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 | $854,050 | Project Dates | 10/01/1980 - 00/00/0000 |
Fiscal Year | 2014 | 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 | |||
As a follow up to our description of NK-cell enteropathy(1), we identified another novel and indolent gastrointestinal (GI) T-cell lymphoproliferative disorder that can be mistaken for an aggressive T-cell lymphoma.(2) We reported 10 cases with a median age of 48 years (range, 15-77 years). The lesions involved oral cavity, esophagus, stomach, small intestine, and colon. The infiltrates were dense, but nondestructive, and composed of small, mature-appearing lymphoid cells. Eight cases were CD4-/CD8+), 1 was CD4+/CD8-, and another was double-negative for CD4 and CD8. T-cell receptor-gamma chain gene rearrangement identified a clonal population in all 10 cases. There was no evidence of STAT3 SH2 domain mutation or activation, an abnormality that has been linked to T-cell large granular lymphocyte leukemia. Six patients received chemotherapy because of an initial diagnosis of peripheral T-cell lymphoma, with little or no response, whereas the other 4 were followed without therapy. After a median follow-up of 38 months (range, 9-175 months), 9 patients were alive with persistent disease and 1 was free of disease. None of the patients showed evidence of progression beyond the GI tract, with the exception of the one case that was double negative for CD4/CD8, possibly an indication for an alternate diagnosis. We propose the name ""indolent T-LPD of the GI tract"" for these lesions that can easily be mistaken for intestinal peripheral T-cell lymphoma, and lead to aggressive therapy. As noted above, mutations in STAT3 and also STAT5 have been linked to some forms of T-cell lymphoma and leukemia, Given the central role of STAT3 and STAT5B in the control of T-cell proliferative responses and in gamma delta T-cell development, and accumulating evidence for their involvement in T-cell tumorigenesis, we and our collaborators reasoned that these genes could potentially play a role in hepatosplenic gamma delta T-cell lymphomas as well. To carry out this study, twenty one cases of HSTCL with available formalin-fixed paraffin-embedded tissue were retrieved from the consultation files of the Hematopathology Section of the National Cancer Institute.(3) Seven cases (33.3%) were found to have a STAT5B somatic mutation. All shared the same hot spot mutation, c.1924A>C (N642H). Two additional cases (9.5 %) had a STAT3 somatic missense mutation (c.1981G>T; p.D661Y and c.1919A>T; p.Y640F). All remaining cases showed wild type STAT3 at the targeted sites. STAT3 and STAT5B missense mutations were mutually exclusive. The high frequency of STAT5B and STAT3 mutations in gamma delta HSTCL strongly suggests that deregulation of the STAT pathway is an important oncogenic event in the pathogenesis of this lymphoma. This study was done in collaboration with Dr. Mark Raffeld, of the Specialized Diagnostics Unit, LP, CCR, NCI. In collaboration with Dr. Andrew Feldman's group at Mayo Clinic, we explored the genetic and clinical diversity of ALK-negative anaplastic large cell lymphoma.(4) ALK-negative anaplastic large cell lymphoma (ALCL) is a CD30-positive T-cell non-Hodgkin lymphoma that morphologically resembles ALK-positive ALCL but lacks chromosomal rearrangements of the ALK gene. 73 ALK-negative ALCLs and 32 ALK-positive ALCLs were studied. Chromosomal rearrangements of DUSP22 and TP63 were identified in 30% and 8% of ALK-negative ALCLs, respectively. These rearrangements were mutually exclusive and were absent in ALK-positive ALCLs. Five-year overall survival rates were 85% for ALK-positive ALCLs, 90% for DUSP22-rearranged ALCLs, 17% for TP63-rearranged ALCLs, and 42% for cases lacking all three genetic markers (p<0.0001). Thus, ALK-negative ALCL is a genetically heterogeneous disease with widely disparate outcomes following standard therapy. DUSP22 and TP63 rearrangements may serve as predictive biomarkers to help guide patient management. The clinical and pathological spectrum of T-cell and NK-cell malignancies was further explored through participation in a " |