ZIA SC 000550 (ZIA) | |||
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Title | Lymphoma Disease Discovery and Definition | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Jaffe, Elaine | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $574,502 | Project Dates | 00/00/0000 - 00/00/0000 |
Fiscal Year | 2017 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Cancer (100.0%) |
Hodgkins disease (10.0%) Leukemia (5.0%) Non Hodgkins Lymphoma (85.0%) |
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Research Type | |||
Technology and/or Marker Testing in a Clinical Setting Resources and Infrastructure Related to Detection, Diagnosis, or Prognosis |
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Abstract | |||
We expanded and extended our studies of Pediatric-type follicular lymphoma (PTFL), which were reported last year. Recently, recurrent genetic alterations of potential importance for its pathogenesis that disrupt pathways associated with the germinal center reaction (TNFRSF14, IRF8), immune escape (TNFRSF14) and anti-apoptosis (MAP2K1) have been described. In an attempt to shed more light onto the pathogenesis of PTFL, an integrative analysis of these mutations was undertaken in a large cohort of 43 cases previously characterized by targeted next generation sequencing and copy number array. Mutations in MAP2K1 were found in 49% (20/41) of the cases, second in frequency to TNFRSF14 alterations (22/41; 54%), and all together were present in 81% of the cases. Immunohistochemical analysis of the MAP2K1 downstream target ERK demonstrated its phosphorylation in the evaluable cases and revealed a good correlation with the allelic frequency of the MAP2K1 mutation. The IRF8 p.K66R mutation was present in 15% (6/39) of the cases and was concomitant with TNFRSF14 mutations in four cases. This hot-spot seems to be highly characteristic for PTFL. In conclusion, TNFRSF14 and MAP2K1 mutations are the most frequent genetic alterations found in PTFL and occur independently in most cases, suggesting that both mutations might play an important role in PTFL lymphomagenesis. We have had a long-standing interest in clarifying the classification of T-cell neoplasms, incorporating traditional pathological and genomic approaches. Expanding on prior work on hepatosplenic T-cell lymphomas, in a large collaborative effort, the genetic basis of this disease was more fully elucidated. Through whole-exome sequencing of 68 HSTLs, recurrently mutated driver genes and copy-number alterations in the disease were identified. Chromatin-modifying genes, including SETD2, INO80, and ARID1B, were commonly mutated in HSTL, affecting 62% of cases. HSTLs manifest frequent mutations in STAT5B (31%), STAT3 (9%), and PIK3CD (9%), for which there currently exist potential targeted therapies. In addition, less frequent events in EZH2, KRAS, and TP53 were described. SETD2 was the most frequently silenced gene in HSTL. SETD2 was shown to act as a tumor suppressor gene. In addition, mutations in STAT5B and PIK3CD activate critical signaling pathways important to cell survival in HSTL.The work thus defines the genetic landscape of HSTL and implicates gene mutations linked to HSTL pathogenesis and potential treatment targets. Primary intestinal T-cell lymphomas (ITCL) comprise mainly enteropathy-associated T-cell lymphomas (EATL). EATL is an aggressive, rare, lymphoma, which represents approximately 5% of mature T-cell lymphomas. Two subtypes are recognized based on distinct morphology, immunophenotype and epidemiology. EATL type I (EATL I) is more common in Western countries, is highly associated with celiac disease (CD), and shows a phenotype akin to that of the majority normal alpha-beta intraepithelial lymphocytes (IEL). EATL type II (EATL II), is more frequent in Asia, is uncommon in patients with CD, and is usually derived from mature activated cytotoxic gamma-delta T-cells. The mechanisms and genetic aberrations responsible for malignant transformation are largely unknown, due to the rarity of these lymphomas. Thirty-four ITCL with formalin-fixed paraffin-embedded tissue were analyzed using a targeted next generation sequencing strategy for mutations in 38 genes. These included genes previously reported to be mutated in T-cell lymphomas, components of the JAK/STAT pathway, and selected genes involved in T-cell receptor signaling and proliferation. Thirty-one and thirty-three samples, respectively, were also tested for mutations within JAK1 codon 1097, and GNAI2 codons 179 and 182 by targeted pyrosequencing, as these recently described mutational hotspots were not covered in the NGS panel. A total of 49 mutations were identified in the 34 ITCL cases, including 46 nonsynonymo |