Monosomy 7 myelodysplastic syndrome and other second malignant neoplasms in children with neurofibromatosis type 1

Abstract

Children with NF1 are susceptible to the development of malignant myeloid disorders both as a primary event and as an SMN. Additional molecular genetic analysis is necessary to determine if the NF1 gene is inactivated by somatic mutation in these secondary leukemias.

Modulation of Ras signaling alters the toxicity of hydroquinone, a benzene metabolite and component of cigarette smoke

“…HQ exposure and pre-existing increased Ras signaling could increase the likelihood of leukemic transformation. Importantly, our observations with HQ are highly consistent with observations in human patients and in mice showing that heterozygous Nf1 inactivation cooperates strongly with genotoxins (particularly radiation) to induce myeloid malignancies and other secondary cancers [17,19]. In addition to NF1, individuals with Noonan syndrome and other RASopathies could be more vulnerable to developing myeloid diseases after exposure to benzene.…”

“…Consistent with its biochemical activity as a negative regulator of Ras signaling, JMML and other NF1-associated neoplasms frequently show somatic inactivation or the normal NF1 allele [13,16]. Patients with NF1 are also at increased risk of developing myeloid leukemia and other genotoxin-induced malignancies [17], and homozygous mutations in NF1 were recently reported in a subset of adult acute myelogenous leukemias (AML) [14]. …”

Rhabdomyosarcoma in patients with constitutional mismatch-repair-deficiency syndrome

“…We speculate that, because of the clinical overlap between CMMR-D syndrome and NF1, some people with RMS and a clinical (mis)diagnosis of NF1 actually have CMMR-D syndrome. The cancer and family history of at least one of these patients strongly suggest this possibility 5 19. Homozygosity of all tested microsatellite markers in the NF1 locus may indicate parental consanguinity in another reported NF1 case with RMS, rendering CMMR-D syndrome a possible alternative diagnosis also in this patient 20.…”

Pilocytic astrocytomas as hamartomas: implications for treatment

“…With genotoxic properties and systemic diffusion, antimitotic chemotherapy now being promoted may be predicted to cause secondary tumours102 developing elsewhere within the body and become increasingly evident many years following treatment 103 104. Such effects would be even more likely in patients treated at a young age, and in those already harbouring germline mutations in tumour suppressor genes such as for neurofibromatosis or tuberous sclerosis 84 105 106…”