Ferrocenyl Dithiophosphonate Ag(I) Complexes: Synthesis, Structures, Luminescence, and Electrocatalytic Water Splitting Tuned by Nuclearity and Ligands.

The heterometallic [Ag(I)/Fe(II)] molecular electrocatalysts for hydrogen production were introduced here to recognize the mutual role of metallic nuclearity and ligand engineering. A series of ferrocenyl dithiophosphonate stabilized mononuclear [Ag(PPh3)2{S2PFc(OR)}] {where R = Me (1), Et (2), nPr (3), iPr (4), iAmyl (5); Fc = Fe (ɳ5-C5H4)(ɳ5-C5H5) } and dinuclear [Ag(PPh3){S2PFc(OR}]2 {where R = Et (2a), and nPr (3a)} complexes were synthesized and characterized by SCXRD, NMR (31P and 1H), ESI-MS, UV-Vis, and FT-IR spectroscopy. The comparative electrocatalytic HER behavior of 1-5 and 2a-3a showed effective current density of 1 mA/cm2 with overpotentials ranging from 772 to 991 mV, demonstrating the influence of extended and branched carbon chains in dithiophosphonates and metallic (mono-/di-) nuclearity, which correlates with documented tetra-nuclear [Ag4(S2PFc(OnPr)4], 6. DFT study suggests the coordinated (µ1-S) site of ligands is the reactivity center and the adsorption energy of intermediate [H*-SM] varies with the engineering of ligand and nuclearity. A catalytic mechanism using mononuclear (1) and di-nuclear (2a) was proposed with the assistance of DFT. Each complex, being the first example of Ag(I) dithiophosphonates, exhibits intense photoluminescence with high quantum yields ranging from 33% to 67%. These results link the lower nuclearity structures to their physical and catalytic properties.

Dithiophosphonate-Protected Eight-Electron Superatomic Ag21 Nanocluster: Synthesis, Isomerism, Luminescence, and Catalytic Activity.

The structure-property relationship considering isomerism-tuned photoluminescence and efficient catalytic activity of silver nanoclusters (NCs) is exclusive. Asymmetrical dithiophosphonate NH4[S2P(OR)(p-C6H4OCH3)] ligated first atomically precise silver NCs [Ag21{S2P(OR)(p-C6H4OCH3)}12]PF6 {where, R = nPr (1), Et (2)} were established by single-crystal X-ray diffraction and characterized by electrospray ionization mass spectrometry, NMR (31P, 1H, 2H), X-ray photoelectron spectroscopy, UV-visible, energy-dispersive X-ray spectroscopy, Fourier transforms infrared, thermogravimetric analysis, etc. NCs 1 and 2 consist of eight silver atoms in a cubic framework and enclose an Ag@Ag12-centered icosahedron to constitute an Ag21 core of Th symmetry, which is concentrically inscribed within the S24 snub-cube, P12 cuboctahedron, and the O12 truncated tetrahedron formed by 12 dithiophosphonate ligands. These NCs facilitate to be an eight-electron superatom (1S21P6), in which eight capping Ag atoms exhibit structural isomerism with documented isoelectronic [Ag21{S2P(OiPr)2}12]PF6, 3. In contrast to 3, the stapling of dithiophosphonates in 1 and 2 triggered bluish emission within the 400 to 500 nm region at room temperature. The density functional theory study rationalized isomerization and optical properties of 1, 2, and 3. Both (1, and 2) clusters catalyzed a decarboxylative acylarylation reaction for rapid oxindole synthesis in 99% yield under ambient conditions and proposed a multistep reaction pathway. Ultimately, this study links nanostructures to their physical and catalytic properties.

Molecular profiling of 888 pediatric tumors informs future precision trials and data-sharing initiatives in pediatric cancer.

To inform clinical trial design and real-world precision pediatric oncology practice, we classified diagnoses, assessed the landscape of mutations, and identified genomic variants matching trials in a large unselected institutional cohort of solid tumors patients sequenced at Dana-Farber / Boston Children's Cancer and Blood Disorders Center. Tumors were sequenced with OncoPanel, a targeted next-generation DNA sequencing panel. Diagnoses were classified according to the International Classification of Diseases for Oncology (ICD-O-3.2). Over 6.5 years, 888 pediatric cancer patients with 95 distinct diagnoses had successful tumor sequencing. Overall, 33% (n = 289/888) of patients had at least 1 variant matching a precision oncology trial protocol, and 14% (41/289) were treated with molecularly targeted therapy. This study highlights opportunities to use genomic data from hospital-based sequencing performed either for research or clinical care to inform ongoing and future precision oncology clinical trials. Furthermore, the study results emphasize the importance of data sharing to define the genomic landscape and targeted treatment opportunities for the large group of rare pediatric cancers we encounter in clinical practice.

Practical Access to Fused Carbazoles via Oxidative Benzannulation and their Photophysical Properties.

An aryne annulation strategy for the synthesis of fused carbazoles is developed using indolyl ß-ketonitrile in a cascade manner. The reaction sequence involves aryne-mediated [2 + 2] cycloaddition cleavage and intramolecular Michael addition, followed by oxidation under transition-metal-free reaction conditions. Subsequently, conversion of benzo[b]carbazole-6-carbonitrile to carbazole quinone is observed upon prolongation of the reaction time. Furthermore, these materials exhibit high quantum efficiency, which promotes the light-emitting diode applications.

Narcissistic self-sorting in Zn(II) porphyrin derived semiconducting nanostructures.

The narcissistic self-sorted phenomenon is explicitly attributed to the structural similarities in organic molecules. Although such relevant materials are rarely explored, self-sorted structures from macrocyclic π-conjugated-based p- and n-type organic semiconductors facilitate the increase of exciton dissociation and charge separation in bulk heterojunction solar cells. Herein, we report two extended π-conjugated derivatives consisting of zinc-porphyrin-linked benzothiadiazole acting as an acceptor (PB) and anthracene as a donor (PA). Despite having the same porphyrin π-conjugated core in PA and PB, variations in donor and acceptor moieties make the molecular packing form one-dimensional (1D) self-assembled nanofibers via H- and J-type aggregates. Interestingly, a dissimilar aggregate of PA and PB exists as a mixture (PA + PB), promoting narcissistic self-sorted structures. Electrochemical impedance investigation reveals that the electronic characteristics of self-sorting assemblies are influenced by the difference in electrostatic potentials for PA and PB, resulting in a transitional electrical conductivity of 0.14 S cm-1. Therefore, the design of such materials for the fabrication of effective photovoltaics is promoted by these extraordinary self-sorted behaviors in comparable organic π-conjugated molecules.

Synthesis of triazole bridged N-glycosides of pyrazolo[1,5-a]pyrimidinones as anticancer agents and their in silico docking studies.

In the pursuit of novel therapeutic agents, we present a comprehensive study on the design, synthesis, and evaluation of a diverse library of triazole bridged N-glycosides of pyrazolo[1,5-a]pyrimidinones, employing a microwave-assisted synthetic approach via 'click chemistry'. This methodology offers efficient and accelerated access to the glycohybrids, showcasing improved reaction conditions that yield high-quality products. In this research endeavor, we have successfully synthesized a series of twenty-seven triazole bridged N-glycosides of pyrazolo[1,5-a]pyrimidinones. Our investigation extends beyond synthetic endeavors to explore the potential therapeutic relevance of these compounds. We subjected them to rigorous in vitro screening against prominent breast cancer cell lines MCF-7, MDA-MB231, and MDA-MB453. Among the library of compounds synthesized, (2S,3S,4R,5S,6S)-2-(acetoxymethyl)-6-(4-((5-(4-methoxyphenyl)-7-oxopyrazolo[1,5-a]pyrimidin-1(7H)-yl)methyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate emerged as a potent compound, exhibiting remarkable anti-cancer activity with an IC50 value of 27.66 µM against the MDA-MB231 cell line. Additionally, (2S,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-((7-oxo-5-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyrimidin-1(7H)-yl)methyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate displayed notable inhibitory potential against the MCF-7 cell line, with an IC50 value of 4.93 µM. Furthermore, in silico docking analysis was performed to validate our experimental findings. These findings underscore the promise of our triazole bridged N-glycosides of pyrazolo[1,5-a]pyrimidinones as potential anti-cancer agents. This research not only enriches the field of glycohybrid synthesis but also contributes valuable insights into the development of novel anti-cancer therapeutics.

Analysis and Visualization of Longitudinal Genomic and Clinical Data from the AACR Project GENIE Biopharma Collaborative in cBioPortal.

International cancer registries make real-world genomic and clinical data available, but their joint analysis remains a challenge. AACR Project GENIE, an international cancer registry collecting data from 19 cancer centers, makes data from >130,000 patients publicly available through the cBioPortal for Cancer Genomics (https://genie.cbioportal.org). For 25,000 patients, additional real-world longitudinal clinical data, including treatment and outcome data, are being collected by the AACR Project GENIE Biopharma Collaborative using the PRISSMM data curation model. Several thousand of these cases are now also available in cBioPortal. We have significantly enhanced the functionalities of cBioPortal to support the visualization and analysis of this rich clinico-genomic linked dataset, as well as datasets generated by other centers and consortia. Examples of these enhancements include (i) visualization of the longitudinal clinical and genomic data at the patient level, including timelines for diagnoses, treatments, and outcomes; (ii) the ability to select samples based on treatment status, facilitating a comparison of molecular and clinical attributes between samples before and after a specific treatment; and (iii) survival analysis estimates based on individual treatment regimens received. Together, these features provide cBioPortal users with a toolkit to interactively investigate complex clinico-genomic data to generate hypotheses and make discoveries about the impact of specific genomic variants on prognosis and therapeutic sensitivities in cancer. SIGNIFICANCE: Enhanced cBioPortal features allow clinicians and researchers to effectively investigate longitudinal clinico-genomic data from patients with cancer, which will improve exploration of data from the AACR Project GENIE Biopharma Collaborative and similar datasets.

Efficient and stereoselective synthesis of sugar fused pyrano[3,2-c]pyranones as anticancer agents.

A highly stereoselective, efficient and facile route was achieved for the synthesis of novel and biochemically potent sugar fused pyrano[3,2-c]pyranone derivatives starting from inexpensive, naturally occurring d-galactose and d-glucose. First, ß-C-glycopyranosyl aldehydes were synthesized from these d-hexose sugars in six steps, with overall yields 41-55%. Next, two different 1-C-formyl glycals were synthesized from these ß-C-glycopyranosyl aldehydes by treatment in basic conditions. The optimization of reaction conditions was carried out following reactions between 1-C-formyl galactal and 4-hydroxycoumarin. Next, 1-C-formyl galactal and 1-C-formyl glucal were treated with nine substituted 4-hydroxy coumarins at room temperature (25 °C) in ethyl acetate for ∼1-2 h in the presence of l-proline to obtain exclusively single diastereomers of pyrano[3,2-c]pyranone derivatives in excellent yields. Four compounds were found to be active for the MCF-7 cancer cell line. The MTT assay, apoptosis assay and migration analysis showed significant death of the cancer cells induced by the synthesized compounds.

Promoter methylation status of key genes and its implications in the pathogenesis of endometriosis, endometrioid carcinoma of ovary and endometrioid endometrial cancer.

Background: Epigenetic processes play an important role in various physiological processes as well as in the pathogenesis of many diseases. The role of altered DNA methylation in the pathogenesis of endometriosis and associated ovarian and endometrial cancers has not been explored in detail. Therefore, this study aimed to determine the promoter methylation status of genes involved in key biological processes in the pathogenesis of these three gynecological diseases. Methods: Tissue samples of endometriosis, endometrioid carcinoma of the ovary, endometrioid endometrial cancer, and control endometrium (n = 10 each) were obtained. DNA was extracted and subjected to bisulfite conversion using commercially available kits. The methylation status of COX2, VEGF, HIF1A, TNF, MYC, and TP53 genes was checked by methylation-specific PCR. The mRNA levels of MYC and TP53 were determined using qRT-PCR in all tissue samples. Results: The promoter methylation status of COX2, VEGF, HIF1A, and TNF genes was significantly reduced in all three diseased study subjects (P < 0.05), whereas no significant difference was observed in the promoter methylation frequency of MYC and TP53 genes. Transcriptional expression of the MYC gene was significantly increased in all diseased groups (P < 0.001) whereas, transcriptional expression of the TP53 gene was significantly reduced in endometriosis and endometrioid carcinoma of the ovary and significantly increased in endometrioid endometrial cancer subjects compared to control subjects (P < 0.001). Conclusion: The findings suggest that the promoter regions of pro-inflammatory and pro-angiogenic genes involved in the common molecular pathophysiology of these three disorders were significantly hypomethylated and could be the reason for their over-expression associated with them. This indicates the role of epigenetics in the pathogenesis of these three diseases.

MatchMiner: an open-source platform for cancer precision medicine.

Widespread, comprehensive sequencing of patient tumors has facilitated the usage of precision medicine (PM) drugs to target specific genomic alterations. Therapeutic clinical trials are necessary to test new PM drugs to advance precision medicine, however, the abundance of patient sequencing data coupled with complex clinical trial eligibility has made it challenging to match patients to PM trials. To facilitate enrollment onto PM trials, we developed MatchMiner, an open-source platform to computationally match genomically profiled cancer patients to PM trials. Here, we describe MatchMiner's capabilities, outline its deployment at Dana-Farber Cancer Institute (DFCI), and characterize its impact on PM trial enrollment. MatchMiner's primary goals are to facilitate PM trial options for all patients and accelerate trial enrollment onto PM trials. MatchMiner can help clinicians find trial options for an individual patient or provide trial teams with candidate patients matching their trial's eligibility criteria. From March 2016 through March 2021, we curated 354 PM trials containing a broad range of genomic and clinical eligibility criteria and MatchMiner facilitated 166 trial consents (MatchMiner consents, MMC) for 159 patients. To quantify MatchMiner's impact on trial consent, we measured time from genomic sequencing report date to trial consent date for the 166 MMC compared to trial consents not facilitated by MatchMiner (non-MMC). We found MMC consented to trials 55 days (22%) earlier than non-MMC. MatchMiner has enabled our clinicians to match patients to PM trials and accelerated the trial enrollment process.

Revisiting the forgotten remnant: Imaging spectrum of Meckel's diverticulum.

Meckel's diverticulum is a true diverticulum of the alimentary tract occurring resulting from the persistence of remnants of the vitello-intestinal duct. They are often asymptomatic and incidentally diagnosed during surgery. Complications such as intestinal obstruction, diverticulitis, intestinal haemorrhage and perforation may occur with Meckel's diverticulum, which renders them symptomatic. The clinical and imaging diagnosis of Meckel's diverticulum is very challenging. As a result of the rare occurrence of complicated Meckel's diverticulum and the difficult preoperative diagnosis, knowledge of its imaging features is limited. The presented case series describes a spectrum of complications caused by Meckel's diverticulum and its CT imaging features. It highlights the importance of a high clinical suspicion by carefully searching for a Meckel's diverticulum on CT in its characteristic location to avoid missing it preoperatively.

AACR Project GENIE: 100,000 Cases and Beyond.

The American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) is an international pan-cancer registry with the goal to inform cancer research and clinical care worldwide. Founded in late 2015, the milestone GENIE 9.1-public release contains data from >110,000 tumors from >100,000 people treated at 19 cancer centers from the United States, Canada, the United Kingdom, France, the Netherlands, and Spain. Here, we demonstrate the use of these real-world data, harmonized through a centralized data resource, to accurately predict enrollment on genome-guided trials, discover driver alterations in rare tumors, and identify cancer types without actionable mutations that could benefit from comprehensive genomic analysis. The extensible data infrastructure and governance framework support additional deep patient phenotyping through biopharmaceutical collaborations and expansion to include new data types such as cell-free DNA sequencing. AACR Project GENIE continues to serve a global precision medicine knowledge base of increasing impact to inform clinical decision-making and bring together cancer researchers internationally. SIGNIFICANCE: AACR Project GENIE has now accrued data from >110,000 tumors, placing it among the largest repository of publicly available, clinically annotated genomic data in the world. GENIE has emerged as a powerful resource to evaluate genome-guided clinical trial design, uncover drivers of cancer subtypes, and inform real-world use of genomic data. This article is highlighted in the In This Issue feature, p. 2007.

Role of serum microRNAs as biomarkers for endometriosis, endometrioid carcinoma of ovary & endometrioid endometrial cancer.

Background & objectives: Accurate and early diagnosis is imperial in the management of endometriosis, endometrioid carcinoma of ovary (ECO) and endometrioid endometrial cancer (EC), yet there are no definitive diagnostic methods available for these diseases. Therefore, the present study was aimed to evaluate the diagnostic potential of differentially expressed miRNAs in serum samples of women with endometriosis, ECO and EC to establish them as diagnostic biomarkers. Methods: Blood samples (5 ml) were obtained from 40 patients (n=10/study group) undergoing laparoscopy/laparotomy/hysterectomy. miRNA-rich RNA was extracted from the serum samples, and quantitative real-time (qRT)-PCR was performed to check the expression levels of miR-16, miR-99b, miR-20a, miR-145, miR-143 and miR-125a in all the samples. Receiver operating characteristic (ROC) curve analysis was done to check the diagnostic potential. Results: In endometriosis, miR-16 was downregulated (P<0.05) whereas miR-99b, miR-125a, miR-143 and miR-145 were upregulated (P<0.05). In ECO group, downregulated expression of miR-16 and miR-125a (P<0.05) was observed, whereas miR-99b, miR-143 and miR-145 were upregulated (P<0.05). In endometrioid EC, miR-16, miR-99b, miR-125 and miR-145 were downregulated (P<0.05), whereas miR-143 was upregulated (P<0.05). ROC curve analysis showed that, for endometriosis, miR-99b, miR-125a, miR-143 and miR-145 served as diagnostic markers. miR-145 showed diagnostic power for ECO, and for endometrioid EC, miR-16, miR-99b, miR-125a and miR-145 showed diagnostic potential. Interpretation & conclusions: The present findings suggested that certain circulating miRNAs (miB99b, miR-16, miR-125a, miR-145) might act as indicators and discriminators of endometriosis and endometrioid subtypes of EC and ovarian cancer and might serve as potential biomarkers for early diagnosis and management of these debilitating diseases.

Diagnostic potential of differentially regulated microRNAs among endometriosis, endometrioid ovarian cancer, and endometrial cancer.

BACKGROUND: There is an increased risk of developing endometrioid ovarian and endometrial cancer in patients with endometriosis and there are no definitive diagnostic biomarkers available for these three associated diseases. Therefore, we evaluated the diagnostic potential of differentially expressed microRNAs (miRNAs) from the tissue samples of endometriosis, endometrioid ovarian cancer, and endometrial cancer to establish them as biomarkers for these diseases. MATERIALS AND METHODS: Ten samples of each, i.e., endometriosis, endometrioid ovarian cancer, endometrial cancer and control healthy endometrium were enrolled after obtaining ethical clearance. Differential expression of miR-16, miR-20a, miR-99b, miR-125a, miR-143, and miR-145 and some of their target genes, i.e., vascular endothelial growth factor (VEGF), hypoxia inducible factor 1A (HIF1A), cyclooxygenase 2 (COX2), and tumor necrosis factor (TNF) were quantified using quantitative reverse transcription polymerase chain reaction. Receiver operating characteristic (ROC) curve analysis was performed to predict the diagnostic potential. RESULTS: miR-16 and miR-20a were significantly downregulated, whereas miR-99b, miR-125a, and miR-143 were significantly upregulated in all three diseased samples. miR-145 was significantly upregulated in endometriosis and endometrioid ovarian cancer but significantly downregulated in endometrial cancer. mRNA levels of VEGF, HIF1A, COX2, and TNF were significantly increased in all three diseased samples as compared to control samples. ROC curve analysis revealed that for endometriosis, miR-99b, and miR-125a were giving highest area under curve (AUC) (0.950 and 0.733, respectively), for endometrioid carcinoma of ovary miR-143 was giving highest AUC (0.933) and for endometrioid endometrial cancer miR-16 (AUC = 0.815), miR-99b (AUC = 0.920), and miR-145 (AUC = 0.985) were found to be best predictors. CONCLUSION: These findings suggest that these miRNAs can act as good predictors and discriminators of these three diseases and might serve as potential biomarkers for them.

Eccrine Hidrocystoma: A Report of Two Cases with Special Reference to Dermoscopic Features.

Eccrine hidrocystomas (EHs) are benign tumors, which arise as cystic dilatation of the eccrine sweat duct. The lesions of EH have a chronic course with periodic flares in summer months, associated with exacerbation in sweating. Diagnosis is mainly clinical with histopathology being confirmatory. Dermoscopy is a noninvasive tool, which may confirm diagnosis of EH without subjecting the patient to a biopsy. We report two representative cases of EH, with emphasis on dermoscopic features and which well responded to topical botulinum toxin-like peptide.

SARS-CoV-2 and the reproductive system: known and the unknown..!!

BACKGROUND: COVID-19 is the most recent zoonotic outbreak of coronaviruses. Mostly, it invades the cells of the respiratory system by binding to the receptor angiotensin-converting enzyme 2 (ACE2) which is also present in other organs like the kidney, testis, ovaries, breast, heart, and intestine, rendering them prone to be infected. The reproductive potential is a must for the sustenance of any species and it is our prime duty to safeguard the reproductive system of the present generation from such a deadly virus. The previously reported coronaviruses like severe acute respiratory syndrome coronavirus (SARS-CoV) had a detrimental impact on reproductive organs. There is a dearth of sufficient research to provide substantial evidence for the harmful effects of this novel virus on the reproductive system. Hence, our review compiles the knowledge available until now to boost research in this regard and to take the necessary steps in time. MAIN BODY OF ABSTRACT: Here we tried to compile all the data available on the effect of SARS-CoV-2 on the reproductive system as well as vertical transmission of the virus. All related articles published from February to August 2020 were reviewed and thoroughly analyzed. SARS-CoV-2 has been found to affect the sperm concentration and motility, thus degrading the fertility of males. In females, it is suspected that this virus affects the oocyte quality and ovarian function, resulting in infertility or miscarriage. Traces of SARS-CoV-2 virus have also been found in the breast milk of the infected mothers and the semen of infected males. Vertical transmission of SARS-CoV-2 has also been reported in some cases. CONCLUSION: Based on the literature review, SARS-CoV-2 seems to have the potential of affecting both male and female reproductive tracts. This review brings together the findings and observations made in the area of reproductive health during the current pandemic. The reproductive system of the young population is preordained for subsequent disorders, infertility, reduced sperm count, and motility. Therefore, the research and medical practices should focus on possible vulnerability being posed by SARS-CoV-2 to the gametes and future generations. We, hereby, recommend close monitoring of young and pregnant COVID-19 patients concerning reproductive health with utmost priority.

Genomic Characterization of de novo Metastatic Breast Cancer.

PURPOSE: In contrast to recurrence after initial diagnosis of stage I-III breast cancer [recurrent metastatic breast cancer (rMBC)], de novo metastatic breast cancer (dnMBC) represents a unique setting to elucidate metastatic drivers in the absence of treatment selection. We present the genomic landscape of dnMBC and association with overall survival (OS). EXPERIMENTAL DESIGN: Targeted DNA sequencing (OncoPanel) was prospectively performed on either primary or metastatic tumors from 926 patients (212 dnMBC and 714 rMBC). Single-nucleotide variants, copy-number variations, and tumor mutational burden (TMB) in treatment-naïve dnMBC primary tumors were compared with primary tumors in patients who ultimately developed rMBC, and correlated with OS across all dnMBC. RESULTS: When comparing primary tumors by subtype, MYB amplification was enriched in triple-negative dnMBC versus rMBC (21.1% vs. 0%, P = 0.0005, q = 0.111). Mutations in KMTD2, SETD2, and PIK3CA were more prevalent, and TP53 and BRCA1 less prevalent, in primary HR+/HER2- tumors of dnMBC versus rMBC, though not significant after multiple comparison adjustment. Alterations associated with shorter OS in dnMBC included TP53 (wild-type: 79.7 months; altered: 44.2 months; P = 0.008, q = 0.107), MYC (79.7 vs. 23.3 months; P = 0.0003, q = 0.011), and cell-cycle (122.7 vs. 54.9 months; P = 0.034, q = 0.245) pathway genes. High TMB correlated with better OS in triple-negative dnMBC (P = 0.041). CONCLUSIONS: Genomic differences between treatment-naïve dnMBC and primary tumors of patients who developed rMBC may provide insight into mechanisms underlying metastatic potential and differential therapeutic sensitivity in dnMBC. Alterations associated with poor OS in dnMBC highlight the need for novel approaches to overcome potential intrinsic resistance to current treatments.