11 research outputs found
Hodgkinâs lymphoma characteristics in HIV-infected and uninfected patients at an urban hospital in the late combined antiretroviral era
Multicentric Castlemanâs disease in HIV/AIDS patients at an urban HIV clinic in Atlanta, Georgia, in the combined antiretroviral therapy era
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Genetic Analysis of Plasmablastic Lymphomas in HIV (+) Patients Reveals Novel Driver Regulators of the Noncanonical NF-ÎşB Pathway
Abstract
Introduction: Plasmablastic lymphoma (PL) is an aggressive variant of lymphoma, with strong association with HIV. Despite significant improvements in the survival of other lymphomas, PL has a short overall survival (14 months). The association with Epstein-Barr virus (EBV) infection and MYC chromosomal translocations are defining features of PL. However, the genetic causes and the role of specific mutation in PL are largely unknown. This limitation hinders the design of therapeutic approaches aimed to improve PL survival. Therefore, we performed a comprehensive analysis of the genetic landscape in PL.
Methodology: Whole exon sequencing of 52 de novo PL tumors from HIV+ patients and matched normal tissues (15%) using high throughput sequencing on the Illumina platform. Of these 52 patient samples, 10 tumor and 4 normal control samples were removed due to poor sequencing quality. Mapping and variant calls were performed using BWA and Varscan softwares. Variants call filtering criteria include: exon location, minimum coverage of 5%, and onside T-test P value ⤠of 0.01 or 0.02). For immunohistochemistry, we use p-TAK1 Thr184-187 (Cell signaling) and p-BTK Tyr551(Termofisher) antibodies.
Results: Analysis of exome sequencing data identified 1562 recurrent somatic mutations (p-value â¤0.01) in 711 genes, including 304 mutations previously identified in cancer driving genes. The most common recurrent pathways affected within the top 2000 gene mutations with pâ¤0.02 comprised mainly of NF-ÎşB signaling followed by immune response (antigen presentation by MHC class II and the alternative and lectin induced complement pathways), reverse signaling by Ephrin B, mTOR/PTEN and EGFR/RAS pathways.
Based on the lack of canonical NF-ÎşB activation previously reported (Chapman J et al. Leukemia 2015; 29: 2270-2273) and the important role of MYD88-p100 signaling pathway in B cell differentiation into plasmablast (Guo et al. Oncogene 2016. 36(29):4224-4232), we investigated the status of p100 signaling in PL using a published gene expression dataset (Chapman J. et al Leukemia 2015). Our analysis demonstrated that most PL (70%) manifest constitutive p100 signaling. Therefore, we focused on mutations in genes involved in the NF-ÎşB activation. Mutations in the NF-ÎşB pathway were identified in all the analyzed cases with an average of 4 mutated genes in each tumor. Consistent with the previously reported downregulation in RNA expression of genes implicated in the BCR and canonical NF-ÎşB signaling, we found deleterious mutations in genes in the BCR pathway that have been previously reported in lymphomas, including MATL1, FYN and SYK (24%, 16% and 15%, respectively). In contrast, we found frequent gene mutations in the MYD88-PI3P pathway that never have been reported in lymphomas, including SHIP2, DOCK8, PLCG2 in 50%, 39% and 37% of the cases, respectively. These findings are of relevance, as this mutations are expected to results in increased MYD88/TAK1 and BTK signaling (Shinners NP et al J. Imm. 2007, 179 (6) 3872-3880) and can be targeted by specific inhibitors. To evaluate the status of phosphorylation of TAK1 and BTK in these tumors, we performed immunohistochemistry analysis in 15 PL, demonstrating high levels of phosphorylation of these proteins in all tumors analyzed.
Conclusion: To our knowledge, this is the first in-depth analysis of PL genome. Our data provide the most comprehensive genetic portrait of PL, provides potential genetic causes of this disease and identify potential druggable targets that deserve further clinical exploration.
Disclosures
Flowers: National Cancer Institute: Research Funding; Millennium/Takeda: Research Funding; Eastern Cooperative Oncology Group: Research Funding; OptumRx: Consultancy; Denovo Biopharma: Consultancy; Genentech/Roche: Research Funding; V Foundation: Research Funding; Abbvie: Consultancy, Research Funding; Acerta: Research Funding; Celgene: Research Funding; Pharmacyclics/ Janssen: Consultancy; Spectrum: Consultancy; Burroughs Wellcome Fund: Research Funding; Bayer: Consultancy; Karyopharm: Consultancy; Gilead: Research Funding; Genentech/Roche: Consultancy; Pharmacyclics: Research Funding; Janssen Pharmaceutical: Research Funding; Abbvie: Research Funding; BeiGene: Research Funding; TG Therapeutics: Research Funding; Gilead: Consultancy. Lossos:Affimed: Research Funding. Bernal-Mizrachi:Takeda Pharmaceutical Company: Research Funding; Kodikaz Therapeutic Solutions: Consultancy, Equity Ownership
Factors Affecting Clinical Outcomes Among Patients Infected With HIV and Anal Cancer Treated With Modern Definitive Chemotherapy and Radiation Therapy
Purpose: Anal cancer affects a disproportionate percentage of persons infected with human immunodeficiency virus (HIV). We analyzed a cohort of patients with HIV and anal cancer who received modern radiation therapy (RT) and concurrent chemotherapy to assess whether certain factors are associated with poor oncologic outcomes. Patients and Methods: We performed a retrospective chart review of 75 consecutive patients with HIV infection and anal cancer who received definitive chemotherapy and RT from 2008 to 2018 at a single academic institution. Local recurrence, overall survival, changes in CD4 counts, and toxicities were investigated. Results: Most patients were male (92%) with large representation from Black patients (77%). The median pretreatment CD4 count was 280 cells/mm3, which was persistently lower at 6 and 12 monthsâ posttreatment, 87 cells/mm3 and 182 cells/mm3, respectively (P < .001). Most (92%) patients received intensity modulated RT; median dose was 54 Gy (Range, 46.8-59.4 Gy). At a median follow-up 5.4 years (Range, 4.37-6.21 years), 20 (27%) patients had disease recurrence and 10 (13%) had isolated local failures. Nine patients died due to progressive disease. In multivariable analysis, clinically node negative involvement was significantly associated with better overall survival (hazard ratio, 0.39; 95% confidence interval, 0.16-1.00, PÂ =Â .049). Acute grade 2 and 3 skin toxicities were common, at 83% and 19%, respectively. Acute grade 2 and 3 gastrointestinal toxicities were 9% and 3%, respectively. Acute grade 3 hematologic toxicity was 20%, and one grade 5 toxicity was reported. Several late grade 3 toxicities persisted: gastrointestinal (24%), skin (17%), and hematologic (6%). Two late grade 5 toxicities were noted. Conclusions: Most patients with HIV and anal cancer did not experience local recurrence; however, acute and late toxicities were common. CD4 counts at 6 and 12 monthsâ posttreatment remained lower than pretreatment CD4 counts. Further attention to treatment of the HIV-infected population is needed