Diffuse Large B-cell Lymphoma Research Articles

MicroRNAs implicated in canine diffuse large B-cell lymphoma prognosis.

Diffuse large B-cell lymphoma (DLBCL) is the most prevalent subtype of non-Hodgkin lymphoma (NHL) in domestic dogs, with many similarities to its human counterpart. The progression of the disease is rapid, and treatment must be initiated early to achieve cancer remission and extend life. This study examined the relationship between progression-free survival (PFS) and microRNA (miRNA) expression in dogs with DLBCL. miRNAs are small non-coding RNA molecules that typically regulate gene expression post-transcriptionally. They are involved in several pathophysiological processes, including the growth and progression of cancer. Based on the analysis of small RNA sequencing (sRNA-seq) data, we validated a group of miRNAs in lymph nodes from 44 DLBCL-affected dogs with known outcomes. We used quantitative PCR to quantify their expression and report a specific subset of miRNAs is associated with decreased PFS in dogs with DLBCL. The miR-192-5p and miR-16-5p expression were significantly downregulated in dogs with increased PFS. These results indicate that miRNA profiling may potentially identify dogs with DLBCL that will experience poor outcomes following treatment. Identifying specific miRNAs that correlate with the progression of canine DLBCL could aid the development of individualized treatment regimens for dogs.

Spotlight on polatuzumab vedotin: new standards for diffuse large B-cell lymphoma?

Despite continuous improvements in the management and treatment of diffuse large B-cell lymphoma (DLBCL), approximately 35% of affected patients experience relapse or are refractory to frontline chemotherapy. For these patients, outcomes are far from satisfactory, and a real unmet need exists both to improve frontline treatment and to create better options for relapsed/refractory disease. Polatuzumab vedotin is an anti-CD79b antibody conjugated to the monomethyl auristatin E microtubule inhibitor. The molecule has recently been under the spotlight for the promising results of the frontline combination with rituximab, cyclophosphamide, doxorubicin and prednisone in the phase III POLARIX study, demonstrating improved progression-free survival over standard rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone. Remarkable improvements in terms of complete response rate and overall survival have also been achieved with polatuzumab vedotin by combining the antibody with the standard rituximab and bendamustine regimen for relapsed/refractory patients. Based on the results of these studies, health authorities in several countries granted approval for polatuzumab vedotin to be used as treatment both for patients with previously untreated DLBCL and for those with relapsed/refractory DLBCL. In this review, we summarize the data of major studies recently concluded with polatuzumab vedotin, and we provide an overview of the ongoing combination trials for frontline and relapsed/refractory DLBCL, outlining reported toxicities.

Specific Mutation Predict Relapse/Refractory Diffuse Large B-Cell Lymphoma.

The application of rituximab has significantly enhanced the overall survival rates in patients with diffuse large B-cell lymphoma (DLBCL). Regrettably, a significant number of patients still progress to relapse/refractory DLBCL (rrDLBCL). Herein, we employed targeted sequencing of 55 genes to investigate if gene mutations could predict the progression to rrDLBCL. Additionally, we compared the mutation profiles at the time of DLBCL diagnosis with those found in rrDLBCL cases. Our findings highlighted significantly elevated mutation frequencies of TP53, MEF2B and CD58 in diagnostic biopsies from patients who progressed to relapse or refractory disease, with CD58 mutations exclusively observed in the rrDLBCL group. In assessing the predictive power of mutation profiles for treatment responses in primary DLBCL patients, we found that the frequency of CARD11 mutations was substantially higher in non-response group as compared with those who responded to immunochemotherapy. In addition, we revealed mutations in HIST2H2AB, BCL2, NRXN3, FOXO1, HIST1H1C, LYN and TBL1XR1 genes were only detected in initial diagnostic biopsies, mutations in the EBF1 gene were solely detected in the rrDLBCL patients. Collectively, this study elucidates some of the genetic mechanisms contributing to the progression of rrDLBCL and suggests that the presence of CD58 mutations might serve as a powerful predictive marker for relapse/refractory outcomes in primary DLBCL patients.

Utility of PD-1, PD-L1, and IDO-1 Stains in Ocular Extranodal Marginal Zone Lymphoma (MZL) and Diffuse Large B-cell Lymphoma (DLBCL).

Extranodal marginal zone lymphoma (EMZL) is the most common subtype of ocular lymphomas. Diffuse large B-cell lymphoma (DLBCL) and EMZL with large-cell transformation present diagnostic challenges. Radiotherapy is the standard treatment for ocular lymphomas, but complications and relapse are common. Diagnostic utility in challenging cases, as well as treatment options using immune checkpoint inhibitors, are unclear in ocular lymphomas. We herein investigated the PD-1, PD-L1, and IDO1 staining patterns in 20 cases of ocular lymphomas, including EMZL (n=14), EMZL with increased large cells (n=2), and DLBCL (n=4). PD-1, PD-L1, and IDO1 staining was not detected in lymphoma cells in any cases but was observed within the tumor microenvironment in all cases. Positivity for PD-1, PD-L1, and IDO1 in inflammatory cells was seen either intratumorally or peritumorally. In all 6 cases with significantly more large B cells, the density of PD-1, PD-L1, and IDO1 expression in the tumor microenvironment was higher than that of the remaining 14 cases without large B cells ( P -value<0.0001), whereas other clinicopathologic features showed no statistical correlation. Increased expression of PD-1, PD-L1, and IDO1 in the inflammatory milieu in cases with large cells may provide diagnostic utility in small biopsies as well as therapeutic potential.

The care pathway of patients with diffuse large B-cell lymphoma described through Italian administrative healthcare data.

The diffuse large B-cell lymphoma (Dlbcl) is the most common non-Hodgkin lymphoma and at highest incidence among the elderly. Despite the improved outcomes of patients treated with the first-line (1L) standard of care until the end of 2022, composed by rituximab and polychemotherapy (R-Chop), during the last 20 years, the rate of relapsed and refractory Dlbcl (rrDlbcl) remains elevated. This study has identified and analyzed patients newly diagnosed with Dlbcl and treated with 1L, from the perspective of the Italian National Health Service (Ssn). From the administrative database of Fondazione Ricerca e Salute (ReS) including ~5.5 million inhabitants/year in Italy, adults with a new in-hospital Dlbcl diagnosis (index date) and treated with 1L in 2018, 2019, 2020 and 2021 were identified and characterized in terms of demographics and comorbidities during a period (from 4 to 8 years) preceding index date. From 1 to 4 years following index date (follow-up), overall survival (Kaplan-Meier curves), percentage distribution of patients by line of therapy including dispensation/administration of chemo-immunotherapy, hemopoietic stem cell transplantation (Hsct), and direct healthcare costs charge to the Ssn, were evaluated. Overall, from the ReS database, 206 patients newly diagnosed with Dlbcl and treated with 1L from 2018 to 2021 in Italy (incidence from 0.9 to 1.7 x100,000 adult inhabitants) were identified. They were mainly older (median age 68 [56; 75] years), males (56%) and affected by ≥2 comorbidities (52%), mostly cardiometabolic. During 4 years of follow-up, 56% of cases in 2018 survived. During the first follow-up year: 73%, 80%, 100% and 35% of cases in 2018, 2019, 2020 and 2021, respectively, received a 2L; 42% and 64% of cases in 2018 and 2020, respectively, received a 3L. At least one Hsct was found as a 2L among cases in 2018, 2020 and 2021. On average, each patient newly diagnosed with Dlbcl and treated with 1L from 2018 to 2021 caused a total expenditure directly charged to the Ssn ranging from € 20,000 to € 30,000 during the first follow-up year (chemo-immunotherapy accounted for 40-53%), which reduced with time in favor of other drugs and Hsct. This analysis confirms the high rate of rrDlbcl and the high economic impact charged to the SSN to support first the chemo-immunotherapy, then the chronic care and the absence of standardized further lines of therapy for patients with rrDlbcl.

819P Efficacy and safety of orelabrutinib plus R-CHOP-like regimens for treatment-naïve diffuse large B-cell lymphoma with double expression

819P Efficacy and safety of orelabrutinib plus R-CHOP-like regimens for treatment-naïve diffuse large B-cell lymphoma with double expression

Ulcer Symptoms Concealing Primary Jejunal Follicular Lymphoma: A Case Report

&lt;p&gt;胃腸道淋巴瘤的臨床表現多樣且非特異，往往難以區分良性或惡性。內視鏡和放射學檢查的表現也不具特定性。在胃腸道，淋巴瘤是一種相對罕見的腫瘤，佔胃腸道惡性腫瘤的1%&amp;ndash;8%，初發性胃、小腸和十二指腸淋巴瘤的比例約為10:3:1。濾泡性淋巴瘤主要發生在十二指腸，瀰漫性大B細胞淋巴瘤在胃和迴腸，黏膜相關淋巴組織淋巴瘤在胃，套細胞淋巴瘤在末端迴腸、空腸和結腸，而腸病相關T細胞淋巴瘤多在空腸。對於濾泡性淋巴瘤，觀察也是一種選擇，手術介入通常僅適於複雜的臨床狀況，如腸阻塞或穿孔。&lt;/p&gt; &lt;p&gt;本篇病例報告一位74歲男性個案，十八年前出現反覆性上腹痛、腹部脹氣、打嗝、腹瀉，偶有便秘，多次上消化道內視鏡檢查診斷胃與十二指腸潰瘍，治療後症狀仍然存在。兩年後出現嘔吐，全套血液、生化、糞便檢驗皆無異常，上消化道內視鏡顯示多發性胃與十二指腸潰瘍，無幽門桿菌感染。腹部超音波顯示明顯胃擴張，電腦斷層檢查未發現腸阻塞或狹窄。小腸鏡顯示第三至第四部分十二指腸狹窄，組織切片為B細胞型態淋巴瘤。個案接受手術，術中發現在屈氏韌帶下方約5 cm處近端空腸有一4.8 cm &amp;times; 3.0 cm &amp;times; 1.3 cm環狀腫瘤併腸繫膜數顆腫大淋巴結，予以切除9.8 cm空腸與淋巴結並接受腸道吻合。病理診斷為第2級濾泡性淋巴瘤。術後接受化學治療及定期追蹤。至今已過十六年，病人情況良好。定期追蹤檢查並無復發。&lt;/p&gt; &lt;p&gt;藉此病例報告提醒基層醫師面對反覆性消化性潰瘍時，必需將消化道淋巴瘤列入鑑別診斷。&lt;/p&gt; &lt;p&gt;&amp;nbsp;&lt;/p&gt;&lt;p&gt;It is challenging to distinguish benign gastrointestinal tumors from malignant ones due to their diverse and nonspecific symptoms, and endoscopic and radiological findings often lack specificity. Lymphoma is relatively uncommon in the gastrointestinal tract, constituting 1%-8% of malignant tumors with a primary tumor ratio of approximately 10:3:1 for the stomach, small intestine, and duodenum. Follicular lymphomas mainly occur in duodenum, diffuse large B-cell lymphomas in stomach and ileum, MALT lymphomas in stomach, mantle cell lymphomas in terminal ileum, jejunum, and colon, and enteropathy-associated T-cell lymphomas in jejunum. For the treatment of follicular lymphomas, observation remains a viable option, while surgical intervention is usually reserved for complicated clinical conditions, such as intestinal obstruction or perforation. &lt;/p&gt; &lt;p&gt; This case report features a 74-year-old male with recurrent epigastric pain, abdominal distention, hiccups, diarrhea and occasional constipation since he was diagnosed with duodenal ulcers eighteen years ago. Repeated panendoscopic examinations showed gastric and duodenal ulcers. Symptoms persisted after treatment and were followed by vomiting two years later. Comprehensive blood, biochemical, and stool analyses revealed no abnormalities. Panendoscopic examination showed multiple ulcers in the stomach and duodenum without Helicobacter pylori infection. Abdominal ultrasound indicated significant gastric dilation, and computed tomography scan revealed neither intestinal obstruction nor stenosis. Small intestinal fiberscope found stenosis in the third to fourth portions of the duodenum, and tissue biopsy suggested B-cell lymphoma. Intraoperatively, a circumferential tumor measuring 4.8 cm &amp;times; 3.0 cm &amp;times; 1.3 cm was identified, located approximately 5 cm proximal to the Ligament of Treitz. It was accompanied by enlarged mesenteric lymph nodes. The excision of 9.8 cm of the jejunum, along with lymph node dissection, was followed by anastomosis. Surgical pathology confirmed grade II follicular lymphoma. Postoperatively, the patient receives chemotherapy and undergoes regular follow-up. The patient has remained in good medical condition over these sixteen years. Follow-up examinations did not show tumor recurrence. This case report aims to remind primary care physicians to consider gastrointestinal lymphoma early in the differential diagnosis of recurrent peptic ulcers.&lt;/p&gt; &lt;p&gt;&amp;nbsp;&lt;/p&gt;

806MO Phase Ib study of NT-I7 (efineptakin alfa), a long-acting IL-7, post-CD19-directed CAR T cell therapy in diffuse large B-cell lymphoma (DLBCL)

806MO Phase Ib study of NT-I7 (efineptakin alfa), a long-acting IL-7, post-CD19-directed CAR T cell therapy in diffuse large B-cell lymphoma (DLBCL)

A Vision Transformer-Based Framework for Knowledge Transfer From Multi-Modal to Mono-Modal Lymphoma Subtyping Models.

Determining lymphoma subtypes is a crucial step for better patient treatment targeting to potentially increase their survival chances. In this context, the existing gold standard diagnosis method, which relies on gene expression technology, is highly expensive and time-consuming, making it less accessibility. Although alternative diagnosis methods based on IHC (immunohistochemistry) technologies exist (recommended by the WHO), they still suffer from similar limitations and are less accurate. Whole Slide Image (WSI) analysis using deep learning models has shown promising potential for cancer diagnosis, that could offer cost-effective and faster alternatives to existing methods. In this work, we propose a vision transformer-based framework for distinguishing DLBCL (Diffuse Large B-Cell Lymphoma) cancer subtypes from high-resolution WSIs. To this end, we introduce a multi-modal architecture to train a classifier model from various WSI modalities. We then leverage this model through a knowledge distillation process to efficiently guide the learning of a mono-modal classifier. Our experimental study conducted on a lymphoma dataset of 157 patients shows the promising performance of our mono-modal classification model, outperforming six recent state-of-the-art methods. In addition, the power-law curve, estimated on our experimental data, suggests that with more training data from a reasonable number of additional patients, our model could achieve competitive diagnosis accuracy with IHC technologies. Furthermore, the efficiency of our framework is confirmed through an additional experimental study on an external breast cancer dataset (BCI dataset).

827P Comparison of efficacy and safety between glofitamab and real-world regimens among Chinese patients with 3L+ relapsed/refractory diffuse large B-cell lymphoma: An external control study

827P Comparison of efficacy and safety between glofitamab and real-world regimens among Chinese patients with 3L+ relapsed/refractory diffuse large B-cell lymphoma: An external control study

ABCL-440 Preliminary Safety and Efficacy Data of Combination Polatuzumab Vedotin Rituximab, Cyclophosphamide Adriamycin, Prednisone (Pola-R-CHP) in Patients With Diffuse Large B-Cell Lymphoma (DLBCL) in the Standard-of-Care Setting: A Single-Center Experience

ABCL-440 Preliminary Safety and Efficacy Data of Combination Polatuzumab Vedotin Rituximab, Cyclophosphamide Adriamycin, Prednisone (Pola-R-CHP) in Patients With Diffuse Large B-Cell Lymphoma (DLBCL) in the Standard-of-Care Setting: A Single-Center Experience

Prognostic and survival factors in head and neck extra-nodal non-Hodgkin's lymphoma

To make a clinical-biological characterization of this pathology and assess the survival of these patients and the associated prognostic factors. A retrospective observational study was designed to identify primary extranodal non-Hodgkin lymphomas of the head and neck diagnosed between January 1, 2005, and January 1, 2016. Cases were considered if they presented with a single tumor in situ or if the extranodal component was clinically predominant. A total of 145 patients were included. Localized stages (I-II) were present in 69.3%. Overall, 91.8% were B-cell phenotype, with diffuse large B-cell lymphoma being the most frequent. Overall, 78% of patients were treated with immunochemotherapy. The overall survival at 3 and 5 years was 75% and 73%, respectively. Adverse prognostic factors were: low hemoglobin, elevated ß2-microglobulin, and lactate dehydrogenase (LDH) levels, Eastern Cooperative Oncology Group (ECOG), stage III/IV, and B symptomatology at diagnosis. The progression-free survival at 3 and 5 years was 71% and 68%. Risk factors for relapse were high ß2-microglobulin, high LDH, and stage III-IV at diagnosis. These pathologies show a good response to treatment with immuno-polychemotherapy. Factors associated with a worse prognosis included low hemoglobin, elevated levels of ß2-microglobulin and LDH, elevated ECOG, stage III/IV, and B symptomatology at diagnosis.

844TiP Orelabrutinib combined with rituximab for the treatment of elderly patients with newly diagnosed non-GCB diffuse large B-cell lymphoma (DLBCL) under the guidance of genetic subtype: A prospective, multicenter, single-arm, response-adaptive clinical study (Origin)

844TiP Orelabrutinib combined with rituximab for the treatment of elderly patients with newly diagnosed non-GCB diffuse large B-cell lymphoma (DLBCL) under the guidance of genetic subtype: A prospective, multicenter, single-arm, response-adaptive clinical study (Origin)

Pirtobrutinib, a highly selective, non-covalent (reversible) BTK inhibitor in patients with B-cell malignancies: analysis of the Richter transformation subgroup from the multicentre, open-label, phase 1/2 BRUIN study

Richter transformation usually presents as an aggressive diffuse large B-cell lymphoma, occurs in up to 10% of patients with chronic lymphocytic leukaemia, has no approved therapies, and is associated with a poor prognosis. Pirtobrutinib has shown promising efficacy and tolerability in patients with relapsed or refractory B-cell malignancies, including those who progress on covalent Bruton tyrosine kinase (BTK) inhibitors. This study aims to report the safety and activity of pirtobrutinib monotherapy in a subgroup of patients with Richter transformation from the multicentre, open-label, phase 1/2 BRUIN study. This analysis included adult patients (aged ≥18 years) with histologically confirmed Richter transformation, an Eastern Cooperative Oncology Group performance status score of 0-2, and no limit of previous therapies, with patients receiving first-line treatment added in a protocol amendment (version 9.0, Dec 15, 2021). Pirtobrutinib 200 mg was administered orally once a day in 28-day cycles. The primary endpoint of phase 1 of the BRUIN trial as a whole, which has been previously reported, was to establish the recommended phase 2 dose for pirtobrutinib monotherapy and the phase 2 primary endpoint was overall response rate. Safety and activity were measured in all patients who received at least one dose of pirtobrutinib monotherapy. This BRUIN phase 1/2 trial was registered with ClinicalTrials.gov and is closed to enrolment (NCT03740529). Between Dec 26, 2019, and July 22, 2022, 82 patients were enrolled, of whom five were enrolled during phase 1 and 77 during phase 2. All but one patient received a starting dose of 200 mg pirtobrutinib once a day as the recommended phase 2 dose. The remaining patient received 150 mg pirtobrutinib once a day, which was not escalated to 200 mg. The median age of patients was 67 years (IQR 59-72). 55 (67%) of 82 patients were male and 27 (33%) were female. Most patients were White (65 [79%] of 82). 74 (90%) of 82 patients received at least one previous Richter transformation-directed therapy. Most patients (61 [74%] of 82) had received previous covalent BTK inhibitor therapy for chronic lymphocytic leukaemia or Richter transformation. The overall response rate was 50·0% (95% CI 38·7-61·3). 11 (13%) of 82 patients had a complete response and 30 (37%) of 82 patients had a partial response. Eight patients with ongoing response electively discontinued pirtobrutinib to undergo stem-cell transplantation. The most common grade 3 or worse adverse event was neutropenia (n=19). There were no treatment-related deaths. Pirtobrutinib shows promising safety and activity among patients with Richter transformation, most of whom received previous Richter transformation-directed therapy, including covalent BTK inhibitors. These data suggest that further investigation is warranted of pirtobrutinib as a treatment option for patients with relapsed or refractory Richter transformation after treatment with a covalent BTK inhibitor. Loxo Oncology.

Comparison of Thiotepa-based Conditioning Regimens for Older Adults with Primary Diffuse Large B-cell Lymphoma of the Central Nervous System Undergoing Autologous Hematopoietic Cell Transplantation

BackgroundIn this study, we compare outcomes of older patients with primary diffuse large B-cell lymphoma of the central nervous system (PCNSL) undergoing autologous hematopoietic cell transplantation (autoHCT) with either thiotepa/carmustine (BCNU/Thio) or thiotepa/busulfan/cyclophosphamide (TBC) conditioning. MethodsWe used a post-publication dataset made available by the Center for International Blood and Marrow Research (CIBMTR) including patients who were ≥65 years in age with PCNSL and underwent autoHCT as consolidation with TBC or BCNU/Thio conditioning. ResultsOut of 147 patients; n=84 received BCNU/Thio and n=63 received TBC. The 1-year NRM in the BCNU/Thio group was 10% versus 22% in the TBC group (p=0.05) and the 2-year relapse rate was 5% versus 5%, respectively (p=1.00). The 2-year PFS in the BCNU/Thio group was 85% versus 71% in the TBC group (p=0.05) and 2-year OS was 86% vs 74% (p=0.08). In a multivariable regression model, BCNU/Thio was associated with a lower risk for NRM [Hazard Ratio (HR), 0.33, p=0.009], improved PFS (HR, 0.41, p=0.008) and OS (HR, 0.37, p=0.007), but there was no association with relapse risk. ConclusionWe found that in older adults with PCNSL undergoing consolidation with autoHCT, BCNU/Thio conditioning is associated with lower NRM and improved OS compared to TBC.

808MO Value of early post-treatment FDG PET/CT in diffuse large B-cell lymphoma patients receiving chimeric antigen receptor T cell therapy

808MO Value of early post-treatment FDG PET/CT in diffuse large B-cell lymphoma patients receiving chimeric antigen receptor T cell therapy

Ouabain-mediated downregulation of ALKBH5 and IGF2BP2 inhibits the malignant progression of DLBCL.

m6A modification is a crucial epigenetic regulatory mechanism in diffuse large B-cell lymphoma (DLBCL). Low-dose cardiotonic drugs have been shown to induce apoptosis in DLBCL cells through epigenetic modulation. However, the involvement of the cardiotonic drug ouabain in the malignant progression of DLBCL remains unclear. Our study revealed that ouabain indeed contributes to the malignant progression of DLBCL through m6A modification. Through qPCR analysis, we observed a negative correlation between ouabain concentration and the expression levels of the demethylase ALKBH5 and the m6A-binding protein IGF2BP2 in DLBCL cells. Furthermore, high expression levels of ALKBH5 and IGF2BP2 were identified in both the GEO database and DLBCL patient tissue samples. Notably, elevated ALKBH5 and IGF2BP2 promoted cell proliferation both in vitro and in vivo. Inhibition of their expression rendered DLBCL cells more sensitive to ouabain treatment, resulting in significant suppression of cell proliferation, G1/S phase cell cycle arrest, and increased apoptosis. In summary, our results clarify that the demethylase ALKBH5 and the m6A-binding protein IGF2BP2 are involved in the malignant progression of DLBCL, and that the cardiotonic drug ouabain can inhibit the proliferation of DLBCL cells by inhibiting the expression of ALKBH5 and IGF2BP2, which provides new insights into the targeted treatment of DLBCL.

Applying Molecular Modeling to the Design of Innovative, Non-Symmetrical CXCR4 Inhibitors with Potent Anticancer Activity.

The identification of new compounds with potential activity against CXC chemokine receptor type 4 (CXCR4) has been broadly studied, implying several chemical families, particularly AMD3100 derivatives. Molecular modeling has played a pivotal role in the identification of new active compounds. But, has its golden age ended? A virtual library of 450,000 tetraamines of general structure 8 was constructed by using five spacers and 300 diamines, which were obtained from the corresponding commercially available cyclic amines. Diversity selection was performed to guide the virtual screening of the former database and to select the most representative set of compounds. Molecular docking on the CXCR4 crystal structure allowed us to rank the selection and identify those candidate molecules with potential antitumor activity against diffuse large B-cell lymphoma (DLBCL). Among them, compound A{17,18} stood out for being a non-symmetrical structure, synthetically feasible, and with promising activity against DLBCL in in vitro experiments. The focused study of symmetrical-related compounds allowed us to identify potential pre-hits (IC50~20 µM), evidencing that molecular design is still relevant in the development of new CXCR4 inhibitor candidates.

Diffuse large B-cell lymphoma (DLBCL) accompanied by a pathologically enlarged pack of lymph nodes: A review

Diffuse large B-cell lymphoma (DLBCL) accompanied by a pathologically enlarged pack of lymph nodes: A review

Direct DNA binding by BRCA1 on β-hCG promoter and its clinical implications

ObjectiveThe role of β-hCG in breast cancer is largely unknown, this study aims to analyse the gene expression and clinical implications of β-hCG and its isoforms in various cancers focussing particularly in Breast Invasive Carcinoma (BRCA). A mechanistic approach deciphering the transcriptional regulation of β-hCG by BRCA1 was also explored. MethodsData from various comprehensive gene expression platforms like UALCAN, GEPIA2, GENT2, TIMER2, LinkedOmics, and STRING were used to analyse the expression of β-hCG and its clinical implications; Immunohistochemistry and ELISA for β-hCG expression analysis from human breast cancer patients; Electrophoretic mobility shift assay (EMSA) to analyse the direct binding of BRCA1 on β-hCG; Immunoblotting and Luciferase assay to understand the regulation of β-hCG by p53 were performed. ResultsResults from UALCAN and GENT2 gene expression cancer database revealed that TNBC subtypes and high-grade metaplastic carcinoma shows elevated expression of β-hCG and infiltration of various immune cells were also identified in BRCA by TIMER2. It was observed that most of the isoforms of β-hCG (CGB) are upregulated in breast cancers irrespective of hormonal status when BRCA1 gene is mutated according to TIMER2. Similar results were observed with Lymphoid neoplasm diffuse large B-cell lymphoma (LGG) and DLBC (Brain lower grade glioma) when BRCA1 is mutated. These results correlate with our earlier reports indicating expression of β-hCG in BRCA1 defective condition. We have also identified direct binding of BRCA1 on β-hCG promoter. ConclusionAll these findings demonstrate the importance of β-hCG as a potential target in BRCA1-deficient carcinomas.