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In this study, we evaluate the impact of whole genome and transcriptome analysis (WGTA) on predictive molecular profiling and histologic diagnosis in a cohort of advanced malignancies. WGTA was used to generate reports including molecular alterations and site/tissue of origin prediction. Two reviewers analyzed genomic reports, clinical history, and tumor pathology. We used National Comprehensive Cancer Network (NCCN) consensus guidelines, Food and Drug Administration (FDA) approvals, and provincially reimbursed treatments to define genomic biomarkers associated with approved targeted therapeutic options (TTOs). Tumor tissue/site of origin was reassessed for most cases using genomic analysis, including a machine learning algorithm (Supervised Cancer Origin Prediction Using Expression [SCOPE]) trained on The Cancer Genome Atlas data. WGTA was performed on 652 cases, including a range of primary tumor types/tumor sites and 15 malignant tumors of uncertain histogenesis (MTUH). At the time WGTA was performed, alterations associated with an approved TTO were identified in 39 (6%) cases; 3 of these were not identified through routine pathology workup. In seven (1%) cases, the pathology workup either failed, was not performed, or gave a different result from the WGTA. Approved TTOs identified by WGTA increased to 103 (16%) when applying 2021 guidelines. The histopathologic diagnosis was reviewed in 389 cases and agreed with the diagnostic consensus after WGTA in 94% of non-MTUH cases (n = 374). The remainder included situations where the morphologic diagnosis was changed based on WGTA and clinical data (0.5%), or where the WGTA was non-contributory (5%). The 15 MTUH were all diagnosed as specific tumor types by WGTA. Tumor board reviews including WGTA agreed with almost all initial predictive molecular profile and histopathologic diagnoses. WGTA was a powerful tool to assign site/tissue of origin in MTUH. Current efforts focus on improving therapeutic predictive power and decreasing cost to enhance use of WGTA data as a routine clinical test.

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and phenocopies a muscle precursor that fails to undergo terminal differentiation. The alveolar subtype (ARMS) has the poorest prognosis and represents the greatest unmet medical need for RMS. Emerging evidence supports the role of epigenetic dysregulation in RMS. Here we show that SMARCA4/BRG1, an ATP-dependent chromatin remodeling enzyme of the SWI/SNF complex, is prominently expressed in primary tumors from ARMS patients and cell cultures. Our validation studies for a CRISPR screen of 400 epigenetic targets identified SMARCA4 as a unique factor for long-term (but not short-term) tumor cell survival in ARMS. A SMARCA4/SMARCA2 protein degrader (ACBI-1) demonstrated similar long-term tumor cell dependence in vitro and in vivo. These results credential SMARCA4 as a tumor cell dependency factor and a therapeutic target in ARMS.

Ovarian carcinoma histotypes are distinct diseases with variable clinical outcomes and response to treatment. There is a need for new subtype-specific treatment modalities, especially for women with widespread and chemo-resistant disease. Stimulator of interferon genes (STING) is a part of the cGAS-STING pathway that mediates innate immune defence against infectious DNA-containing pathogens and also detects tumour-derived DNA and generates intrinsic antitumour immunity. The STING signalling pathway is suppressed by several mechanisms in a variety of malignant diseases and, in some cancers that may be a requirement for cellular transformation. The aim of this study was to use immunohistochemistry to evaluate STING protein expression across normal tissue, paratubal and ovarian cysts, and ovarian tumour histotypes including ovarian carcinomas. Herein, we show that the fallopian tube ciliated cells express STING protein, whereas the secretory cells are negative. STING expression differs among ovarian cancer histotypes; low-grade serous ovarian carcinomas and serous borderline tumours have uniform high STING expression, while high-grade serous and endometrioid carcinomas have heterogeneous expression, and clear cell and mucinous carcinomas show low expression. As low-grade serous carcinomas are known to be genomically stable and typically lack a prominent host immune response, the consistently high STING expression is unexpected. High STING expression may reflect pathway activation or histogenesis and the mechanisms may be different in different ovarian carcinoma histotypes. Further studies are needed to determine whether the STING signalling pathway is active and whether these tumours would be candidates for therapeutic interventions that trigger innate immunity activation.

Background: Despite an overall poor prognosis, about 15% of patients with advanced-stage tubo-ovarian high-grade serous carcinoma (HGSC) survive ten or more years after standard treatment., Methods: We evaluated the tumor microenvironment of this exceptional, understudied group using a large international cohort enriched for long-term survivors (LTS; 10+ years; n = 374) compared to medium-term (MTS; 5-7.99 years; n = 433) and short-term survivors (STS; 2-4.99 years; n = 416). Primary tumor samples were immunostained and scored for intra-epithelial and intra-stromal densities of 10 immune-cell subsets (including T cells, B cells, plasma cells, myeloid cells, PD-1+ cells, and PD-L1+ cells) and epithelial content., Results: Positive associations with LTS compared to STS were seen for 9/10 immune-cell subsets. In particular, the combination of intra-epithelial CD8+ T cells and intra-stromal B cells showed near five-fold increased odds of LTS compared to STS. All of these associations were stronger in tumors with high epithelial content and/or the C4/Differentiated molecular subtype, despite immune-cell densities generally being higher in tumors with low epithelial content and/or the C2/Immunoreactive molecular subtype., Conclusions: The tumor microenvironment of HGSC long-term survivors is distinguished by the intersection of T and B cell co-infiltration, high epithelial content and C4/Differentiated molecular subtype, features which may inspire new approaches to immunotherapy., Funding: Ovarian Cancer Research Program (OCRP) of the Congressionally Directed Medical Research Program (CDMRP), U.S. Department of Defense (DOD); American Cancer Society; BC Cancer Foundation; Canada's Networks of Centres of Excellence; Canadian Cancer Society; Canadian Institutes of Health Research; Cancer Councils of New South Wales, Victoria, Queensland, South Australia and Tasmania, Cancer Foundation of Western Australia; Cancer Institute NSW; Cancer Research UK; Deutsche Forschungsgesellschaft; ELAN Funds of the University of Erlangen-Nuremberg; Fred C. and Katherine B. Andersen Foundation; Genome BC; German Cancer Research Center; German Federal Ministry of Education and Research, Programme of Clinical Biomedical Research; Instituto de Salud Carlos III; Mayo Foundation; Minnesota Ovarian Cancer Alliance; Ministerio de Economía y Competitividad; MRC; National Center for Advancing Translational Sciences; National Health and Medical Research Council of Australia (NHMRC); Ovarian Cancer Australia; Peter MacCallum Foundation; Sydney West Translational Cancer Research Centre; Terry Fox Research Institute; The Eve Appeal (The Oak Foundation); UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge; University of Pittsburgh School of Medicine; U.S. National Cancer Institute of the National Institutes of Health; VGH & UBC Hospital Foundation; Victorian Cancer Agency.

Objective: Targeted therapy in folate receptor alpha (FOLR1)-positive high grade serous ovarian carcinoma (HGSOC) is now a mainstay for platinum-resistant disease. However, the rate of FOLR1-positivity in low grade serous ovarian carcinoma (LGSOC) is not well documented. Less common than HGSOC, LGSOC tends to respond poorly to traditional platinum-based chemotherapeutic regimens, particularly in recurrence. Thus, there is an urgent need to identify molecular targets that may assist in identifying more efficacious treatments for LGSOC. In this work, we assessed the genomic and transcriptomic landscapes in FOLR1-positive/negative LGSOC compared to its high-grade counterpart., Methods: Using a large precision oncology database, next-generation sequencing and immunohistochemistry was performed on a cohort of 281 LGSOC and 5086 HGSOC. Associated MAPK activation was calculated based on NGS results and patient survival analysis was completed stratified by molecular alteration., Results: Compared with LGSOC (24.6 %), HGSOC tumors have significantly higher prevalence of FOLR1+ status (43.5 %) and significantly higher PD-L1+ status. Conversely, LGSOC had higher prevalence of KRAS and NRAS mutations, with a near exclusivity for BRAF mutation compared to HGSOC. FOLR1- LGSOC and HGSOC had similar prevalences of T cell-inflamed tumors, though FOLR1+ LGSOC had a significantly lower prevalence of T-Cell inflamed tumors than FOLR1+ HGSOC. MAPK activation, quantified via MAPK activation score (MPAS), was significantly higher in low-grade tumors compared to HGSOC, yet no difference between FOLR1+ vs FOLR1- LGSOC was observed., Conclusions: Though less than in high-grade disease, a notable portion of low-grade tumors were FOLR1+, suggesting FOLR1 expression in LGSOC could be a viable target for this rare histology, particularly in the recurrent setting., Competing Interests: Declaration of competing interest The authors have no competing interests to declare that are relevant to the content of this article., (Copyright © 2024. Published by Elsevier Inc.)

Purpose: The new CAP guideline published in August 2022 recommends using immunohistochemistry (IHC) to test for mismatch repair defects in gastroesophageal (GE), small bowel (SB), or endometrial carcinoma (EC) cancers over next-generation sequencing assessment of microsatellite instability (NGS-MSI) for immune checkpoint inhibitor (ICI) therapy eligibility and states there is a preference to use IHC over NGS-MSI in colorectal carcinoma (CRC)., Methods: We assessed the concordance of NGS-MSI and IHC-MMR from a very large cohort across the spectrum of solid tumors., Results: Of the over 190,000 samples with both NGS-MSI and IHC-MMR about 1,160 were initially flagged as discordant. Of those samples initially flagged as discordant, 50.9% remained discordant after being reviewed by an additional pathologist. This resulted in a final discordance rate of 0.31% (590/191,767). Among CRC, GE, SB and EC, 55.4% of mismatch repair proficient/MSI high (MMRp/MSI-H) tumors had at least one somatic pathogenic mutation in an MMR gene or POLE . Mismatch repair deficient/microsatellite stable (MMRd/MSS) tumors had a significantly lower rate of high tumor mutational burden than MMRp/MSI-H tumors. Across all solid tumors, MMRd/MSI-H tumors had significantly longer overall survival (OS; hazard ratio [HR], 1.47, P < .001) and post-ICI survival (HR, 1.82, P < .001) as compared with MMRp/MSS tumors. The OS for the MMRd/MSS group was slightly worse compared to the MMRp/MSI-H tumors, but this difference was not statistically significant (HR, 0.73, P = .058), with a similar pattern when looking at post-ICI survival (HR, 0.43, P = .155)., Conclusion: This study demonstrates that NGS-MSI is noninferior to IHC-MMR and can identify MSI-H tumors that IHC-MMR is unable to detect and conversely IHC-MMR can identify MMRd tumors that NGS-MSI misses.