Histopathologic and proteogenomic heterogeneity reveals features of clear cell renal cell carcinoma aggressiveness.

Clear cell renal cell carcinomas (ccRCCs) represent ∼75% of RCC cases and account for most RCC-associated deaths. Inter- and intratumoral heterogeneity (ITH) results in varying prognosis and treatment outcomes. To obtain the most comprehensive profile of ccRCC, we perform integrative histopathologic, proteogenomic, and metabolomic analyses on 305 ccRCC tumor segments and 166 paired adjacent normal tissues from 213 cases.

Assessment of prostate cancer progression using a translational needle photoacoustic sensing probe: Preliminary study with intact human prostates .

In our previous studies, we demonstrated the ability of an interstitial all-optical needle photoacoustic (PA) sensing probe and PA spectral analysis (PASA) to assess the aggressiveness of prostate cancer. In this clinical translation investigation, we integrated the optical components of the needle PA sensing probe into a 18G steel needle. The translational needle PA sensing probe was evaluated using intact human prostates in a simulated ultrasound-guided transperineal prostate biopsy.

Metastatic prostate cancer diagnosed by fine-needle aspiration: Contemporary cytopathologic and biomarker assessment with clinical correlates.

Introduction: The diagnosis of metastatic prostatic cancer (MPC) by fine needle aspiration (FNA) can usually be rendered by typical cytomorphologic and immunohistochemical (IHC) features. However, MPC diagnosis may be complicated by transformation to atypical phenotypes such as small cell carcinoma, typically under pressure from androgen deprivation therapy (ADT). Predictive and prognostic biomarkers can also be assessed by IHC.

Characterization of Intercalated Cell Markers KIT and in Chromophobe Renal Cell Carcinoma and Other Renal Neoplasms.

Chromophobe renal cell carcinoma (chromophobe RCC) is the third major subcategory of renal tumors after clear cell RCC and papillary RCC, accounting for approximately 5% of all RCC subtypes. Other oncocytic neoplasms seen commonly in surgical pathology practice include the eosinophilic variant of chromophobe RCC, renal oncocytoma, and low-grade oncocytic unclassified RCC. In our recent next-generation sequencing based study, we nominated a lineage-specific novel biomarker (long intergenic non-protein coding RNA 1187) which was found to be enriched in chromophobe RCC.

BRCA1-associated RING domain-1 (BARD1) loss and GBP1 expression enhance sensitivity to DNA damage in Ewing sarcoma.

Ewing sarcoma is a fusion oncoprotein-driven primary bone tumor. A subset of patients (~10%) with Ewing sarcoma are known to harbor germline variants in a growing number of genes involved in DNA damage repair. We recently reported our discovery of a germline mutation in the DNA damage repair protein (BRCA1-associated RING domain-1) in a patient with Ewing sarcoma.

Transcriptional profiling of matched patient biopsies clarifies molecular determinants of enzalutamide-induced lineage plasticity.

The androgen receptor (AR) signaling inhibitor enzalutamide (enza) is one of the principal treatments for metastatic castration-resistant prostate cancer (CRPC). Several emergent enza clinical resistance mechanisms have been described, including lineage plasticity in which the tumors manifest reduced dependency on the AR. To improve our understanding of enza resistance, herein we analyze the transcriptomes of matched biopsies from men with metastatic CRPC obtained prior to treatment and at progression (n = 21).

Uridine Diphosphate Glucuronosyl Transferase 2B28 (UGT2B28) Promotes Tumor Progression and Is Elevated in African American Prostate Cancer Patients.

Prostate cancer (PCa) is the second most diagnosed cancer in the United States and is associated with metabolic reprogramming and significant disparities in clinical outcomes among African American (AA) men. While the cause is likely multi-factorial, the precise reasons for this are unknown. Here, we identified a higher expression of the metabolic enzyme UGT2B28 in localized PCa and metastatic disease compared to benign adjacent tissue, in AA PCa compared to benign adjacent tissue, and in AA PCa compared to European American (EA) PCa.

Discovery of a Highly Potent and Selective Dual PROTAC Degrader of CDK12 and CDK13.

Selective degradation of the cyclin-dependent kinases 12 and 13 (CDK12/13) presents a novel therapeutic opportunity for triple-negative breast cancer (TNBC), but there is still a lack of dual CDK12/13 degraders. Here, we report the discovery of the first series of highly potent and selective dual CDK12/13 degraders by employing the proteolysis-targeting chimera (PROTAC) technology. The optimal compound effectively degraded CDK12 and CDK13 with DC values of 2.

An update on diagnostic tissue-based biomarkers in testicular tumors.

Testicular cancer is rare overall but comprises the most common solid malignancy diagnosed in young men aged ∼20-40 years. Most testicular neoplasms generally fall into 2 broad categories: germ cell tumors (GCTs; ∼95%) and sex cord-stromal tumors (SCSTs ∼5%). Given the relative rarity of these tumors, diagnostic biomarkers are highly relevant for their diagnosis.

Targeting ESR1 mutation-induced transcriptional addiction in breast cancer with BET inhibition.

Acquired mutations in the ligand-binding domain (LBD) of the gene encoding estrogen receptor α (ESR1) are common mechanisms of endocrine therapy resistance in patients with metastatic ER+ breast cancer. The ESR1 Y537S mutation, in particular, is associated with development of resistance to most endocrine therapies used to treat breast cancer. Employing a high-throughput screen of nearly 1,200 Federal Drug Administration-approved (FDA-approved) drugs, we show that OTX015, a bromodomain and extraterminal domain (BET) inhibitor, is one of the top suppressors of ESR1 mutant cell growth.

De novo neuroendocrine features in prostate cancer.

Neuroendocrine tumors of the prostate are rare and encompass a group of entities that are classified based on a combination of morphological and immunohistochemical features. Despite the 2016 World Health Organization classification of prostatic neuroendocrine tumors, variants have been reported that do not fit well in the categorization scheme. While the majority of these tumors arise in the setting of castration-resistant prostate cancer (postandrogen deprivation therapy), de novo cases may occur.

Histopathology and Genetic Causes of Primary Aldosteronism in Young Adults.

Context: Due to its rare incidence, molecular features of primary aldosteronism (PA) in young adults are largely unknown. Recently developed targeted mutational analysis identified aldosterone-driver somatic mutations in aldosterone-producing lesions, including aldosterone-producing adenomas (APAs), aldosterone-producing nodules (APNs), and aldosterone-producing micronodules, formerly known as aldosterone-producing cell clusters.

Objective: To investigate histologic and genetic characteristics of lateralized PA in young adults.

Precursors of urinary bladder cancer: molecular alterations and biomarkers.

Clinical surveillance and follow-up of patients diagnosed with or at risk for urinary bladder cancers represent long-term, invasive, and costly processes for which supplemental biomarker information could help provide objective, personalized risk assessment. In particular, there are several precursors and possible precursors to urinary bladder cancer for which clinical behavior is heterogenous and interobserver variability in histopathologic diagnosis make it difficult to standardize management. This review seeks to highlight these precursor lesions from a diagnostic perspective (including flat urothelial lesions, papillary urothelial lesions, squamous lesions, and glandular lesions) and qualify known multiomic biomarkers that may help explain their behavior, predict patient risk, and acknowledge the nuance inherent to the question of whether these lesions are "benign" or "preneoplastic.

Oncofusion-driven de novo enhancer assembly promotes malignancy in Ewing sarcoma via aberrant expression of the stereociliary protein LOXHD1.

Ewing sarcoma (EwS) is a highly aggressive tumor of bone and soft tissues that mostly affects children and adolescents. The pathognomonic oncofusion EWSR1::FLI1 transcription factor drives EwS by orchestrating an oncogenic transcription program through de novo enhancers. By integrative analysis of thousands of transcriptomes representing pan-cancer cell lines, primary cancers, metastasis, and normal tissues, we identify a 32-gene signature (ESS32 [Ewing Sarcoma Specific 32]) that stratifies EwS from pan-cancer.

Characterization of SARS-CoV-2 and host entry factors distribution in a COVID-19 autopsy series.

Background: SARS-CoV-2 is a highly contagious virus that causes the disease COVID-19. We have recently reported that androgens regulate the expression of SARS-CoV-2 host entry factors ACE2 and TMPRSS2, and androgen receptor (AR) in lung epithelial cells. We also demonstrated that the transcriptional repression of the AR enhanceosome inhibited SARS-CoV-2 infection in vitro.

Shifting the Soil: Metformin Treatment Decreases the Protumorigenic Tumor Microenvironment in Epithelial Ovarian Cancer.

Controversy persists regarding metformin's role in cancer therapy. Our recent work suggested metformin acts by impacting the tumor microenvironment (TME), normalizing the epigenetic profile of cancer-associated mesenchymal stem cells (CA-MSC). As CA-MSC can negatively impact tumor immune infiltrates, we evaluated metformin's impact on the human TME, focusing on the interplay of stroma and immune infiltrates.

Leveraging artificial intelligence to predict ERG gene fusion status in prostate cancer.

Background: TMPRSS2-ERG gene rearrangement, the most common E26 transformation specific (ETS) gene fusion within prostate cancer, is known to contribute to the pathogenesis of this disease and carries diagnostic annotations for prostate cancer patients clinically. The ERG rearrangement status in prostatic adenocarcinoma currently cannot be reliably identified from histologic features on H&E-stained slides alone and hence requires ancillary studies such as immunohistochemistry (IHC), fluorescent in situ hybridization (FISH) or next generation sequencing (NGS) for identification.

Methods: OBJECTIVE: We accordingly sought to develop a deep learning-based algorithm to identify ERG rearrangement status in prostatic adenocarcinoma based on digitized slides of H&E morphology alone.

Pathogenic ATM and BAP1 germline mutations in a case of early-onset, familial sarcomatoid renal cancer.

Metastatic renal cell carcinoma (RCC) remains an incurable malignancy, despite recent advances in systemic therapies. Genetic syndromes associated with kidney cancer account for only 5%-8% of all diagnosed kidney malignancies, and genetic predispositions to kidney cancer predisposition are still being studied. Genomic testing for kidney cancer is useful for disease molecular subtyping but provides minimal therapeutic information.

CRISPRs in the human genome are differentially expressed between malignant and normal adjacent to tumor tissue.

Clustered Regularly Interspaced Short Palindromic Repeats (CRISPRs) have been identified in bacteria, archaea and mitochondria of plants, but not in eukaryotes. Here, we report the discovery of 12,572 putative CRISPRs randomly distributed across the human chromosomes, which we termed hCRISPRs. By using available transcriptome datasets, we demonstrate that hCRISPRs are distinctively expressed as small non-coding RNAs (sncRNAs) in cell lines and human tissues.