Metallo-protease Peptidase M84 from Bacillusaltitudinis induces ROS-dependent apoptosis in ovarian cancer cells by targeting PAR-1.

We have purified Peptidase M84 from Bacillus altitudinis in an effort to isolate anticancer proteases from environmental microbial isolates. This metallo-protease had no discernible impact on normal cell survival, but it specifically induced apoptosis in ovarian cancer cells. PAR-1, a GPCR which is reported to be overexpressed in ovarian cancer cells, was identified as a target of Peptidase M84. We observed that Peptidase M84 induced PAR-1 overexpression along with activating its downstream signaling effectors NF-κB and MAPK to promote excessive reactive oxygen species (ROS) generation. This evoked apoptotic death of the ovarian cancer cells through the intrinsic route. In in vivo set-up, weekly intraperitoneal administration of Peptidase M84 in syngeneic mice significantly diminished ascites accumulation, increasing murine survival rates by 60%. Collectively, our findings suggested that Peptidase M84 triggered PAR-1-mediated oxidative stress to act as an apoptosis inducer. This established Peptidase M84 as a drug candidate for receptor mediated targeted-therapy of ovarian cancer.

Improved intra-operative decision making in RA-TKR with the help of pre-operative CT scan.

Background: Robotic-assisted total knee replacement (RA-TKR) is a significant advancement in orthopedic surgery, but intra-operative decision-making remains challenging. Pre-operative imaging techniques, particularly CT scans, have gained momentum, providing insights into the patient's anatomy, improving implant positioning and alignment. However, further research is needed to explore their influence on RA-TKR planning and execution. Materials and methods: The hospital based cross-sectional study was conducted in Orthopedics department of Sparsh Speciality Hospital, Bangalore & Sunshine Hospital, Hyderabad. A total of 1020 participants in the age group over 50 years during the study period were included based on convenient sampling. The axial CT images were taken preoperatively and RA-TKA was done for all the patients. Results: The study participant's average age was 64.01 ± 7.13. Out of 1020 patients 259 (24.4%) were males and 761 (74.6%) were females. The median femoral, tibia and Polyethylene predicted and the actual component were same with the side of surgery and BMI. The median femoral predicted actual component was significantly higher among the age category of more than 80 years when compared to other age groups. The median femoral, tibia and Polyethylene predicted was higher in males when compared to females. Conclusion: Pre-operative CT scans enhance RA-TKR procedures by providing precise anatomical insights, enhancing implant placement, and identifying potential issues, improving surgical outcomes and patient satisfaction.

Cysteine-free cone snail venom peptides: Classification of precursor proteins and identification of mature peptides.

The cysteine-free acyclic peptides present in marine cone snail venom have been much less investigated than their disulfide bonded counterparts. Precursor protein sequences derived from transcriptomic data, together with mass spectrometric fragmentation patterns for peptides present in venom duct tissue extracts, permit the identification of mature peptides. Twelve distinct gene superfamiles have been identified with precursor lengths between 64 and 158 residues. In the case of Conus monile, three distinct mature peptides have been identified, arising from two distinct protein precursors. Mature acyclic peptides are often post-translationally modified, with C-terminus amidation, a feature characteristic of neuropeptides. In the present study, 20 acyclic peptides from Conus monile and Conus betulinus were identified. The common modifications of C-terminus amidation, gamma carboxylation of glutamic acid (E to ϒ), N-terminus conversion of Gln (Q) to a pyroglutamyl residue (Z), and hydroxylation of Pro (P) to Hyp (O) are observed in one or more peptides identified in this study. Proteolytic trimming of sequences by cleavage at the C-terminus of Asn (N) residues is established. The presence of an asparagine endopeptidase is strengthened by the identification of legumain-like sequences in the transcriptome assemblies from diverse Conus species. Such sequences may be expected to have a cleavage specificity at Asn-Xxx peptide bonds.

Relationship between femoral component placement and patient-specific anatomical rotational landmarks in robotic arm assisted total knee Arthroplasty- a multicentric study.

Introduction: Osteoarthritis of the knee is a common problem in the elderly, leading to severe morbidity. Total Knee Arthroplasty (TKA) is a widely validated surgery to provide a remarkable extent of knee function and simultaneously alleviates pain for knee osteoarthritis (OA). It is clearly understood that precision of the rotational alignment and accuracy of the technique in the placement of the femoral component is a prerequisite for excellent and successful outcomes of TKA. Advanced technology has now allowed surgeons to understand patient-specific variabilities in anatomical reference landmarks and the relationship of component positioning in relation to the reference landmarks to achieve accurate gap balancing with minimal soft tissue release.14 Robotic Arm Assisted-Total Knee Arthroplasty (RAA-TKA) is a semi-automated system that enables us in replicating the same. Using this technology, the bony resections, component positions, probable component sizing and gap balancing can be tentatively planned preoperatively with CT Scan Analysis and executed intraoperatively. Hence this study was undertaken to estimate the relationship between femoral component placement to normal rotational landmarks such as the Posterior Condylar Axis (PCA) and to quantitatively evaluate coronal and sagittal plane correction obtained. Also, we aimed to use the data to detect any anatomical variations in the study population and evaluate the accuracy of predicted component sizing, including gender-based evaluation. Materials and methods: A Prospective Observational Study of 1073 knees of patients of either sex above 50 years of age with Kellgren Lawrence Grade 4 Osteoarthritis of the knee which were confirmed with X-Ray undergoing RAA-TKA using MAKO Robotic System using Stryker Triathlon (Cruciate Substituting) CS Knee was conducted during the period between 2022 and 2023 in two South Indian hospitals specializing in joint replacement surgeries. Results: We found a statistically significant difference between the native Posterior Condylar Axis (PCA) (4.82 ± 2.15°) and final femoral component external rotation (3.24 ± 1.29°) with a p-value of <0.001 at 95% confidence interval. The accuracy of component size prediction was 99.8%. Also, analysis in our study has shown the most common implant sizes to be 4 in males and 2 in females. We also found no statistically significant difference based on age, size, laterality, or primary varus deformity. Conclusions: RAA-TKA provides patient-specific alignment/restricted kinematic alignment which might further enhance the outcome for the patient. Reliable deformity correction in coronal and sagittal planes can be achieved. Accurate flexion and extension gap balancing can be done through component placement and with minimal soft tissue dissection. Irrespective of all the advantages noted in RAA-TKA, further follow-up and long-term outcome studies are required to properly gauge and analyze this new technology.

Osteochondroma of Dorsal Scapula: A Case Report and Review of Literature.

Introduction: Osteochondroma of the scapula constitutes only 3-5% of all osteochondromas; osteochondroma on dorsal aspect of scapula is a rare entity. Diagnosis is almost always clinicoradiologically. Additional computed tomography scan and magnetic resonance imaging may be required for osteochondroma of flat bones such as scapula. Indications for surgery include pain, deformity, dysfunction, neural or vascular compromise, failure of conservative management, or in clinical settings with the high suspicion of malignant transformation and occasionally cosmesis. Outcome of a surgery should be assessed by Patient-Reported Outcome Measures (PROMs) which appraises what "matters to the patient." Case Report: A 10-year-old boy presented to us with painless swelling over the right upper back since 3 years of age and discomfort over the area while sleeping on his back for 6 months. Diagnosis confirmed it to be a pedunculated osteochondroma arising from the dorsal scapula. Here, we report the diagnosis, treatment, and successful Patient-Reported Outcome using QuickDASH© score for an osteochondroma of dorsal scapula using CARE© case reporting guidelines. Conclusion: We report a rare site of osteochondroma, review the relevant literature, and also stress upon the necessity of analyzing PROMs after surgical treatment of benign tumors of bone which would enable us to evaluate the result of surgery on symptoms, functioning, and health-related quality of life from the patient's perspective.

Evaluation of anterior approach in failed closed reduction and delayed presentation of supracondylar humerus fractures in children.

BACKGROUND: The treatment of displaced paediatric supracondylar fracture is a challenging problem and requires strict vigilance and a proper management protocol. Prospective investigation of the treatment options for fractures that cannot be reduced by closed reduction is recommended in literature. Operative treatment is indicated for the fractures that cannot be reduced satisfactorily by closed methods. It is also considered the best option for late presenting fractures. The aim of this study was to assess and compare the clinical outcome using open reduction through anterior approach in delayed presentation and failed closed reduction of supracondylar fracture humerus in children. MATERIALS AND METHODS: 15 patients of failed closed reduction and 11 patients of delayed presentation of supracondylar humerus fractures were operated with anterior approach. The demographic data, time from injury to presentation and from admission to surgery, reasons for delayed presentation, type of fracture, operative findings and time, K-wire configuration, length of hospitalization, post operative complications were noted. The patients were followed up for a period of 12 months and final range of motion, Baumann's angle, and cosmetic, functional and overall outcome by Flynn's criteria were evaluated and analyzed. RESULTS: The overall outcome was very satisfactory according to Flynn's criteria. 80.77% patients had excellent, 15.38% patients had good, and 3.85% patient had fair results with no poor results. Our results show distinct advantage of anterior approach which are on a par with or better than the previous studies using anterior approach, adding to their evidence. CONCLUSION: Open reduction using anterior approach is a very safe, logical and effective technique of treating failed closed reduction or late presentation of supracondylar fractures humerus in children with excellent cosmetic and functional results, and offers distinctive advantage over other approaches.

Lipidomic Profiling of Clinical Prostate Cancer Reveals Targetable Alterations in Membrane Lipid Composition.

Dysregulated lipid metabolism is a prominent feature of prostate cancer that is driven by androgen receptor (AR) signaling. Here we used quantitative mass spectrometry to define the "lipidome" in prostate tumors with matched benign tissues (n = 21), independent unmatched tissues (n = 47), and primary prostate explants cultured with the clinical AR antagonist enzalutamide (n = 43). Significant differences in lipid composition were detected and spatially visualized in tumors compared with matched benign samples. Notably, tumors featured higher proportions of monounsaturated lipids overall and elongated fatty acid chains in phosphatidylinositol and phosphatidylserine lipids. Significant associations between lipid profile and malignancy were validated in unmatched samples, and phospholipid composition was characteristically altered in patient tissues that responded to AR inhibition. Importantly, targeting tumor-related lipid features via inhibition of acetyl-CoA carboxylase 1 significantly reduced cellular proliferation and induced apoptosis in tissue explants. This characterization of the prostate cancer lipidome in clinical tissues reveals enhanced fatty acid synthesis, elongation, and desaturation as tumor-defining features, with potential for therapeutic targeting. SIGNIFICANCE: This study identifies malignancy and treatment-associated changes in lipid composition of clinical prostate cancer tissues, suggesting that mediators of these lipidomic changes could be targeted using existing metabolic agents.

Case Report of a Rare Cause of Reactive Arthritis: Leptospirosis.

INTRODUCTION: Leptospirosis is a zoonosis caused by infection with pathogenic Leptospira species. Leptospirosis has protean manifestations and rare, unusual presentations should be kept in mind in relevant epidemiological scenario. Reactive arthritis refers to acute non-purulent arthritis complicating an infection elsewhere in the body. It is attributed to an immune activation following certain infections; it is, therefore considered as aseptic arthritis. Very few case reports are available attributing leptospirosis as an established cause of reactive arthritis. We present a case of reactive arthritis of the hip joint due to leptospirosis. CASE REPORT: Here, we present a case of a 12-years- old female child who was admitted to our hospital with complaints of fever, headache, and pain in the right hip joint since past 5 days from admission. Subsequent elaboration revealed a past history of fever, headache, and myalgia for around 5-7 days around a week before the present complaints. There was rat infestation near her house and her father was working as sewage cleaner. Routine investigations, Ultrasonography (USG), Magnetic Resonance Imaging (MRI) of both hips and subsequently, diagnostic hip aspiration was performed. USG revealed synovitis, MRI revealed hip joint arthritis of infective or inflammatory origin. Diagnostic hip aspiration was negative for any microorganism. On 10th day of admission, patient started developing icterus with yellowish discolouration of urine. Patient was evaluated for the cause of jaundice. Screening for Leptospira was positive. Synovial biopsy of hip was performed, which showed inflammation with no specific pathology and no growth of any microorganism. In addition, Leptospira IgM MAC ELISA was done which was positive. Patient was thus confirmed to be having leptospirosis and reactive arthritis as a consequence of it. CONCLUSION: The presentation of reactive arthritis secondary to leptospirosis is rare. Leptospirosis can be an etiological factor for reactive arthritis, especially if reactive arthritis is complicated with jaundice.

An integrated functional and clinical genomics approach reveals genes driving aggressive metastatic prostate cancer.

Genomic sequencing of thousands of tumors has revealed many genes associated with specific types of cancer. Similarly, large scale CRISPR functional genomics efforts have mapped genes required for cancer cell proliferation or survival in hundreds of cell lines. Despite this, for specific disease subtypes, such as metastatic prostate cancer, there are likely a number of undiscovered tumor specific driver genes that may represent potential drug targets. To identify such genetic dependencies, we performed genome-scale CRISPRi screens in metastatic prostate cancer models. We then created a pipeline in which we integrated pan-cancer functional genomics data with our metastatic prostate cancer functional and clinical genomics data to identify genes that can drive aggressive prostate cancer phenotypes. Our integrative analysis of these data reveals known prostate cancer specific driver genes, such as AR and HOXB13, as well as a number of top hits that are poorly characterized. In this study we highlight the strength of an integrated clinical and functional genomics pipeline and focus on two top hit genes, KIF4A and WDR62. We demonstrate that both KIF4A and WDR62 drive aggressive prostate cancer phenotypes in vitro and in vivo in multiple models, irrespective of AR-status, and are also associated with poor patient outcome.

Validation of a 22-Gene Genomic Classifier in Patients With Recurrent Prostate Cancer: An Ancillary Study of the NRG/RTOG 9601 Randomized Clinical Trial.

Importance: Decipher (Decipher Biosciences Inc) is a genomic classifier (GC) developed to estimate the risk of distant metastasis (DM) after radical prostatectomy (RP) in patients with prostate cancer. Objective: To validate the GC in the context of a randomized phase 3 trial. Design, Setting, and Participants: This ancillary study used RP specimens from the phase 3 placebo-controlled NRG/RTOG 9601 randomized clinical trial conducted from March 1998 to March 2003. The specimens were centrally reviewed, and RNA was extracted from the highest-grade tumor available in 2019 with a median follow-up of 13 years. Clinical-grade whole transcriptomes from samples passing quality control were assigned GC scores (scale, 0-1). A National Clinical Trials Network-approved prespecified statistical plan included the primary objective of validating the independent prognostic ability of GC for DM, with secondary end points of prostate cancer-specific mortality (PCSM) and overall survival (OS). Data were analyzed from September 2019 to December 2019. Intervention: Salvage radiotherapy (sRT) with or without 2 years of bicalutamide. Main Outcomes and Measures: The preplanned primary end point of this study was the independent association of the GC with the development of DM. Results: In this ancillary study of specimens from a phase 3 randomized clinical trial, GC scores were generated from 486 of 760 randomized patients with a median follow-up of 13 years; samples from a total of 352 men (median [interquartile range] age, 64.5 (60-70) years; 314 White [89.2%] participants) passed microarray quality control and comprised the final cohort for analysis. On multivariable analysis, the GC (continuous variable, per 0.1 unit) was independently associated with DM (hazard ratio [HR], 1.17; 95% CI, 1.05-1.32; P = .006), PCSM (HR, 1.39; 95% CI, 1.20-1.63; P < .001), and OS (HR, 1.17; 95% CI, 1.06-1.29; P = .002) after adjusting for age, race/ethnicity, Gleason score, T stage, margin status, entry prostate-specific antigen, and treatment arm. Although the original planned analysis was not powered to detect a treatment effect interaction by GC score, the estimated absolute effect of bicalutamide on 12-year OS was less when comparing patients with lower vs higher GC scores (2.4% vs 8.9%), which was further demonstrated in men receiving early sRT at a prostate-specific antigen level lower than 0.7 ng/mL (-7.8% vs 4.6%). Conclusions and Relevance: This ancillary validation study of the Decipher GC in a randomized trial cohort demonstrated association of the GC with DM, PCSM, and OS independent of standard clinicopathologic variables. These results suggest that not all men with biochemically recurrent prostate cancer after surgery benefit equally from the addition of hormone therapy to sRT. Trial Registration: ClinicalTrials.gov identifier: NCT00002874.

Post-transcriptional Gene Regulation by MicroRNA-194 Promotes Neuroendocrine Transdifferentiation in Prostate Cancer.

Potent therapeutic inhibition of the androgen receptor (AR) in prostate adenocarcinoma can lead to the emergence of neuroendocrine prostate cancer (NEPC), a phenomenon associated with enhanced cell plasticity. Here, we show that microRNA-194 (miR-194) is a regulator of epithelial-neuroendocrine transdifferentiation. In clinical prostate cancer samples, miR-194 expression and activity were elevated in NEPC and inversely correlated with AR signaling. miR-194 facilitated the emergence of neuroendocrine features in prostate cancer cells, a process mediated by its ability to directly target a suite of genes involved in cell plasticity. One such target was FOXA1, which encodes a transcription factor with a vital role in maintaining the prostate epithelial lineage. Importantly, a miR-194 inhibitor blocked epithelial-neuroendocrine transdifferentiation and inhibited the growth of cell lines and patient-derived organoids possessing neuroendocrine features. Overall, our study reveals a post-transcriptional mechanism regulating the plasticity of prostate cancer cells and provides a rationale for targeting miR-194 in NEPC.

The DNA methylation landscape of advanced prostate cancer.

Although DNA methylation is a key regulator of gene expression, the comprehensive methylation landscape of metastatic cancer has never been defined. Through whole-genome bisulfite sequencing paired with deep whole-genome and transcriptome sequencing of 100 castration-resistant prostate metastases, we discovered alterations affecting driver genes that were detectable only with integrated whole-genome approaches. Notably, we observed that 22% of tumors exhibited a novel epigenomic subtype associated with hypermethylation and somatic mutations in TET2, DNMT3B, IDH1 and BRAF. We also identified intergenic regions where methylation is associated with RNA expression of the oncogenic driver genes AR, MYC and ERG. Finally, we showed that differential methylation during progression preferentially occurs at somatic mutational hotspots and putative regulatory regions. This study is a large integrated study of whole-genome, whole-methylome and whole-transcriptome sequencing in metastatic cancer that provides a comprehensive overview of the important regulatory role of methylation in metastatic castration-resistant prostate cancer.

Physiological and biochemical responses of Amaranthus cruentus to polycyclic aromatic hydrocarbon pollution caused by thermal power units.

Pollution due to release of polycyclic aromatic hydrocarbons from thermal power plants is a major global issue as the same is highly toxic and carcinogenic. The current research aims to investigate the responses of a dietary plant Amaranthus cruentus towards PAH pollution. For the said purpose, the plant was collected from agricultural land in close vicinity to thermal power units and the effects of PAH pollution on its chlorophyll and various nutraceutical content was evaluated. Oxidative stress biomarkers and antioxidant defense enzymes status and PAH accumulation was quantified as well. Real-time evidence of cell death, depletion of nutraceutical resources, and stomata configuration was generated through various histochemical studies and SEM analysis. Results indicated significant decline of chlorophyll a to the extent of 77% when compared to control. Oxidative stress markers, namely, superoxide radical, H2O2, and hydroxyl radical in pollution exposed plants were 12.7, 2.2, and 2.4 times respectively higher over the control which eventually resulted in 35% more cell death for the pollution exposed group. Total phenolics and flavonoids showed a decline of 57.6% and 41.3% respectively in the group exposed to PAH pollution. Similar decreasing trend was also observed for ascorbic acid, α-tocopherol, ß-carotene, total proteins, and carbohydrate contents as well. PAH-induced stress also resulted in complete imbalance in the redox homeostasis of the plant which was evident from increase in super oxide dismutase, catalase, and peroxidase antioxidant enzymes by more than 2-fold when compared to control. PAH accumulation in sample group was 10-20 times more when compared to control. Proteomic analysis also indicated upregulation of some proteins related to stress situation. Results are evident of the fact that severe depletion of nutraceutical resources of dietary plants can take place if subjected to oxidative stress arising from PAH pollution.

Author Correction: Association of imputed prostate cancer transcriptome with disease risk reveals novel mechanisms.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Association of imputed prostate cancer transcriptome with disease risk reveals novel mechanisms.

Here we train cis-regulatory models of prostate tissue gene expression and impute expression transcriptome-wide for 233,955 European ancestry men (14,616 prostate cancer (PrCa) cases, 219,339 controls) from two large cohorts. Among 12,014 genes evaluated in the UK Biobank, we identify 38 associated with PrCa, many replicating in the Kaiser Permanente RPGEH. We report the association of elevated TMPRSS2 expression with increased PrCa risk (independent of a previously-reported risk variant) and with increased tumoral expression of the TMPRSS2:ERG fusion-oncogene in The Cancer Genome Atlas, suggesting a novel germline-somatic interaction mechanism. Three novel genes, HOXA4, KLK1, and TIMM23, additionally replicate in the RPGEH cohort. Furthermore, 4 genes, MSMB, NCOA4, PCAT1, and PPP1R14A, are associated with PrCa in a trans-ethnic meta-analysis (N = 9117). Many genes exhibit evidence for allele-specific transcriptional activation by PrCa master-regulators (including androgen receptor) in Position Weight Matrix, Chip-Seq, and Hi-C experimental data, suggesting common regulatory mechanisms for the associated genes.

The Immune Landscape of Prostate Cancer and Nomination of PD-L2 as a Potential Therapeutic Target.

BACKGROUND: Immunotherapy has been less successful in treating prostate cancer than other solid tumors. We sought to better understand the immune landscape in prostate cancer and identify immune-related biomarkers and potential therapeutic targets. METHODS: We analyzed gene expression data from 7826 prospectively collected prostatectomy samples (2013-2016), and 1567 retrospective samples with long-term clinical outcomes, for a total of 9393 samples, all profiled on the same commercial clinical platform in a CLIA-certified lab. The primary outcome was distant metastasis-free survival (DMFS). Secondary outcomes included biochemical recurrence-free survival (bRFS), prostate cancer-specific survival (PCSS), and overall survival (OS). All statistical tests were two-sided. RESULTS: Unsupervised hierarchical clustering of hallmark pathways demonstrated an immune-related tumor cluster. Increased estimated immune content scores based on immune-specific genes from the literature were associated with worse bRFS (hazard ratio [HR] = 1.26 [95% confidence interval [CI] = 1.12 to 1.42]; P < .001), DMFS (HR = 1.34 [95% CI = 1.13 to 1.58]; P < .001), PCSS (HR = 1.53 [95% CI = 1.21 to 1.92]; P < .001), and OS (HR = 1.27 [95% CI = 1.07 to 1.50]; P = .006). Deconvolution using Cibersort revealed that mast cells, natural killer cells, and dendritic cells conferred improved DMFS, whereas macrophages and T-cells conferred worse DMFS. Interestingly, while PD-L1 was not prognostic, consistent with its low expression in prostate cancer, PD-L2 was expressed at statistically significantly higher levels (P < .001) and was associated with worse bRFS (HR = 1.17 [95% CI = 1.03 to 1.33]; P = .01), DMFS (HR = 1.25 [95% CI = 1.05 to 1.49]; P = .01), and PCSS (HR = 1.45 [95% CI = 1.13 to 1.86]; P = .003). PD-L2 was strongly associated with immune-related pathways on gene set enrichment analysis suggesting that it is playing an important role in immune modulation in clinical prostate cancer samples. Furthermore, PD-L2 was correlated with radiation response pathways, and also predicted response to postoperative radiation therapy (PORT) on multivariable interaction analysis (P = .03). CONCLUSION: In the largest study of its kind to date, these results illustrate the complex relationship between the tumor-immune interaction, prognosis, and response to radiotherapy, and nominate PD-L2 as a potential novel therapeutic target in prostate cancer, potentially in combination with radiotherapy.

Long non-coding RNAs in prostate cancer: Biological and clinical implications.

Prostate cancer (PCa) is a major health issue in the Western world. Current clinical imperatives for this disease include better stratification of indolent versus aggressive disease to enable improved patient management, as well as the identification of more effective therapies for the prevention and treatment of metastatic and therapy-resistant PCa. The advent of next-generation transcriptomics led to the identification of an important class of molecules, long non-coding RNAs (lncRNAs). LncRNAs have critical functions in normal physiology, but their dysregulation has also been implicated in the development and progression of a variety of cancers, including PCa. Importantly, a subset of lncRNAs are highly prostate-specific, suggesting potential for utility as both biomarkers and therapeutic targets. In this review, we summarise the biology of lncRNAs and their mechanisms of action in the development and progression of prostate cancer. Additionally, we cast a critical eye over the potential for this class of molecules to impact on clinical practice.

Clinical and Genomic Implications of Luminal and Basal Subtypes Across Carcinomas.

PURPOSE: Carcinomas originate from epithelial tissues, which have apical (luminal) and basal orientations. The degree of luminal versus basal differentiation in cancer has been shown to be biologically important in some carcinomas and impacts treatment response. EXPERIMENTAL DESIGN: Although prior studies have focused on individual cancer types, we used a modified clinical-grade classifier (PAM50) to subtype 8,764 tumors across 22 different carcinomas into luminal A, luminal B, and basal-like tumors. RESULTS: We found that all epithelial tumors demonstrated similar gene expression-based luminal/basal subtypes. As expected, basal-like tumors were associated with increased expression of the basal markers KRT5/6 and KRT14, and luminal-like tumors were associated with increased expression of the luminal markers KRT20. Luminal A tumors consistently had improved outcomes compared with basal across many tumor types, with luminal B tumors falling between the two. Basal tumors had the highest rates of TP53 and RB1 mutations and copy number loss. Luminal breast, cervical, ovarian, and endometrial tumors had increased ESR1 expression, and luminal prostate, breast, cervical, and bladder tumors had increased androgen receptor (AR) expression. Furthermore, luminal B tumors had the highest rates of AR and ESR1 mutations and had increased sensitivity in vitro to bicalutamide and tamoxifen. Luminal B tumors were more sensitive to gemcitabine, and basal tumors were more sensitive to docetaxel. CONCLUSIONS: This first pan-carcinoma luminal/basal subtyping across epithelial tumors reveals global similarities across carcinomas in the transcriptome, genome, clinical outcomes, and drug sensitivity, emphasizing the biological and translational importance of these luminal versus basal subtypes.