Aggressive Clinical Phenotype Research Articles

Genetic landscape of interval and screen detected breast cancer

Interval breast cancers (IBCs) are cancers diagnosed between screening episodes. Understanding the biological differences between IBCs and screen-detected breast-cancers (SDBCs) has the potential to improve mammographic screening and patient management. We analysed and compared the genomic landscape of 288 IBCs and 473 SDBCs by whole genome sequencing of paired tumour-normal patient samples collected as part of the UK 100,000 Genomes Project. Compared to SDBCs, IBCs were more likely to be lobular, higher grade, and triple negative. A more aggressive clinical phenotype was reflected in IBCs displaying features of genomic instability including a higher mutation rate and number of chromosomal structural abnormalities, defective homologous recombination and TP53 mutations. We did not however, find evidence to indicate that IBCs are associated with a significantly different immune response. While IBCs do not represent a unique molecular class of invasive breast cancer they exhibit a more aggressive phenotype, which is likely to be a consequence of the timing of tumour initiation. This information is relevant both with respect to treatment as well as informing the screening interval for mammography.

Genetically Distinct Oligosarcoma Arising from Oligodendroglioma: Systematic Review & Illustrative Case Example

BackgroundOligosarcoma is a rare central nervous system (CNS) neoplasm that may arise following oligodendroglioma resection, which demonstrates a unique genetic profile and aggressive clinical phenotype. We present a systematic review and illustrative case example emphasizing the clinical and prognostic features of this unusual and unfavorable neuro-oncologic disease. MethodsSystematic literature review and illustrative case report. ResultsA 41-year-old man who had undergone two neurosurgical resections for a WHO grade II oligodendroglioma (Ki-67=5-10%, 1p/19q co-deleted, IDH2 mutated), without adjuvant chemoradiation, presented with seizures seven years after resection. An extra-axial mass was identified adjacent to the resection cavity, in which gross total resection was achieved. Pathology confirmed WHO grade IV oligosarcoma (Ki-67=20%). Adjuvant chemoradiation was initiated, with disease control observed over 6 months of follow-up.7 publications met inclusion criteria. Oligosarcoma has been confirmed in 36 lesions, arising in 35 patients; 5 were primary oligosarcoma, while 31 occurred in the setting of prior resected oligodendroglioma or oligoastrocytoma. Features shared by these lesions include re–gain of H3K27me3 expression, 1p/19q codeletion, homozygous deletion of CDKN2A/B, loss of 6q, loss of NF1 and YAP1, and attenuation of CpG island methylator (G-CIMP). Median survival after oligosarcoma diagnosis was 1.3 years (range, 0-5.2; n=35). ConclusionOligosarcoma is a prognostically unfavorable CNS neoplasm with characteristic imaging and pathologic features, and a strong association with previously resected oligodendroglioma. Aggressive treatment is recommended, including gross total resection and adjuvant chemoradiation. Further study is required to define optimal treatment protocol for this CNS malignancy.

Indolent behavior of malignant Bethesda III nodules compared to Bethesda V/VI nodules.

The Bethesda System classifies all fine needle aspiration specimens into one of six categories. We speculated that cancers within each Bethesda category would have distinct clinical behavior. This is a retrospective analysis of patients from a single academic medical center with a histologic diagnosis of thyroid cancer who had an initial diagnosis of Bethesda III, IV, V, or VI cytology. A total of 556 cases were included, with 87 cases of Bethesda III, 109 cases of IV, 120 cases of V, and 240 cases of VI. Bethesda III showed similarities with V/VI compared to IV with predominance of papillary thyroid cancer. The interval from diagnosis to surgery was longer in Bethesda III compared to Bethesda V/VI (median 78 vs. 41 days, p<0.001) (Figure 1). Yet, patients with Bethesda III had a higher probability of achieving remission (62 vs.46 %, p<0.03), a lower possibility of recurrence (8 vs. 24%, p<0.001) and a shorter interval to achieve remission (median 1218 vs.1682 days p = 0.02) compared to Bethesda V/VI which did not change after adjusting for age, gender, radioactive iodine therapy, mode of surgery and tumor size. More than 70% of Bethesda III that later presented with recurrence had T3/T4 disease or distant metastasis. Cancers with Bethesda III cytology had a less aggressive clinical phenotype with better prognosis compared to V/VI despite histological similarities. The time to remission was shorter in Bethesda III despite a longer interval between diagnosis and surgery. The initial cytological diagnosis may guide management.

P1109 Differences of Clinical Phenotype Between Familial and Sporadic Crohn's Disease in East China

Abstract Background Family history is one of the strongest risk factors for Crohn's disease (CD) while few studies have focused on whether family history influences the clinical features, disease course, and severity of CD. There is still controversy about the difference between sporadic and familial CD. This study aimed to compare the phenotypic features of familial CD with sporadic CD in Chinese populations. Methods We included 2,043 patients diagnosed with CD. Familial CD was defined as CD patients having one or more first-, second-, third-, fourth-degree or above relatives with CD. Sporadic CD patients hospitalized during the same period were matched 1:3 by age and gender. Differences in clinical characteristics, phenotype distributions, extra-intestinal manifestations, and complications at diagnosis, as well as treatment regimens and surgeries, were compared between familial and sporadic CD. Results A total of 55 familial CD and 165 sporadic CD were identified. The familial CD was associated with a higher rate of past appendectomy history (20.00% vs 6.67%, P=0.009), more intestinal perforation at onset (12.73% vs 3.03%, P=0.012), more anal lesion (85.45% vs 68.48%, P=0.023) and gastrointestinal perforation (14.55% vs 5.45%, P=0.040) at diagnosis, higher rate of past intestinal surgery history (50.91% vs 29.70%, P=0.007), more number of intestinal surgeries (1.50[IQR 1.00-2.00] vs 1.00[IQR 1.00-1.00], P=0.037), longer duration of follow-up (54.00 months[IQR 21.50-125.00] vs 41.00 months[IQR 14.00-79.00], P=0.017), lower rate of taking biologicals for current maintenance (61.82% vs 76.97%, P=0.043), lower tendency to upgrade to biologicals during follow-up (69.09% vs 85.37%, P=0.013), higher possibility to experience gastrointestinal obstruction (23.64% vs 11.52%, P=0.047) and abdominal abscess during follow-up (9.09% vs 2.42%, P=0.045). Conclusion Familial CD is associated with a more aggressive clinical phenotype compared with sporadic CD.

Pan-Cancer Analysis of PGAM1 and Its Experimental Validation in Uveal Melanoma Progression.

Phosphoglycerate mutase 1 (PGAM1) is a key enzyme regulating cancer glycolysis. However, the expression and function of PGAM1 in uveal melanoma (UVM) are unknown and systematic analysis is lacking. This study performed a comprehensive analysis of PGAM1 expression across 33 cancer types in multiple public databases. Results demonstrated PGAM1 is aberrantly overexpressed in most tumors compared to normal tissues, and this overexpression is associated with poor prognosis, advanced tumor staging, and aggressive clinical phenotypes in multiple cancers including UVM, lung, breast and bladder carcinomas. In addition, PGAM1 expression positively correlated with infiltration levels of tumor-promoting immune cells including macrophages, NK cells, myeloid dendritic cells, etc. Further experiments showed that PGAM1 was overexpressed in UVM cell lines and tissues, and it was positively associated with a poor prognosis of UVM patients. And knockdown of PGAM1 inhibited migration/invasion and induced apoptosis in UVM cells, followed by decreased levels of PD-L1, Snail, and BCl-2 and increased levels of E-cadherin. Additionally, the correlation analysis and molecular docking results suggest that PGAM1 could interact with PD-L1, Snail and BCl-2. Thus, PGAM1 may promote UVM pathogenesis via modulating immune checkpoint signaling, EMT and apoptosis. Collectively, this study reveals PGAM1 as a valuable prognostic biomarker and potential therapeutic target in aggressive cancers including UVM.

Blood mononuclear cell molecular landscape associated with tumor progression in triple-negative breast cancer

Introduction. triple negative breast cancer is an aggressive clinical phenotype characterized by poor prognosis. immune system plays an important role in the development, treatment response, and progression of solid tumor. The search for immune-related markers associated with the prediction of treatment efficacy and disease prognosis, and based on the use of high-resolution molecular techniques, is a promising area of research, the results of which can be translated into clinical practice. Case description. The molecular profile of blood mononuclear cells in a 48-year-old female patient with histologically proven triple negative breast cancer (estrogen Receptor – 0; progesteron Receptor – 0; Her2/neu – 0; gata-3 – 0, androgen Receptor – 0 and Ki67 – 70 %) was described. The patient did not response to neoadjuvant chemotherapy with 4 cycles of paclitaxel + carboplatin followed by 2 cycles of adriamycin + cyclophosphamide. The patient underwent surgery. disease progression (pelvic bone metastases) occurred 2 months after surgery. The features of blood lymphocytes and monocytes associated with a lack of response to neoadjuvant chemotherapy and disease progression were described.Conclusion. This clinical case demonstrates that sequencing of peripheral blood mononuclear cells can be used as a method for identifying predictive markers of therapy efficacy and developing personalized treatments for patients with triple negative breast cancer.

C9orf142 transcriptionally activates MTBP to drive progression and resistance to CDK4/6 inhibitor in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) presents the most challenging subtype of all breast cancers because of its aggressive clinical phenotypes and absence of viable therapy targets. In order to identify effective molecular targets for treating patients with TNBC, we conducted an integration analysis of our recently published TNBC dataset of quantitative proteomics and RNA-Sequencing, and found the abnormal upregulation of chromosome 9 open reading frame 142 (C9orf142) in TNBC. However, the functional roles of C9orf142 in TNBC are unclear. In vitro and in vivo functional experiments were performed to assess potential roles of C9orf142 in TNBC. Immunoblotting, real-time quantitative polymerase chain reaction (RT-qPCR),and immunofluorescent staining were used to investigate the expression levels of C9orf142 and its downstream molecules. The molecular mechanisms underlying C9orf142-regulated mouse double minute 2 (MDM2)-binding protein (MTBP) were determined by chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays. In TNBC tissues and metastatic lymph nodes, we observed that C9orf142 exhibited abnormal up-regulation, and its elevated expression was indicative of unfavorable prognosis for TNBC patients. Both in vitro and in vivo functional experiments demonstrated that C9orf142 accelerated TNBC growth and metastasis. Further mechanism exploration revealed that C9orf142 transcriptionally activated MTBP, thereby regulating its downstream MDM2/p53/p21 signaling axis and the transition of cell cycle from G1 to S phase. Functional rescue experiment demonstrated that knockdown of MTBP attenuated C9orf142-mediated tumour growth and metastasis. Furthermore, depletion of C9orf142 remarkably increased the responsiveness of TNBC cells to CDK4/6 inhibitor abemaciclib. Together, these findings unveil a previously unrecognized effect of C9orf142 in TNBC progression and responsiveness to CDK4/6 inhibitor, and emphasize C9orf142 as a promising intervention target for TNBC treatment.

Surgical management and outcome of newly diagnosed glioblastoma without contrast enhancement (low-grade appearance): a report of the RANO resect group.

Resection of the contrast-enhancing (CE) tumor represents the standard of care in newly diagnosed glioblastoma. However, some tumors ultimately diagnosed as glioblastoma lack contrast enhancement and have a 'low-grade appearance' on imaging (non-CE glioblastoma). We aimed to (a) volumetrically define the value of non-CE tumor resection in the absence of contrast enhancement, and to (b) delineate outcome differences between glioblastoma patients with and without contrast enhancement. The RANO resect group retrospectively compiled a global, eight-center cohort of patients with newly diagnosed glioblastoma per WHO 2021 classification. The associations between postoperative tumor volumes and outcome were analyzed. Propensity score-matched analyses were constructed to compare glioblastomas with and without contrast enhancement. Among 1323 newly diagnosed IDH-wildtype glioblastomas, we identified 98 patients (7.4%) without contrast enhancement. In such patients, smaller postoperative tumor volumes were associated with more favorable outcome. There was an exponential increase in risk for death with larger residual non-CE tumor. Accordingly, extensive resection was associated with improved survival compared to lesion biopsy. These findings were retained on a multivariable analysis adjusting for demographic and clinical markers. Compared to CE glioblastoma, patients with non-CE glioblastoma had a more favorable clinical profile and superior outcome as confirmed in propensity score analyses by matching the patients with non-CE glioblastoma to patients with CE glioblastoma using a large set of clinical variables. The absence of contrast enhancement characterizes a less aggressive clinical phenotype of IDH-wildtype glioblastomas. Maximal resection of non-CE tumors has prognostic implications and translates into favorable outcome.

Brain Metastasis in HER2-Positive Breast Cancer: Case Report and Review of Literature

Introduction: Breast cancer (BC) is one of the most common cancers in women in developed countries. Approximately 15 to 20% of patients with BC have tumors with elevated levels of Human Epidermal Growth Factor Receptor 2 (HER2), which are associated with an aggressive clinical phenotype and poor prognosis. Brain metastases (BM) appears in more than 15% in the HER2-positive breast cancer population, which cause serious decrease in survival.

TFEB and TFE3 drive kidney cystogenesis andtumorigenesis.

Birt-Hogg-Dubé (BHD) syndrome is an inherited familial cancer syndrome characterized by the development of cutaneous lesions, pulmonary cysts, renal tumors and cysts and caused by loss-of-function pathogenic variants in the gene encoding the tumor-suppressor protein folliculin (FLCN). FLCN acts as a negative regulator of TFEB and TFE3 transcription factors, master controllers of lysosomal biogenesis and autophagy, by enabling their phosphorylation by the mechanistic Target Of Rapamycin Complex 1 (mTORC1). We have previously shown that deletion of Tfeb rescued the renal cystic phenotype of kidney-specific Flcn KO mice. Using Flcn/Tfeb/Tfe3 double and triple KO mice, we now show that both Tfeb and Tfe3 contribute, in a differential and cooperative manner, to kidney cystogenesis. Remarkably, the analysis of BHD patient-derived tumor samples revealed increased activation of TFEB/TFE3-mediated transcriptional program and silencing either of the two genes rescued tumorigenesis in human BHD renal tumor cell line-derived xenografts (CDXs). Our findings demonstrate in disease-relevant models that both TFEB and TFE3 are key drivers of renal tumorigenesis and suggest novel therapeutic strategies based on the inhibition of these transcription factors.

Treatment Strategies for KRAS-Mutated Non-Small-Cell Lung Cancer.

Activating mutations in KRAS are highly prevalent in solid tumours and are frequently found in 35% of lung, 45% of colorectal, and up to 90% of pancreatic cancers. Mutated KRAS is a prognostic factor for disease-free survival (DFS) and overall survival (OS) in NSCLC and is associated with a more aggressive clinical phenotype, highlighting the need for KRAS-targeted therapy. Once considered undruggable due to its smooth shallow surface, a breakthrough showed that the activated G12C-mutated KRAS isozyme can be directly inhibited via a newly identified switch II pocket. This discovery led to the development of a new class of selective small-molecule inhibitors against the KRAS G12C isoform. Sotorasib and adagrasib are approved in locally advanced or metastatic NSCLC patients who have received at least one prior systemic therapy. Currently, there are at least twelve KRAS G12C inhibitors being tested in clinical trials, either as a single agent or in combination. In this study, KRAS mutation prevalence, subtypes, rates of occurrence in treatment-resistant invasive mucinous adenocarcinomas (IMAs), and novel drug delivery options are reviewed. Additionally, the current status of KRAS inhibitors, multiple resistance mechanisms that limit efficacy, and their use in combination treatment strategies and novel multitargeted approaches in NSCLC are discussed.

Treatment sequencing for patients with localized duodenal and ampullary adenocarcinoma.

783 Background: Duodenal adenocarcinomas (DA) and ampullary adenocarcinoma (AA) are rare, comprising less than 1% of all gastrointestinal cancers. Optimal treatment sequencing strategies for patients with localized DA and AA have not been prospectively validated. We analyzed the clinical outcomes of patients with localized DA and AA treated with curative intent, multimodality therapy based on treatment sequencing – upfront surgery versus neoadjuvant therapy. Methods: Our institutional database was interrogated to identify adult patients with localized DA and AA diagnosed between January 2000 to December 2019. Adjusted survival analyses were performed to compare outcomes of patients that received neoadjuvant therapy (NAT - concurrent chemo-radiation +/-induction chemotherapy) versus upfront surgery (+/- adjuvant chemotherapy). Survival time was calculated from date of diagnosis to either death (overall survival; OS) or relapse/death (relapse free survival; RFS). Log-rank test and multiple Cox proportional hazards regression were performed to compare survival between treatment groups and adjust for relevant variables. Results: We identified 79 patients – 32 (41%) with DA and 47 (59%) with AA; Median age at diagnosis was 67. Forty two patients (53%) were male. Sixty-two patients underwent surgery – 27 (43.6%) patients with DA and 35 patients (56.4%) with AA. Among patients with DA, 18 (67%) were treated with upfront surgery, while 9 (33%) were treated with NAT. Among patients with AA, 32 (91%) were treated with upfront surgery while 3 (9%) were treated with NAT. Lymph node (LN) positivity rate in DA and AA patients treated with upfront surgery was 15% and 46% respectively, compared to 50% and 0% respectively, in patients treated with NAT (p = 0.26, p &gt; 0.99 respectively). DA patients treated with upfront surgery had a median relapse free survival (mRFS) of 3.8 years compared to 1.4 years for those treated with NAT (p = 0.370). The median overall survival m(OS) was not reached (NR) for DA patients treated with upfront surgery (4 years +) or NAT (2.6 years +) p = 0.875). AA patients treated with upfront surgery had a median RFS of 4.7 years compared to NR for patients treated with NAT (p = 0.117) while the mOS of AA patients treated with upfront surgery and NAT were 5.9 years and NR respectively (p = 0.158). Conclusions: Among DA patients, there was no difference in outcome based on sequence of treatment delivery – NAT versus upfront surgery. DA patients with more aggressive clinical phenotype were likely treated with NAT, hence similar outcomes in both groups should prompt consideration of NAT for all patients with DA. Role of NAT in AA is not clear considering the small sample size.

Prevalence of Monoclonal Gammopathy of Clinical Significance (MGCS) Among Patients with Monoclonal Gammopathies: Report from a Referral Center

Monoclonal gammopathies (MG) may be associated with a variety of syndromes due to the properties of the monoclonal protein, ectopic production of cytokines or other mechanisms. These syndromes may involve the kidneys, peripheral nerve, skin, eyes or other non-organ confined systemic syndromes. These disorders are usually associated with a nonmalignant or premalignant B-cell or plasma cell clone that does not fulfill the typical criteria of symptomatic myeloma or Waldenström's macroglobulinemia. These heterogeneous syndromes have attracted increasing attention and have been termed as "Monoclonal Gammopathy of Clinical Significance" (MGCS), however, their diagnosis remains challenging, requiring a high degree of suspicion or invasive target organ biopsies. Because of the difficulties in their recognition, it is not known how common these syndromes are among patients with monoclonal gammopathies. On the other hand, MG is a frequent finding: a recent prospective study in Iceland reported a prevalence of ~5% among subjects over the age of 40. Thus, the prevalence of MGCS may be significantly underestimated due to the heterogeneous phenotype, the difficulties in establishing the diagnosis and low degree of suspicion. In order to provide an estimate of the prevalence of MGCS among patients with known MG, we analyzed the database of a plasma cell dyscrasia referral center, in Athens, Greece. This is a prospectively maintained database which includes all patients with monoclonal gammopathies who are referred to our center for evaluation or treatment. Since AL amyloidosis is associated with a more aggressive clinical phenotype and requires prompt initiation of therapy, we evaluated these patients separately in our analysis. Because of an increasing interest in MGCS after 2010, and subsequent rising awareness and diagnostic sensitivity, we excluded earlier referrals and focused only on patients who were referred after 1/1/2010. The analysis included all patients who were referred for evaluation because of MG with or without concomitant symptoms or laboratory abnormalities. From 1/1/2010 to 31/12/2021, 3138 patients were referred for evaluation. The final diagnosis was MGUS or asymptomatic myeloma or asymptomatic WM in 1437 patients, symptomatic MM in 1145 patients, AL amyloidosis in 320 patients, symptomatic WM in 108 patients and a MGCS-related syndrome was diagnosed in 128 patients (4.1%). Among those with MGCS, the majority had either MGRS (n=51) or IgM-related neuropathy (n=58); other specific diagnoses included POEMS syndrome, Schnitzler's syndrome, necrobiotic xanthogranuloma or scleromyxedema, and other rare syndromes (TEMPI syndrome, IgM retinopathy, Clarkson's syndrome). Peripheral neuropathy with a concomitant MG was the most common co-existing condition among non-AL amyloidosis patients: 73% had IgM and 37% a non-IgM MG. A causal relationship between MG and neuropathy was established for 42% of those with non-IgM neuropathy (mainly due to POEMS syndrome). The median age of the MGCS patients was 64, not significantly different in clinical terms from that of patients with SMM/MGUS, AL amyloidosis, symptomatic MM and symptomatic WM (which was 65, 65, 67 and 70 years respectively). The baseline level of monoclonal immunoglobulin among MGCS patients was low (median 0.4 gr/dl) and significantly lower than in patients with MGUS/SMM/aWM (median 1.04 gr/dl). The median BM infiltration by clonal cells in patients with MGCS was 10%, and was 7% in the MGUS/SMM group, 15% in patients with AL amyloidosis, 50% in patients with symptomatic MM and 40% for patients with symptomatic WM. Most patients with MGCS received anticlonal therapy; other non-clone targeting therapies were used in patients with Schnitzler's syndrome and Clarkson's disease. A significant proportion of patients with IgM-related neuropathy received only supportive therapy. In conclusion, MGCS was found in ~4% of patients with MG in a plasma cell dyscrasia referral center. The establishment of MGCS diagnosis requires high degree of clinical suspicion due to their rarity and highly heterogeneous clinical presentation. Despite the bias associated with the analysis from a referral center, given the frequency of MG in the general population, there is probably a significant number of patients with MGCS who remain underdiagnosed and may suffer from complications associated with an otherwise non-malignant plasma cell dyscrasia.

Cardiac involvement in MPS patients: incidence and response to therapy in an Italian multicentre study

BackgroundMucopolysaccharidoses (MPSs) are a group of lysosomal storage disorders caused by the deficit of lysosomal hydrolases involved in the degradation of glycosaminoglycans (GAGs). The course is chronic and progressive, with multisystemic involvement that often leads to cardiovascular disease. We describe the overall incidence and type of cardiac damage in a cohort of Italian MPS patients, and their progression over time, also with reference to treatment efficacy in patients under Enzyme Replacement Therapy (ERT). Moreover, we report a possible association between genetic variants and cardiac phenotype in homozygous and hemizygous patients to understand whether a more aggressive clinical phenotype would predict a greater cardiac damage.ResultsOur findings confirm that cardiac involvement is very common, already at diagnosis, in MPS VI (85.7% of our cohort), and in MPS II (68% of our cohort) followed by MPS I subjects (55% of our cohort). The most frequent heart defect observed in each MPS and at any time-point of evaluation was mitral insufficiency; 37% of our patients had mitral insufficiency already at diagnosis, and 60% at post-ERT follow-up. After at least six years of treatment, we observed in some cases (including 6 MPS II, 2 MPS IV and 2 MPS VI) a total regression or improvement of some signs of the cardiac pathology, including some valve defects, though excluding aortic insufficiency, the only valvulopathy for which no regression was found despite ERT. The general clinical phenotype proved not to be strictly correlated with the cardiac one, in fact in some cases patients with an attenuated phenotype developed more severe heart damage than patients with severe phenotype.ConclusionsIn conclusion, our analysis confirms the wide presence of cardiopathies, at different extent, in the MPS population. Since cardiac pathology is the main cause of death in many MPS subtypes, it is necessary to raise awareness among cardiologists about early cardiac morpho-structural abnormalities. The encouraging data regarding the long-term effects of ERT, also on heart damage, underlines the importance of an early diagnosis and timely start of ERT.

Chromatin complexes subunit BAP18 promotes triple-negative breast cancer progression through transcriptional activation of oncogene S100A9

Triple-negative breast cancer (TNBC) is a highly lethal disease due to aggressive clinical phenotype and the lack of validated therapeutic targets. Our recent quantitative proteomic analysis of 90 cases of TNBC tissues and 72 cases of matched adjacent normal tissues revealed that the expression levels of BPTF-associated protein of 18 KDa (BAP18), a component of the MLL1 and NURF chromatin complexes, were upregulated in TNBC tissues relative to normal tissues. However, the biological function and the underlying mechanism of BAP18 in TNBC progression remain unexplored. Here, we report that BAP18 promoted TNBC cell proliferation, migration, and invasion in vitro and xenograft tumor growth and lung colonization in vivo. Mechanistic investigations revealed that S100 calcium-binding protein A9 (S100A9), a member of the S100 protein family that is frequently upregulated in breast tumors and acts as an oncogenic driver in breast cancer progression, was a downstream target gene of BAP18. BAP18 was recruited to histone H3 trimethylation at lysine 4 (H3K4me3)-marked promoter of S100A9 and enhanced its promoter activities. Notably, knockdown of BAP18 by short hairpin RNA in TNBC cells suppressed xenograft tumor growth in mice, the noted effect was partially reverted by re-expression of S100A9 in BAP18-depleted cells. Taken together, these results suggest that BAP18 promotes TNBC progression through, at least in part, transcriptional activation of oncogene S100A9, and represents a potential therapeutic target for TNBC.

Re-Expression of Poly/Oligo-Sialylated Adhesion Molecules on the Surface of Tumor Cells Disrupts Their Interaction with Immune-Effector Cells and Contributes to Pathophysiological Immune Escape.

Simple SummaryThe immune system consists of various mechanisms contributing to the battle against cancer cells or hazardous pathogens. However, in cancer progression the immune system is often unable to eliminate neoplastic cells, although immune effector cells infiltrate the tumor environment. The current paper reviews the causes for this immune escape. Specifically, we comprehensively discuss various roles of sialic acids in this process. Specific focus is given to adhesion molecules re-expressed on membranes of tumor cells, which carry oligo- and polysialic acid chains. These carrier proteins loaded with sialic acids direct the interaction between immune effector and tumor cells and thus prevent the “kiss of death” between the latter and the former cells. We also discuss strategies suited to reduce the degree of sialic acid presence on the surface of tumor cells, which can be the basis for future therapeutic intervention.Glycans linked to surface proteins are the most complex biological macromolecules that play an active role in various cellular mechanisms. This diversity is the basis of cell–cell interaction and communication, cell growth, cell migration, as well as co-stimulatory or inhibitory signaling. Our review describes the importance of neuraminic acid and its derivatives as recognition elements, which are located at the outermost positions of carbohydrate chains linked to specific glycoproteins or glycolipids. Tumor cells, especially from solid tumors, mask themselves by re-expression of hypersialylated neural cell adhesion molecule (NCAM), neuropilin-2 (NRP-2), or synaptic cell adhesion molecule 1 (SynCAM 1) in order to protect themselves against the cytotoxic attack of the also highly sialylated immune effector cells. More particularly, we focus on α-2,8-linked polysialic acid chains, which characterize carrier glycoproteins such as NCAM, NRP-2, or SynCam-1. This characteristic property correlates with an aggressive clinical phenotype and endows them with multiple roles in biological processes that underlie all steps of cancer progression, including regulation of cell–cell and/or cell–extracellular matrix interactions, as well as increased proliferation, migration, reduced apoptosis rate of tumor cells, angiogenesis, and metastasis. Specifically, re-expression of poly/oligo-sialylated adhesion molecules on the surface of tumor cells disrupts their interaction with immune-effector cells and contributes to pathophysiological immune escape. Further, sialylated glycoproteins induce immunoregulatory cytokines and growth factors through interactions with sialic acid-binding immunoglobulin-like lectins. We describe the processes, which modulate the interaction between sialylated carrier glycoproteins and their ligands, and illustrate that sialic acids could be targets of novel therapeutic strategies for treatment of cancer and immune diseases.

Relapse-independent multiple sclerosis progression under natalizumab.

The objective of this study was to investigate confirmed progression independent of relapse activity in relapsing-remitting multiple sclerosis patients under long-term natalizumab treatment. We performed a retrospective, cross-sectional study of clinical data captured between 1994 and 2019 at two German multiple sclerosis tertiary referral centres. Data files of all relapsing-remitting multiple sclerosis patients treated with natalizumab for ≥24 months were analysed. Confirmed progression independent of relapse activity was defined as ≥12 week confirmed disability progression on a roving Expanded Disability Status Scale reference score by 1 point in patients with an Expanded Disability Status Scale score ≤3 or 0.5 in patients with an Expanded Disability Status Scale score ≥3.5 in the absence of a relapse. Cox proportional hazard models were used to analyse the probability of developing confirmed progression independent of relapse activity depending on both disease and natalizumab treatment duration. Among the 184 patients identified, 44 (24%) developed confirmed progression independent of relapse activity under natalizumab irrespective of the Expanded Disability Status Scale score at natalizumab onset. Time to confirmed progression independent of relapse activity was not affected by Expanded Disability Status Scale at natalizumab onset (categorized by Expanded Disability Status Scale score ≤3.5 versus >3.5) nor by duration of disease nor by duration of therapy. Confirmed progression independent of relapse activity occurred earlier in the disease course in patients with an earlier natalizumab therapy onset with regard to disease duration. A stepwise forward regression analysis revealed disease duration as the main factor for confirmed progression independent of relapse activity development (P = 0.005). Taken together, confirmed progression independent of relapse activity occurs in a substantial proportion of patients on long-term natalizumab treatment and independent of Expanded Disability Status Scale score at natalizumab onset. Our findings suggest that patients who are initiated on natalizumab early during disease course, usually in order to treat an aggressive clinical phenotype, have a higher risk of early confirmed progression independent of relapse activity.

NGS Analysis Confirms Common TP53 and RB1 Mutations, and Suggests MYC Amplification in Ocular Adnexal Sebaceous Carcinomas.

Ocular adnexal (OA) sebaceous carcinomas generally demonstrate more aggressive clinical and histopathological phenotypes than extraocular cases, but the molecular drivers implicated in their oncogenesis remain poorly defined. A retrospective review of surgical and ocular pathology archives identified eleven primary resection specimens of OA sebaceous carcinomas with adequate tissue for molecular analysis; two extraocular cases were also examined. Next-generation sequencing was used to evaluate mutations and copy number changes in a large panel of cancer-associated genes. Fluorescence in situ hybridization (FISH) confirmed MYC copy number gain in select cases, and immunohistochemistry to evaluate MYC protein expression. The commonest mutations occurred in TP53 (10/13) and RB1 (7/13). Additional mutations in clinically actionable genes, or mutations with a frequency of at least 25%, included the NF1 (3/12), PMS2 (4/12), ROS1 (3/12), KMT2C (4/12), MNX1 (6/12), NOTCH1 (4/12), PCLO (3/12), and PTPRT (3/12) loci. Low level copy number gain suggestive of amplification of the MYC locus was seen in two cases, and confirmed using FISH. MYC protein expression, as assessed by immunohistochemistry, was present in almost all sebaceous carcinoma cases. Our findings support the concept that alterations in TP53 and RB1 are the commonest alterations in sebaceous carcinoma, and suggest that MYC may contribute to the oncogenesis of these tumors.

Functional Characterization of Two Novel Mutations in SCN5A Associated with Brugada Syndrome Identified in Italian Patients.

Background. Brugada syndrome (BrS) is an autosomal dominantly inherited cardiac disease characterized by “coved type” ST-segment elevation in the right precordial leads, high susceptibility to ventricular arrhythmia and a family history of sudden cardiac death. The SCN5A gene, encoding for the cardiac voltage-gated sodium channel Nav1.5, accounts for ~20–30% of BrS cases and is considered clinically relevant. Methods. Here, we describe the clinical findings of two Italian families affected by BrS and provide the functional characterization of two novel SCN5A mutations, the missense variant Pro1310Leu and the in-frame insertion Gly1687_Ile1688insGlyArg. Results. Despite being clinically different, both patients have a family history of sudden cardiac death and had history of arrhythmic events. The Pro1310Leu mutation significantly reduced peak sodium current density without affecting channel membrane localization. Changes in the gating properties of expressed Pro1310Leu channel likely account for the loss-of-function phenotype. On the other hand, Gly1687_Ile1688insGlyArg channel, identified in a female patient, yielded a nearly undetectable sodium current. Following mexiletine incubation, the Gly1687_Ile1688insGlyArg channel showed detectable, albeit very small, currents and biophysical properties similar to those of the Nav1.5 wild-type channel. Conclusions. Overall, our results suggest that the degree of loss-of-function shown by the two Nav1.5 mutant channels correlates with the aggressive clinical phenotype of the two probands. This genotype-phenotype correlation is fundamental to set out appropriate therapeutical intervention.

The genomic landscape of Chinese patients with upper tract urothelial carcinoma.

e16583 Background: Upper tract urothelial carcinoma (UTUC) is known to have a distinct aggressive clinical phenotype and its genomic characterization is poorly understood, especially in Asian population. In this study, we aimed to characterize the genomic landscape of Chinese UTUC patients and explore the clinical relevance, which is the largest cohort of UTUC to date. Methods: Overall, 122 Chinese patients with UTUC were enrolled. Tumor and germline DNA from patients were analyzed using a targeted next-generation sequencing assay to identify somatic mutations in 520 cancer associated genes. Mutations like deletion, amplification and gene fusion were included. Tumor mutational burden (TMB) and microsatellite instability (MSI) status were also evaluated. The frequency of genomic alterations in patients with UTUC was compared with that of the Western counterpart from previous studies. Results: In total, 13 low-grade and 109 high-grade UTUC patients were included in this study. The most frequent genomic alterations were identified in genes like TERT (50.0%; 61.5% low-grade vs 48.6% high-grade), KMT2D (48.4%; 61.5% vs 46.8%), FGFR3 (41.0%; 69.2% vs 37.6%), TP53 (37.7%; 7.7% vs 41.3%), CDKN2A (22.1%; 23.1% vs 22.0%), KDM6A (20.5%; 15.4% vs 21.1%) with different mutation frequencies in the two subgroups of patients. Despite the overall similarity (including FGFR3, ARID1A and CDKN2A), the comparison between our cohort and the two Western UTUC cohorts (n = 119, 24 low-grade and 95 high-grade) revealed significant differences in mutation frequencies of KMT2D (48.4% vs 36.1%), TERT (50.0% vs 26.9%), TP53 (37.7% vs 21.9%) and KDM6A (20.5% vs 32.8%) . Chi-square analysis revealed that patients with history of other cancers (4/17 vs. 3/105, P = 0.001) were more likely to have a MSI-high status. In addition, females (9/44 vs. 6/78, P = 0.039) and patients with cancer history (6/17 vs. 9/105, P = 0.002) were more likely to have high TMB (≥20 mutations/Mb; median: 6.48 mutations/Mb). At last, the frequency of germline P/LP variants were also similar but different in the spectrum between our cohort and the Western UTUC population. Differences in mutation frequency of APC (0 vs 2.6%), BRAC2 (2.6% vs 0.9%), CHEK2 (0.3% vs 1.8%), MSH2 (2.6% vs 5.3%) and MSH6 (0 vs 1.8%) were significant. Conclusions: This study revealed that Chinese UTUC patients had a similar frequency of genomic alterations with western patients. However, there were significant differences in the prevalence of several mutated genes including KMT2D, TERT, TP53 and KDM6A, suggesting the ethnicity differences between the two populations. Our findings laid the foundation of a deeper understanding of UTUC biology and will provide potential targets for the development of precision therapies in UTUC.