Therapy-induced malignant neoplasms in Nf1 mutant mice
ABSTRACT Therapy-induced cancers are a severe complication of genotoxic therapies. We used heterozygous Nf1 mutant mice as a sensitized genetic background to investigate tumor induction by radiation (RAD) and cyclophosphamide (CY). Mutagen-exposed Nf1(+/-) mice developed secondary cancers that are common in humans, including myeloid malignancies, sarcomas, and breast cancers. RAD cooperated strongly with heterozygous Nf1 inactivation in tumorigenesis. Most of the solid tumors showed loss of the wild-type Nf1 allele but retained two Trp53 alleles. Comparative genomic hybridization demonstrated distinct patterns of copy number aberrations in sarcomas and breast cancers from Nf1 mutant mice, and tumor cell lines showed deregulated Ras signaling. Nf1(+/-) mice provide a tractable model for investigating the pathogenesis of common mutagen-induced cancers and for testing preventive strategies.
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- "As expected from previous reports (Jacks 1994, Brannan 1994, Maghoub 1999, Chao 2005), the survival of unirradiated Nf1 +/− mice was reduced compared to WT littermates (p=0.02, logrank test) with deaths occurring after one year of age (Figure 1A). "
ABSTRACT: Secondary malignant neoplasms (SMN) are increasingly common complications of cancer therapy that have proven difficult to model in mice. Clinical observations suggest that the development of SMN correlates with radiation dose; however, this relationship has not been investigated systematically. We developed a novel procedure for administering fractionated cranial irradiation (CI) and investigated the incidence and spectrum of cancer in control and heterozygous Nf1 mutant mice irradiated to a moderate (15 Gy) or high dose (30 Gy). Heterozygous Nf1 inactivation cooperated with CI to induce solid tumors and myeloid malignancies, with mice developing many of the most common SMNs found in human patients. CI-induced malignancies segregated according to radiation dose as Nf1(+/-) mice developed predominately hematologic abnormalities after 15 Gy, whereas solid tumors predominated at 30 Gy, suggesting that radiation dose thresholds exist for hematologic and nonhematologic cancers. Genetic and biochemical studies revealed discrete patterns of somatic Nf1 and Trp53 inactivation and we observed hyperactive Ras signaling in many radiation-induced solid tumors. This technique for administering focal fractionated irradiation will facilitate mechanistic and translational studies of SMNs.Cancer Research 01/2011; 71(1):106-15. DOI:10.1158/0008-5472.CAN-10-2732 · 9.28 Impact Factor
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- "The relationship between heritable mutations and these treatments is not yet clear, although in laboratory models alkylating agents increase the incidence of myeloproliferative disorder with reduced latency in Nf1 mutant mice [Mahgoub et al., 1999]. Moreover, the combination of radiation and alkylating agents induces a spectrum of soft tissue sarcomas and breast carcinomas with subsequent inactivation of the normal Nf1 allele and, in some cases, loss of heterozygosity at the Trp53 locus [Chao et al., 2005]. This suggests that there may be some combined effect of chemotherapy and radiation on the development of secondary malignancies in some patients with underlying genetic cancer predisposition. "
ABSTRACT: Each year in the United States, an average of one to two children per 10,000 develop cancer. The etiology of most childhood cancer remains largely unknown but is likely attributable to random or induced genetic aberrations in somatic tissue. However, a subset of children develops cancer in the setting of an underlying inheritable condition involving a germline genetic mutation or chromosomal aberration. Despite overall improved survival rates for children with cancer over recent decades, many patients experience neurological and neurocognitive complications during the course of their illness and/or as late effects of treatment. Improvements in therapy, longer survival times, and improved imaging techniques have all increased both the time that patients are at risk and the ability to detect such complications. How an underlying inherited disorder influences the incidence, timing, etiology, and treatment of such sequelae has not been extensively documented, but evidence exists for an increased risk for secondary malignancies and in some cases life-threatening sensitivity/toxicity to conventionally dosed cancer treatments, thus emphasizing the need for the early recognition of such syndromes. This review outlines the major tumor- and treatment-related neurodevelopmental sequelae in pediatric cancer patients, with particular attention to children with an underlying inheritable disorder.Developmental Disabilities Research Reviews 01/2008; 14(3):229-37. DOI:10.1002/ddrr.30 · 0.29 Impact Factor
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ABSTRACT: Mutations leading to activation of the RAF-mitogen-activated protein kinase/extracellular signal-regulated (ERK) kinase (MEK)-ERK pathway are key events in the pathogenesis of human malignancies. In a screen of 82 acute myeloid leukemia (AML) samples, 45 (55%) showed activated ERK and thus were further analyzed for mutations in B-RAF and C-RAF. Two C-RAF germ-line mutations, S427G and I448V, were identified in patients with therapy-related AML in the absence of alterations in RAS and FLT3. Both exchanges were located within the kinase domain of C-RAF. In vitro and in vivo kinase assays revealed significantly increased activity for (S427G)C-RAF but not for (I448V)C-RAF. The involvement of the S427G C-RAF mutation in constitutive activation of ERK was further confirmed through demonstration of activating phosphorylations on C-RAF, MEK, and ERK in neoplastic cells, but not in nonneoplastic cells. Transformation and survival assays showed oncogenic and antiapoptotic properties for both mutations. Screening healthy individuals revealed a <1/400 frequency of these mutations and, in the case of I448V, inheritance was observed over three generations with another mutation carrier suffering from cancer. Taken together, these data are the first to relate C-RAF mutations to human malignancies. As both mutations are of germ-line origin, they might constitute a novel tumor-predisposing factor.Cancer Research 05/2006; 66(7):3401-8. DOI:10.1158/0008-5472.CAN-05-0115 · 9.28 Impact Factor