Alpha interferon gene deletions in post‐transplant lymphoma

Abstract

Summary. Post-transplant lymphoproliferative disorder (PTLD) is a well-recognized complication of organ transplant and has been associated with high mortality using conventional chemotherapy. We have investigated 11 cases of PTLD for alterations to the interferon alpha (IFNA) and p16 genes on chromosome 9p using archival material. 4/9 (44%) cases had deletions of the IFNA genes, in contrast to 1/59 (1 . 7%) cases of intermediate/high-grade de novo NHL drawn from the same geographical region. PTLD may therefore represent a distinct NHL subgroup exhibiting distinct gene pathology.

Immunomodulatory and antitumor effects of type I interferons and their application in cancer therapy

“…However, other studies indicate that a 400kb deletion including p16 INK4a , but not the IFN gene cluster, is critical in lymphoblastic leukemias [ 80 ]. Deletion in the gene encoding IFN-α has also been correlated with post-transplant lymphoproliferative disorder [ 81 ]. Homozygous deletion of IFN-α contributes to the recurrence of head and neck squamous cell carcinoma (HNSC) [ 82 ].…”

Posttransplant primary CNS lymphoma

“…The use of immunosuppressive agents such as cyclosporine and rescue drugs in instances of rejection, such as muromonab-CD3 (OKT3), also increases the risk of PTLD (Walker et al, 1995). Deletions of the interferon-a gene have been found in patients with PTLD, and treatment with interferon-a has led to clinical improvement through an effect on type 2 helper T cells (Faro et al, 1996;Wood et al 1997).…”

Interferon and cytotoxic chemotherapy for the treatment of post‐transplant lymphoproliferative disorder

“…Post‐transplant lymphoproliferative disorders (PTLD) are extraordinarily biologically diverse tumors that have been difficult to treat because of their diversity and the lack of accurate markers that predict malignant potential (1, 2). Tumor characteristics used unsuccessfully to predict response to treatment have included features of histology (polymorphic or monomorphic, clonality, the presence of Epstein–Barr virus [EBV], tumor cell origin – B‐cell or T‐cell) and clinical signs and symptoms (fever, weight loss, local, systemic or CNS tumor involvement, rapid tumor growth, sepsis, allograft dysfunction, time post‐transplant) (3–9). In addition, variable tumor classification schemes and immunosuppressive and antiviral protocols have made it difficult to pool experiences from different transplant centers in order to develop a consensus approach to management (10).…”

“…Bcl‐6, a proto‐oncogene that normally codes for a nuclear protein that functions as a sequence‐specific transcriptional repressor (25); 4. Fas receptor, mutations of which may impair the induction of apoptosis by fas; 5. p53, a tumor suppressor gene; 6. p15 and p16, tumor suppressor genes on chromosome region 9p21 (5); 7. the interferon alpha gene cluster, which maps close to the p15 and p16 genes and is frequently co‐deleted in a number of different neoplasms including high‐grade NHL and PTLD (5); 8. c‐myc, which is responsible for regulation of cell proliferation but also capable of sensitizing cells to apoptotic triggers (25, 26), and 9. N‐ras, a proto‐oncogene (5, 19, 25, 27–31).…”

“…Other factors enhancing the development of PTLD may include specific immunosuppressive drugs (e.g., OKT3), chronic antigenic stimulation by the allograft, and the presence of cytomegalovirus infection (7, 62, 63). Factors limiting tumor regression following reduced immunosuppression include the presence of mutations of Bcl‐6 and c‐myc, the loss of 9p, or high‐level expression of bcl‐2 (5, 25, 64). Thus B‐cell overgrowth resulting in PTLD may be promoted by a multitude of mechanisms, some extrinsic and some intrinsic to the B cell.…”