Neurofibromatosis and childhood leukaemia/lymphoma: a population-based UKCCSG study

Abstract

Sm_mary There is a well-known raised risk of leukaemia in children with neurofibromatosis type 1 (NF-1).We carried out the first detailed population-based study of leukaemia and non-Hodgkin lymphoma (NHL) associated with NF-I in order to estimate the risk and elucidate the relationship between these conditions. Over the 17 year study period there were five cases of chronic myelomonocytic leukaemia (CMML) in patients with NF-1 (relative risk 221; 95% CI 71-514), 12 cases of acute lymphoblastic leukaemia (ALL) (relative nrsk 5.4; 95% CI 2.8-9.4) and five cases of NHL (relative risk 10.0; 95% CI 3.3-23.4). Marrow cytogenetics could be reviewed for seven patients. Specific abnormalities found were monosomy 21 in a child with CMML and 7p+, 17p-in a child with ALL. No abnormalities were reported of 17q, which includes the NFI gene. CMML occurred predominantly in boys, who also had a family history of NF-1. ALL and NHL were more often found in children with no previous family history.

Neurofibromatosis and childhood leukaemia

“…Sir -We read with interest the article on the increased risk for childhood leukaemias in neurofibromatosis (Stiller et al, 1994). This study confirmed the results of the first population-based study on the incidence of various malignant disorders in neurofibromatosis type 1 (NF-1) (Matsui et al, 1993).…”

A prospective study of neurofibromatosis type 1 cancer incidence in the UK

“…Other studies have reported an increased incidence of juvenile myelomonocytic leukaemia (JMML) in children with NF1 (Stiller et al, 1994). This malignancy has been reported to have an association with the presence of juvenile xanthogranulomas in this population.…”

“…Previous data have indicated overall additional malignancy risks in NF1 of between 5 and 15% (Sorensen et al, 1986;Huson et al, 1988;Baptiste et al, 1989;Matsui et al, 1993;Stiller et al, 1994;Friedman and Birch, 1997;Zoller et al, 1997;Evans et al, 2002), and these figures are commonly used when counselling patients; therefore, a more specific risk based on a larger study population would be useful. In addition, the advent of surveillance techniques for early detection and subsequent treatment of malignancy suggested that a more detailed analysis of the question of malignancy risk in NF1 was needed.…”

NF1 inactivation cooperates with N-Ras in in vivo lymphogenesis activating Erk by a mechanism independent of its Ras-GTPase accelerating activity

“…They also emphasize the importance of searching for additional functions for the NF1 protein and of intensifying the screening for NF1 mutations in human lymphomas. An increased incidence of non-Hodgkin lymphoma has already been reported in NF1 patients (Stiller et al, 1994); however, the actual involvement of NF1 mutations in lymphomahgenesis, as in many other tumor types, remains still unknown because the large size of this gene has slowed down the process of screening for mutations other than large deletions or rearrangements.…”

“…Mutations that inactivate the NF1 gene have been found in a variety of sporadic (Li et al, 1992;Andersen et al, 1993;Johnson et al, 1993) and neuro®bromatosis associated tumors (Legius et al, 1993;Stiller et al, 1994;Shen et al, 1996), including neuro®brosarcoma, pheochromocytoma, astrocytoma, neuroblastoma, melanoma, colon carcinoma, chronic myeloid leukemia, acute lymphoblastic leukemia and non-Hodgkin lymphoma. In addition to being mutated in tumors, Ras and NF1 are able to interact and function in the same proliferative pathway, suggesting a possible cooperating e ect for the deregulation of these two proteins in tumorigenesis.…”