Primary cytotoxic T cell lymphomas (CTCLs) are a rare subset of aggressive, poor-prognosis T-cell lymphomas targeting the skin; they include primary cutaneous γδT-cell lymphoma, primary cutaneous VD8+ aggressive epidermotropic T cell lymphoma (PCAETCL), and cytotoxic CTCL not otherwise specified. Lee et al report that all 3 subsets have JAK-STAT activation, but PCAETCL uniquely carries JAK2 gene fusions that may render them especially susceptible to JAK inhibitors.

Neuroendocrine neoplasms (NEN) encompass a diverse set of malignancies with limited precision therapy options. Recently, therapies targeting DLL3 have shown clinical efficacy in aggressive NENs, including small cell lung cancers and neuroendocrine prostate cancers. Given the continued development and expansion of DLL3-targeted therapies, we sought to characterize the expression of DLL3 and identify its clinical and molecular correlates across diverse neuroendocrine and non-neuroendocrine cancers. Here, we interrogated paired DNA and RNA-sequencing from 1,589 NENs across 29 sites, as well as 203,252 tumors across 47 cancer types. We found that high transcriptomic levels of DLL3 correlated with more aggressive histologic and mutational patterns in NENs, with adverse survival outcomes being reflected in NENs originating from the lung, pancreas, stomach, and small bowel. The heterogeneity in DLL3 expression across NENs was largely explained by site of origin, with lung, prostate, and bladder NENs exhibiting relatively high levels of DLL3, whereas gastroenteropancreatic NENs displayed relatively low expression levels. Although the therapeutic targeting of DLL3 may be less applicable for gastroenteropancreatic NENs, we did find an upregulation of alternative targets such as SEZ6, CELSR3, and SSTR2 in these settings. Lastly, expanding our investigation into non-neuroendocrine cancers, we detected an enrichment of DLL3 in both low-grade and high-grade gliomas, Merkel cell carcinomas, medulloblastomas, and melanomas, with such enrichment being associated with prolonged overall survival in gliomas, but worse overall survival in melanomas. Altogether, we demonstrate that DLL3 represents an attractive target for subsets of neuroendocrine and non-neuroendocrine cancers and uncover opportunities for future therapeutic strategies. Significance: DLL3-targeted therapies have recently shown robust clinical efficacy in aggressive neuroendocrine cancers, positioning them to fulfill a great unmet need in these settings. Here, we examine the clinical and biological correlates of DLL3 expression in both neuroendocrine and non-neuroendocrine cancers. Our findings may stimulate the development and application of DLL3-targeted therapies, as well as other precision therapies, in neuroendocrine cancers and beyond.

Purpose: Around 10% to 15% of prostate cancers harbor recurrent aberrations in the Forkhead Box A1 gene, FOXA1, whereby the alteration type and the effect on the forkhead (FKH) domain affect protein function. We developed a FOXA1 classification system to inform clinical management. Experimental Design: A total of 5,014 prostate cancer samples were examined using whole-exome and -transcriptome sequencing from the Caris Life Sciences database. We denoted class 1 FOXA1 alterations as missense and in-frame insertions/deletions with subclasses oriented with respect to the FKH domain. These were in the first part of the FKH domain [class 1A: amino acids (AA) 168–246], within the Wing2 region of FKH (class 1B: AA 247–269), or outside FKH (class 1C: AA 1–167, 270+). Two hotspot missense mutations at R219 were denoted class 2. Class 3 included predicted truncating mutations with subclasses partitioned based on the FKH domain (class 3A: AA 1–269 and class 3B: AA 270+). Class 4 represented FOXA1 amplifications. Real-world overall survival and therapy outcomes were determined from insurance claims. Results: FOXA1 alterations did not influence survival when considered in aggregate but had distinct prognostic effects when stratified by class. In primary prostate samples, class 1A alterations were associated with overall improved survival (HR, 0.57; P = 0.03); a similar trend was seen in metastatic biopsies with class 1B (HR, 0.84; P = 0.09). Conversely, in primary specimens, class 1C exhibited worse survival upon second-generation androgen receptor signaling inhibitor treatment (HR, 1.93; P < 0.001). Class 2 mutations (R219C/S) were enriched in neuroendocrine prostate cancers and were associated with overall poor survival (HR, 2.05; P < 0.001) and worse outcomes to first-line androgen-deprivation therapies (HR, 2.5; P < 0.001). Class 3A alterations indicated improved survival (HR, 0.70; P = 0.01), whereas class 3B alterations portended poor outcomes (HR, 1.50; P < 0.001). Amplifications (class 4) indicated poor outcomes in metastatic samples (HR, 1.48; P = 0.02). Molecularly, different FOXA1 alteration classes harbored distinct mutational and immunologic features as well as unique transcriptional programs. Finally, relative to European Americans, African Americans had increased class 1C alterations, whereas Asian/Pacific Islander patients had increased class 1B alterations. Conclusions: FOXA1 alterations should not be interpreted in aggregate, as different classes are associated with divergent molecular features and clinical outcomes. Our revised classification schema facilitates clinical decision-making for patients with prostate cancer and uncovers important racial differences.

PURPOSE: Nuclear protein in testis carcinoma (NC) is an underdiagnosed and aggressive squamous/poorly differentiated cancer characterized by rearrangement of the gene NUTM1 on chromosome 15q14. Co-occurring alternations have not been fully characterized. METHODS: We analyzed the genomic and immune landscape of 54 cases of NC that underwent DNA- and RNA-based NGS sequencing (Caris). RESULTS: While NC is driven by NUTM1 fusion oncoproteins, co-occurring DNA mutations in epigenetic or cell cycle pathways were observed in 26% of cases. There was no significant difference between the fusion partner of NUTM1 and co-occurring gene mutations. RNA sequencing analysis showed increased MYC pathway activity in NC compared with head and neck squamous cell carcinoma (HNSCC) and lung squamous cell carcinoma (LUSC), which is consistent with the known pathophysiology of NC. Characterization of the NC tumor microenvironment using RNA sequencing revealed significantly lower immune cell infiltration compared with HNSCC and LUSC. NC was 10× higher in patients with HNSCC and LUSC younger than 50 years than in those older than 70 years. CONCLUSION: To our knowledge, this is the first series of NC profiled broadly at the DNA and RNA level. We observed fewer intratumoral immune cells by RNA sequencing, which may be associated with anecdotal data of lack of immunotherapy benefit in NC. High MYC pathway activity in NC supports ongoing trials targeting MYC suppression. The incidence of NC among patients younger than 50 years with LUSC/HNSCC supports testing for NC in these patients. The prognosis of NCs remains dismal, and future studies should focus on improving the response to immunotherapy and targeting MYC.