the genomic landscape of MPNST-like melanoma, we performed a single-center, retrospective cohort study at a tertiary academic cancer center. Consecutive patients with a confirmed histologic diagnosis of MPNST-like melanoma were screened, and those whose tissues were locally available were included in this analysis. Archival tissue from six patients (eight samples) was submitted for whole-exome and transcriptome sequencing analysis. We compared these data with available genomic studies of cutaneous melanoma and MPNST. NF1 was altered (mutated, deleted, or amplified) in 67% of patients. Genes related to cell cycle regulation were frequently altered, with frequent deletion of ZNF331, which, to the best of our knowledge, has not been previously described in cutaneous melanoma. The serine protease inhibitor SERPINB4 was deleted in 100% of the patients. We show that MPNST-like melanoma presents overlapping genomic features with cutaneous melanoma and MPNST, but it is unique by the frequency of loss of function of ZNF331 and SERPINB4.

Background In high grade serous ovarian cancer (HGSOC), there is a spectrum of sensitivity to first line platinum‐based chemotherapy. This study molecularly characterizes HGSOC patients from two distinct groups of chemotherapy responders (good vs. poor). Methods Following primary debulking surgery and intravenous carboplatin/paclitaxel, women with stage III–IV HGSOC were grouped by response. Patients in the good response (GR) and poor response (PR) groups respectively had a progression‐free intervals (PFI) of ≥12 and ≤6 months. Analysis of surgical specimens interrogated genomic and immunologic features using whole exome sequencing. RNA‐sequencing detected gene expression outliers and inference of immune infiltrate, with validation by targeted NanoString arrays. PD‐L1 expression was scored by immunohistochemistry (IHC). Results A total of 39 patient samples were analyzed (GR = 20; PR = 19). Median PFI for GR and PR patient cohorts was 32 and 3 months, respectively. GR tumors were enriched for loss‐of‐function BRCA2 mutations and had a significantly higher nonsynonymous mutation rate compared to PR tumors (p = 0.001). Samples from the PR cohort were characterized by mutations in MGA and RAD51B and trended towards a greater rate of amplification of PIK3CA, MECOM, and ATR in comparison to GR tumors. Gene expression analysis by NanoString correlated increased PARP4 with PR and increased PD‐L1 and EMSY with GR. There was greater tumor immune cell infiltration and higher immune cell PD‐L1 protein expression in the GR group. Conclusions Our research demonstrates that tumors from HGSOC patients responding poorly to first line chemotherapy have a distinct molecular profile characterized by actionable drug targets including PARP4., In patients with suboptimally‐debulked, advanced high grade serous ovarian cancer (HGSOC), the spectrum of responses to first line platinum‐based chemotherapy (PtC) vary from durable to non‐existent, highlighting an unmet medical need for those with poor responses. Our study molecularly characterizes a cohort of HGSOC patients with distinct responses, either good or poor, to PtC. The good and poor responders have median progression‐free intervals of 32 and 3 months, respectively, and molecular analysis of tumors identifies differences in DNA damage response pathways and immunity, namely, tumors from poor responders to first line PtC have a distinct molecular profile characterized by actionable drug targets including PARP4.

e22072 Background: Malignant Peripheral Nerve Sheath Tumor (MPNST)-like melanoma is a rare entity wherein cutaneous melanoma mimics histomorphological features of MPNST. The genomic landscape of MPNST-like melanoma has not been previously described. We report the genomic findings of 6 patients diagnosed with MPNST-like melanoma. Methods: We identified consecutive patients with confirmed histological diagnosis of MPNST-like melanoma. Archival tissue was submitted for whole exome and transcriptome sequencing analysis and genomic findings were compared to publicly available data on the genomic landscape of both melanoma and limited genetic descriptions of MPNST. Results: Six patients diagnosed with MPNST-like melanoma between November 2002 and July 2018 had archival tissue available (8 samples). Mean age at diagnosis was 60.5 years (38-74). The mean tumor mutational burden (TMB) was 35.72 mutations/exon coding megabase, ranging from 4.27 to 86.36. NF1 alterations were found in 4 (67%) of cases: one had 3 truncating mutations (W696 + X1870_splice + R1590C) associated with NF1 amplification, one had a deep deletion and another two had truncating mutations (I1908L and W696 + A1530V). Two tumors had non-V600 BRAF mutations that predict alteration in kinase function. We observed deletions of cell cycle regulators: CDKN2A and CDKN2B in 33%; and ZNF331 (19q13.42) in 83% of cases. SERPINB4 (18q21.3), described previously as a tumor suppressor in oral squamous cell carcinomas, was deleted in all samples. The patient with NF1 amplification and truncating mutations received immunotherapy due to metastatic disease and achieved a complete response; his tumor had a TMB of 72.6. Another patient who died of metastatic melanoma, treated with chemotherapy in the pre-immunotherapy era, lacked any NF1 mutation but had a Q61K NRAS mutation; the tumor had a TMB of 15. The remaining patients were treated with surgical resection alone and continue on follow-up. Conclusions: MPNST-like melanoma shares some frequently altered genes in cutaneous melanoma but possesses an excess of NF-1 mutations or deletions, in keeping with its neural-like phenotype. The high frequency of SERPINB4 alterations suggests a critical tumor suppressor role in this subtype of melanoma, warranting further investigation. Additionally, cell cycle dysregulation caused by deletion of ZNF331 and CDKN2A/B may be important in MPNST-like melanoma carcinogenesis.

3562 Background: Next generation sequencing targeted panels increasingly inform clinical decisions, but may miss actionable findings detectable by whole exome sequencing (WES) and RNA-seq. There has been no direct comparison of WES plus RNA-seq against targeted panel sequencing to determine its added utility. To address this, we performed WES and RNA-seq analysis in a cohort of 100 patients with no actionable findings on prior panel sequencing. Methods: Ontario-wide Cancer Targeted Nucleic Acid Evaluation (OCTANE; NCT02906943) has sequenced 2,106 patients using a 161-gene Oncomine or 555-gene Hi5 panel. 100 patients (98 Hi5, 2 Oncomine) were chosen for further sequencing. Tumor (100x coverage) and normal (50x) exomes and tumor transcriptomes were sequenced on Illumina HiSeq2500 or NextSeq550. Interpretation included knowledgebase annotation (e.g. OncoKB, CIViC), mutation signatures, homologous recombination deficiency (HRD) scores, gene expression, and pathway analysis. Findings were deemed “actionable” if they could directly inform management or trial eligibility. Results: WES and RNA-seq identified one or more novel actionable findings in 38 patients. Of these, the main actionable finding was tumor mutation burden (TMB), mutation signature, or HRD score in 19 (50%), a copy number variant in 16 (42%), a fusion in 2 (5%), and a point mutation in 1 (2.6%). WES identified a MALAT1-GLI1 fusion in a cancer of unknown primary (CUP) whose transcriptome was consistent with gastric cancer, together suggesting the diagnosis of a rare gastroblastoma. To date, two cases have received exome-supported targeted therapy: (1) a metastatic high grade serous ovarian cancer, HRD-high, treated with olaparib then cisplatin for a combined 15 months, and (2) a metastatic neuroendocrine rectal tumor with RICTOR amplification treated with everolimus starting in Dec 2016 until last follow-up in Sep 2019. Of 62 patients with no actionable finding, expanded sequencing identified one or more known cancer drivers in 25 (40%): 17 CNVs, 3 fusions, and 5 point mutations or indels. In 16 patients, an oncogenic variant found on panel was not captured by WES, and may represent artifacts, germline mutations, or subclonal/localized variants. Conclusions: WES and RNA-seq expanded detection of actionable biomarkers and oncogenic mutations, especially CNV, TMB/signatures, and HRD. Two cases have undergone exome-supported targeted treatment. We performed the first WES of a rare gastroblastoma, originally a CUP but reclassified by expanded fusion detection and RNA-seq.

Legionella pneumophila outbreak investigations require the development of reliable typing methods to better understand the genetic relationships of the isolates involved. Here, we report the draft genome sequences of four clinical Legionella pneumophila isolates obtained between 2000 and 2012 in Ontario, Canada.