4 research outputs found
Performance of the Lymph2Cx Cell of Origin Classifier of Diffuse Large B-Cell Lymphoma in Comparison to Two Immunohistochemical Algorithms
Integrative Analysis of Clinicopathological Features Defines Novel Prognostic Models for Mantle Cell Lymphoma in the Immunochemotherapy Era: A Report from The North American Mantle Cell Lymphoma Consortium
BACKGROUND: Patients with mantle cell lymphoma (MCL) exhibit a wide variation in clinical presentation and outcome. However, the commonly used prognostic models are outdated and inadequate to address the needs of the current multidisciplinary management of this disease. This study aims to investigate the clinical and pathological features of MCL in the immunochemotherapy era and improve the prognostic models for a more accurate prediction of patient outcomes.
METHODS: The North American Mantle Cell Lymphoma Project is a multi-institutional collaboration of 23 institutions across North America to evaluate and refine prognosticators for front-line therapy. A total of 586 MCL cases diagnosed between 2000 and 2012 are included in this study. A comprehensive retrospective analysis was performed on the clinicopathological features, treatment approaches, and outcomes of these cases. The establishment of novel prognostic models was based on in-depth examination of baseline parameters, and subsequent validation in an independent cohort of MCL cases.
RESULTS: In front-line strategies, the use of hematopoietic stem cell transplantation was the most significant parameter affecting outcomes, for both overall survival (OS, p \u3c 0.0001) and progression-free survival (PFS, p \u3c 0.0001). P53 positive expression was the most significant pathological parameter correlating with inferior outcomes (p \u3c 0.0001 for OS and p = 0.0021 for PFS). Based on the baseline risk factor profile, we developed a set of prognostic models incorporating clinical, laboratory, and pathological parameters that are specifically tailored for various applications. These models, when tested in the validation cohort, exhibited strong predictive power for survival and showed a stratification resembling the training cohort.
CONCLUSIONS: The outcome of patients with MCL has markedly improved over the past two decades, and further enhancement is anticipated with the evolution of clinical management. The innovative prognostic models developed in this study would serve as a valuable tool to guide the selection of more suitable treatment strategies for patients with MCL
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Mutations of ATM Confer a Risk of Inferior Survival in Patients with TP53- wild Type Mantle Cell Lymphoma
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Whole Exome and Transcriptome Sequencing in 1042 Cases Reveals Distinct Clinically Relevant Genetic Subgroups of Follicular Lymphoma
Follicular Lymphoma (FL) is the most common indolent lymphoma derived from light zone germinal center B cells and characterized by a t(14;18) translocation resulting in upregulation of BCL2 in over 80% of cases. This translocation alone is not sufficient for tumorogenesis, and must be combined with additional genetic mutations to transform B cells. FL is incurable and the disease course can be highly varied, with survival ranging from a few months to decades following diagnosis and treatment with standard chemoimmunotherapy. The heterogeneity of FL poses major challenges to identifying the association of genetic alterations and clinical outcome. Current WHO guidelines recommend establishing grade for each FL case with grade 3 thought to be more aggressive than 1 and 2. The genetic basis and clinical implications of grade in FL are unclear. Recent sequencing studies have identified many genes found to be recurrently mutated in FL including KMT2D and CREBBP. However, the degree to which genetic alterations cooperate with each other or contribute to clinical outcome is unclear. Based on the observed mutational rates in follicular lymphoma, we estimated 900 cases were needed to comprehensively delineate the genetic alterations that underlie histologic grade and clinical outcome. Accordingly, we enrolled a cohort of 1042 patients with newly diagnosed FL. All treated patients received rituximab-containing standard regimens. To go beyond the identification of gene-coding events, we developed a very large panel of 110 Mbp covering exonic (~40Mbp) and non-exonic regions (~70Mbp) of interest to enable a wide range of genomic analysis including mutation calling in both coding and non-coding regions, rearrangement detection, viral identification, and copy number analysis. In addition to the whole exome, we extended coverage to include introns, promoters, and untranslated regions of all known driver genes in cancer. We included the entirety of the immunoglobulin loci, T-cell receptor loci and CD3 loci to detect clonotypes and rearrangements. We also included lymphoma-relevant long non-coding RNAs, microRNAs, enhancers, and breakpoint-prone regions. For viral detection, we targeted the genomes of eight cancer-related viruses: Epstein-Barr virus, human papillomavirus, human immunodeficiency virus, hepatitis B, hepatitis C, Kaposi's sarcoma-associated herpesvirus, human T-lymphotropic virus, and Merkel cell polyomavirus. In addition, to enable high resolution identification of copy number variation (CNV) calls, the entire genome was tiled with probes spaced 10kb apart. DNA and RNA were extracted from all tumors and their paired normal samples, prepared into DNA and RNA sequencing libraries and subjected to sequencing on the Illumina platform to a targeted coverage of 150X. Somatic events were identified and further filtered to identify driver events in both coding and non-coding regions. FLs demonstrated a significant degree of genetic heterogeneity with over 100 genes mutated with a frequency of at least 2%. Nearly 100% of FL cases had a mutation in at least one chromatin-modifying gene. The most frequently mutated genes in follicular lymphoma were KMT2D, BCL2, IGLL5 and CREBBP. In addition, we identified frequent mutations in SPEN, BIRC6 and SETD2. To our knowledge, this is the first description of alterations in these genes in FL. Transcriptome analysis indicated a strong correlation between BIRC6 mutations and the previously described immune response 2 signature that is associated with a poor prognosis. We further performed unbiased clustering of genetic alterations in these FL cases. We identified a cluster that was specifically enriched in BCL6 and TP53 alterations and was strongly associated with grade 3 FLs which are predicted to have poorer outcomes with low intensity therapies. We further examined the genetic profiles of 1001 DLBCLs in comparison to this cohort of FLs. Our data indicate a continuum of highly overlapping genetic alterations with DLBCL displaying more complex patterns that included alterations in MYC, TP53 and CDKN2A (mainly copy number losses), indicating shared pathogenetic mechanisms underlying FL and DLBCL, particularly those germinal center B cell origin. Disclosures Koff: Burroughs Wellcome Fund: Research Funding; V Foundation: Research Funding; Lymphoma Research Foundation: Research Funding; American Association for Cancer Research: Research Funding. Leppä:Roche: Honoraria, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Gang:ROCHE: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Hsi:Abbvie: Research Funding; Eli Lilly: Research Funding; Cleveland Clinic&Abbvie Biotherapeutics Inc: Patents & Royalties: US8,603,477 B2; Jazz: Consultancy. Flowers:AbbVie: Consultancy, Research Funding; Denovo Biopharma: Consultancy; BeiGene: Consultancy, Research Funding; Burroughs Wellcome Fund: Research Funding; Eastern Cooperative Oncology Group: Research Funding; National Cancer Institute: Research Funding; V Foundation: Research Funding; Optimum Rx: Consultancy; Millenium/Takeda: Research Funding; TG Therapeutics: Research Funding; Gilead: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Karyopharm: Consultancy; AstraZeneca: Consultancy; Pharmacyclics/Janssen: Consultancy, Research Funding; Spectrum: Consultancy; Bayer: Consultancy; Acerta: Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding. Neff:Enzyvant: Consultancy; EUSA Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees. Fedoriw:Alexion Pharmaceuticals: Other: Consultant and Speaker. Reddy:Genentech: Research Funding; BMS: Consultancy, Research Funding; Celgene: Consultancy; KITE Pharma: Consultancy; Abbvie: Consultancy. Mason:Sysmex: Honoraria. Behdad:Loxo-Bayer: Membership on an entity's Board of Directors or advisory committees; Thermo Fisher: Membership on an entity's Board of Directors or advisory committees; Pfizer: Other: Speaker. Burton:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Dave:Data Driven Bioscience: Equity Ownership