Cutaneous T‐Cell Lymphoma. A hypothesis on disease pathophysiology involving deficiency in DNA repair

Abstract

Cutaneous T-cell lymphoma (CTCL) is a rare disease occurring in Europe among two persons per million per year. It affects men more often than women (2:1). It is primarily a skin disease. In about 20% of patients, it becomes fatal with tumours in the skin and spreading to lymph glands. Approximately 3% of patients show a leukemic form called Sezary's syndrome, where malignant cells are present in blood with accompanying erythrodermia. CTCL is a T-lymphocyte disease occurring late in life as the average age of patients is around 66 years in Europe, Japan and the US. This article focuses on cell lines and immune surveillance in CTCL, and especially the pronounced chromosomal instability. It leads to the hypothesis that chromosomal changes is the key event linked to DNA repair deficiencies, which in a subpopulation of T cells leads to CTCL development over years.

The Incidence of Other Primary Cancers in Patients with Cutaneous Lymphoma

“…This is supported by the fact that the expression of Ku70, which is involved in non-homologous end joining DNA repair, is significantly reduced in the T cells of patients with CTCL 18 19 . The significantly prolonged repair time of damaged DNA in the lymphocytes of patients with CTCL also supports this 17 . Deficiencies in DNA repair proteins such as Ku70/Ku80 have also been suggested as a causal factor in lung cancer 20 and breast cancer 18 21 , and even in non-melanoma skin cancers 22 , which showed significantly higher SIR in patients with CL in our study.…”

“…In addition, the SIR of lung cancer, skin cancer and breast cancer were significantly higher. Recently, the deficiencies in the DNA repair pathways and chromosomal instability have been suggested as key factors in the development of CTCL 17 . This is supported by the fact that the expression of Ku70, which is involved in non-homologous end joining DNA repair, is significantly reduced in the T cells of patients with CTCL 18 19 .…”

PARP Inhibitors and Haematological Malignancies—Friend or Foe?

“…PARP-1 expression predicts for worse patient survival in cutaneous lymphomas [ 82 , 85 , 137 ], where chromosomal instability is often observed in cutaneous lymphoma and DSB repair pathways are reduced [ 138 ], suggesting that these cancers may be sensitive to treatment with PARPi. Indeed, Sezary syndrome patient samples are sensitive to treatment with the next-generation olaparib, AZD-2461, ex vivo [ 82 ].…”

Application of a Microfluidic Chip with Mechanical Stimuli for Culturing Mouse Embryos in vitro

“…CTCL is a rare extranodal T-cell lymphoproliferative disorder (non-Hodgkin's lymphoma), which primarily affects the skin by clonal accumulation of neoplastic T-lymphocytes [1,2,26]. Most of the patients have poor prognosis and overall survival up to 5 years or less [29]. Treatment is often empiric and stage based because of the limited insight into the genetic basis of CTCL [9] and single drug therapy is usually not applicable.…”