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Background: Adenocarcinoma of the esophagus and stomach demands a deeper molecular understanding to advance treatment strategies and improve patient outcomes. Here, we profiled the genome and transcriptome landscape of these cancers, explored molecular characteristics that are undetectable by other sequencing platforms, and analyzed their potential clinical ramifications., Methods: Our study employed state-of-the-art integrative analyses of whole genome and transcriptome sequencing on 51 matched tumor and germline samples from 46 patients. Mutations and rearrangements in clinically relevant cancer genes were investigated and correlated with OncoKB, a knowledge-based precision oncology database, to identify treatment implications. Genome-wide signatures and manually curated molecular profiles were also determined., Results: The analyses revealed 90 targetable oncogenic mutations and fusions in 63 % of the patients, including novel NTRK, NRG1, ALK, and MET fusions, and structural variants in cancer genes like RAD51B. Also, molecular signatures associated with mismatch repair and homologous recombination deficiency were elucidated. Notably, we identified CDK12-type genomic instability associated with CDK12 fusions., Conclusions: Our findings support the potential of whole genome and transcriptome sequencing analyses as a comprehensive approach to identify treatment targets in adenocarcinoma of the stomach and the esophagus, and their application in precision oncology., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Kevin Hadi reports a relationship with Isabl that includes: employment. Aditya Deshpande reports a relationship with Isabl that includes: employment. Max F. Levine reports a relationship with Isabl that includes: employment. Minal Patel reports a relationship with Isabl that includes: employment. Juan Medina Martinez reports a relationship with Isabl that includes: employment. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Background/aim: Mesonephric adenocarcinoma in males is an exceptionally rare malignancy arising from mesonephric remnants. Accurate diagnosis requires thorough histopathological and molecular analysis., Case Report: A 33-year-old male presented with right lower quadrant pain, and imaging revealed a pelvic mass compressing adjacent structures. Biopsy confirmed mesonephric adenocarcinoma. Genetic profiling revealed mutations in tuberous sclerosis complex 2 (TSC2) and phosphatidylinositol-4,5-biphosphate 3-kinase catalytic subunit alpha (PIK3CA), offering potential for targeted therapy., Conclusion: This case highlights the diagnostic and therapeutic challenges of mesonephric adenocarcinoma in males. Molecular profiling provided insights into tumor biology and potential targeted treatments. Multidisciplinary collaboration and surveillance remain essential for managing rare malignancies effectively., (Copyright © 2025 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Despite advances in the development of highly effective androgen receptor (AR)-directed therapies for the treatment of men with advanced prostate cancer, acquired resistance to such therapies frequently ensues. A significant subset of patients with resistant disease develop AR-negative tumors that lose their luminal identity and display neuroendocrine features (neuroendocrine prostate cancer (NEPC)). The cellular heterogeneity and the molecular evolution during the progression from AR-positive adenocarcinoma to AR-negative NEPC has yet to be characterized. Utilizing a new genetically engineered mouse model, we have characterized the synergy between Rb1 loss and MYCN (encodes N-Myc) overexpression which results in the formation of AR-negative, poorly differentiated tumors with high metastatic potential. Single-cell-based approaches revealed striking temporal changes to the transcriptome and chromatin accessibility which have identified the emergence of distinct cell populations, marked by differential expression of Ascl1 and Pou2f3, during the transition to NEPC. Moreover, global DNA methylation and the N-Myc cistrome are redirected following Rb1 loss. Altogether, our data provide insight into the progression of prostate adenocarcinoma to NEPC.

Loss of androgen receptor (AR) signaling dependence occurs in approximately 15%-20% of advanced treatment-resistant prostate cancers, and this may manifest clinically as transformation from a prostate adenocarcinoma histology to a castration-resistant neuroendocrine prostate cancer (CRPC-NE). The diagnosis of CRPC-NE currently relies on a metastatic tumor biopsy, which is invasive for patients and sometimes challenging to diagnose due to morphologic heterogeneity. By studying whole-exome sequencing and whole-genome bisulfite sequencing of cell free DNA (cfDNA) and of matched metastatic tumor biopsies from patients with metastatic prostate adenocarcinoma and CRPC-NE, we identified CRPC-NE features detectable in the circulation. Overall, there was markedly higher concordance between cfDNA and biopsy tissue genomic alterations in patients with CRPC-NE compared with castration-resistant adenocarcinoma, supporting greater intraindividual genomic consistency across metastases. Allele-specific copy number and serial sampling analyses allowed for the detection and tracking of clonal and subclonal tumor cell populations. cfDNA methylation was indicative of circulating tumor content fraction, reflective of methylation patterns observed in biopsy tissues, and was capable of detecting CRPC-NE-associated epigenetic changes (e.g., hypermethylation of ASXL3 and SPDEF; hypomethylation of INSM1 and CDH2). A targeted set combining genomic (TP53, RB1, CYLD, AR) and epigenomic (hypo- and hypermethylation of 20 differential sites) alterations applied to ctDNA was capable of identifying patients with CRPC-NE.

Small-cell prostate carcinoma (SCPC) is an aggressive malignancy that is managed similarly to small-cell lung cancer. SCPC can evolve from prostate adenocarcinoma in response to androgen deprivation therapy, but, in rare cases, is present at initial cancer diagnosis. The molecular aetiology of de novo SCPC is incompletely understood, owing to the scarcity of tumour tissue and the short life-expectancy of patients. Through a retrospective search of our regional oncology pharmacy database, we identified 18 patients diagnosed with de novo SCPC between 2004 and 2017. Ten patients had pure SCPC pathology, and the remainder had some admixed adenocarcinoma foci, but all were treated with first-line platinum-based chemotherapy. The median overall survival was 28 months. We performed targeted DNA sequencing, whole exome sequencing and mRNA profiling on formalin-fixed paraffin-embedded archival tumour tissue. We observed frequent biallelic deletion and/or mutation of the tumour suppressor genes TP53, RB1, and PTEN, similarly to what was found in treatment-related SCPC. Indeed, at the RNA level, pure de novo SCPC closely resembled treatment-related SCPC. However, five patients had biallelic loss of DNA repair genes, including BRCA1, BRCA2, ATM, and MSH2/6, potentially underlying the high genomic instability of this rare disease variant. Two patients with pure de novo SCPC harboured ETS gene rearrangements involving androgen-driven promoters, consistent with the evolution of de novo SCPC from an androgen-driven ancestor. Overall, our results reveal a highly aggressive molecular landscape that underlies this unusual pathological variant, and suggest opportunities for targeted therapy strategies in a disease with few treatment options. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd., (Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)