Arlm1 is a male-specific modifier of astrocytoma resistance on mouse Chr 12

Schaick, Jessica C. Amlin-Van; Kim, Sungjin; DiFabio, Christina; Lee, Min Hyung; Broman, Karl W.; Reilly, Karlyne M.

doi:10.1093/neuonc/nor206

Cited by 22 publications

(16 citation statements)

References 61 publications

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“…High-grade gliomagenesis in the setting of combined NF1 and p53 loss has also been modeled in NPcis mice, which carry a genetic construct of tightly linked mutant alleles of NF1 and p53 (38). Similar to our results, when NPcis mice were maintained on a C57BL/6J background, high-grade gliomas occurred with a male predominance (12,39,40). Importantly, 129S4/SvJae mice were highly resistant to the gliomagenic effects of NPcis mutations.…”

Section: Discussionsupporting

confidence: 89%

Sexually dimorphic RB inactivation underlies mesenchymal glioblastoma prevalence in males

Sun¹,

Warrington²,

Luo³

et al. 2014

J. Clin. Invest.

132

162

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R e s e a R c h a R t i c l e4 1 2 3 jci.orgVolume 124 Number 9 September 2014 IntroductionThroughout life, there are sex-specific differences in the prevalence of multiple human diseases. Many of these disparities, such as the rise in autoimmune diseases in women during their reproductive years or the increase in cardiovascular diseases in postmenopausal women, can be related to differences in sex hormone abundance (1). However, not all sex disparity in human disease correlates with the dynamics of circulating sex hormones. Regardless of age, brain cancers are more common in males than in females (2). In fact, multiple brain tumor types in children exhibit marked sex disparity. For example, group 3 and group 4 medulloblastomas occur in nearly twice as many boys as girls (3, 4). These tumors occur with peak incidences in young (<5-year-old) and peripubertal children, respectively. Thus, while the hormonal milieu of young and peripubertal children is significantly different, there is a potent effect of sex on tumorigenesis in both age groups. These observations suggest that the sex disparity in medulloblastoma cannot be simply ascribed to the effects of circulating sex hormones. Therefore, an examination of alternate mechanisms through which sex can influence brain tumorigenesis is warranted. Glioblastoma (GBM), the most common malignant brain tumor in adults, also exhibits a greater prevalence in men (5). Despite enormous breakthroughs in basic cancer research, outcome from GBM remains dismal. For those treated with surgery, radiation, and chemotherapy, overall survival remains approximately 14 months (6). In addition to more frequently developing GBM, males also have a lower 5-year survival rate compared with that of females with GBM and other malignant CNS tumors (7). Understanding how sex affects GBM biology could elucidate mechanisms relevant to both its genesis and response to treatment. In the current study, we investigated whether the effect of sex in GBM involves cell-intrinsic sexual dimorphism in tumor progenitors. Identification of such cell-intrinsic mechanisms has broad implications for all of cancer biology and cancer care. ResultsMale predominance in GBM is subtype specific. Based on their gene expression profiles, GBMs can be divided into classical, mesenchymal, neural, and proneural subtypes (8). The Cancer Genome Atlas (TCGA) data set, as originally reported by Verhaak et al. (8), indicates that mesenchymal and neural subtypes of GBM occur in at least twice as many men as women (Table 1). To determine whether similar sex differences are evident in other large GBM data sets, we developed methods for sex assignment based on the genetic signature of the sex chromosomes that could be applied to publically accessible gene expression profiling data, which frequently have incomplete or no sex information on the samples (Supplemental Figure 1; supplemental material available online with this article; doi:10.1172/ JCI71048DS1). We examined 2 additional data sets (GSE16011, ref. 9, and GSE13041, ref. 10)...

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Section: Discussionsupporting

confidence: 89%

Sexually dimorphic RB inactivation underlies mesenchymal glioblastoma prevalence in males

Sun¹,

Warrington²,

Luo³

et al. 2014

J. Clin. Invest.

132

162

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“…Our study also found an increased risk for need for therapy in females with NF1 and OPG, confirming recent studies suggesting that sex plays a role in the development of gliomas and neuronal dysfunction in patients with NF1. 21,22 A recent large multicenter study of visual outcomes in children with NF1 and OPG showed that at completion of chemotherapy, visual acuity improved in 32% of subjects, remained stable in 40%, and declined in 28%. 23 There are a number of limitations to this study.…”

Section: Discussionmentioning

confidence: 99%

The Use of Magnetic Resonance Imaging Screening for Optic Pathway Gliomas in Children with Neurofibromatosis Type 1

Prada

Hufnagel

Hummel

et al. 2015

The Journal of Pediatrics

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“…Studies in mouse models also support roles for modifier genes in NF1. Astrocytoma resistance alleles were recently identified as spinal cord resistance to astrocytoma modifier 1 ( Scram1 ) and astrocytoma resistance locus in males 1 ( Arlm1 ) loci 38,51,52 . It is unclear whether disease modifier genes in NF1 are also relevant in NF1 -mutant sporadic tumours.…”

Section: Nf1 Genetics: Mutations and Modifiersmentioning

confidence: 99%

A RASopathy gene commonly mutated in cancer: the neurofibromatosis type 1 tumour suppressor

2015

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Neurofibromatosis type 1 (NF1) is a common genetic disorder that predisposes affected individuals to tumours. The NF1 gene encodes a RAS GTPase-activating protein called neurofibromin and is one of several genes that (when mutant) affect RAS–MAPK signalling, causing related diseases collectively known as RASopathies. Several RASopathies, beyond NF1, are cancer predisposition syndromes. Somatic NF1 mutations also occur in 5–10% of human sporadic cancers and may contribute to resistance to therapy. To highlight areas for investigation in RASopathies and sporadic tumours with NF1 mutations, we summarize current knowledge of NF1 disease, the NF1 gene and neurofibromin, neurofibromin signalling pathways and recent developments in NF1 therapeutics.

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Arlm1 is a male-specific modifier of astrocytoma resistance on mouse Chr 12

Cited by 22 publications

References 61 publications

Sexually dimorphic RB inactivation underlies mesenchymal glioblastoma prevalence in males

Sexually dimorphic RB inactivation underlies mesenchymal glioblastoma prevalence in males

The Use of Magnetic Resonance Imaging Screening for Optic Pathway Gliomas in Children with Neurofibromatosis Type 1

A RASopathy gene commonly mutated in cancer: the neurofibromatosis type 1 tumour suppressor

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