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 | $599,762 | Project Dates | 01/01/1980 - 00/00/0000 |
Fiscal Year | 2015 | 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 Prognosi |
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Abstract | |||
Most cases of Hepatosplenic T-cell lymphoma (HSTCL) are derived from gamma delta T-cells and exhibit an immature cytotoxic phenotype. Cytogenetic studies from our group and others indicated a high frequency of nonrandom chromosomal abnormalities including isochromosome 7q. However, the specific genes responsible for neoplastic transformation had not been identified. STAT5 activation has been linked to T-cell development and homeostasis, as well as to the initiation of gamma delta T-cell differentiation. Deregulation of the STAT3 pathway has been reported in a number of T-cell malignancies. We reasoned that these genes could potentially play a role in hepatosplenic T-cell lymphomas. (Nicolae, Xi et al. 2014) Twenty-one cases of HSTCL with suitable FFPE material for analysis were identified from our archive. In collaboration with Dr. Mark Raffeld, targeted analysis for STAT3 and STAT5B mutations was performed. 9/21 HTSCL cases (42.8%) contained STAT mutations. The high frequency of STAT5B and STAT3 mutations in HSTCL strongly suggests that deregulation of the STAT pathway is an important oncogenic event in the pathogenesis of this lymphoma. Lymphomatoid granulomatosis (LYG) is a rare angiocentric and angiodestructive EBV-associated B-cell lymphoproliferative disorder. We recently completed a comprehensive review of the pathological specimens for patients entered on the NCI clinical protocol.(Song, Pittaluga et al. 2015) Sixty-nine patients were initially referred as possible LYG, with 14 cases excluded based on pathological review at the NIH. Of the 55 patients that were included in the study, 34 of the patients (62%) had prior therapy before enrolling in the LYG clinical trial, while 19 patients (35%) did not, and for 2 patients it was unknown whether there was prior treatment (4%). For the patients that had prior treatment, both the pre and post therapy biopsies were reviewed. We employed a grading system initially developed at the NCI; 30% were grade 1, 22% were grade 2 (22%), and 48% grade 3. B-cell clonality by PCR correlated with histological grade. However, necrosis could be found in all histological grades. Most patients who develop LYG do not have any overt evidence of immunodeficiency, although some patients exhibit low levels of CD8+ T-cells.(Dunleavy, Chattopadhyay et al. 2010) Therefore, the underlying pathogenesis for the inability to control EBV in this disease is unknown. As such, we attempted to assess the immune microenvironment in the LYG lesions. Regulatory T cells (Tregs) are characterized by a specific phenotype (CD4+CD25+ FOXP3+) and have been shown to suppress tumor-specific T-cell immunity in the tumor cell microenvironment. We performed FOXP3 immunostaining and found that there were more FOXP3-positive T cells in LYG grade 3 (median 39/10 hpfs) versus grades 1 or 2 (median 18/10 hpfs) suggesting that an increased number of Tregs in grade 3 may contribute to disease progression. These studies help illuminate the nature of the immune defect in LYG. We showed that EBV may be expressed in the lymphocyte-predominant (LP) cells of nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) in both children and adults.(Huppmann, Nicolae et al. 2014) The conventional wisdom had been that NLPHL is negative for EBV, while classical Hodgkin's lymphoma (CHL) is positive in 15-25% of cases. A single study from Vietnam reported cases of NLPHL positive for EBV.(Chang, Khen et al. 2005) It was unknown if this finding was restricted to Asian cases, or could also be seen in Western populations. Therefore, we coordinated a large collaborative study involving three North American centers (NIH, Massachusetts General Hospital, and the British Columbia Cancer Agency), to analyze 302 cases of NLPHL, 145 in pediatric patients and 157 in adults. Five (3.4%) pediatric and 7 (4.5%) adult NLPHL cases contained EBV(+) LP cells. No differences in clinical outcome were observed, although given the retrospective nature of the study, clinic |