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Association between mutation of the NF2 gene and monosomy 22 in menopausal women with sporadic meningiomas.

ABSTRACT: BACKGROUND: Meningioma was the first solid tumor shown to contain a recurrent genetic alteration e.g. monosomy 22/del(22q), NF2 being the most relevant gene involved. Although monosomy 22/del(22q) is present in half of all meningiomas, and meningiomas frequently carry NF2 mutations, no study has been reported so far in which both alterations are simultaneously assessed and correlated with the features of the disease. METHODS: Here, we analyzed the frequency of both copy number changes involving chromosome 22 and NF2 mutations in 20 sporadic meningiomas using high-density SNP-arrays, interphase-FISH and PCR techniques. RESULTS: Our results show a significant frequency of NF2 mutations (6/20 patients, 30%), most of which (5/6) had not been previously reported in sporadic meningiomas. NF2 mutations involved five different exons and led to a truncated protein (p.Leu163CysfsX46, p.Phe62LeufsX61, p.Asp281MetfsX15, p.Phe285LeufsX11, p.Gln389ArgfsX37) and an in frame deletion of Phe119. Interestingly, all NF2 mutated cases were menopausal women with monosomy 22 but not del(22q). CONCLUSIONS: These results confirm and extend on previous observations about the high frequency and heterogeneity of NF2 mutations in sporadic meningiomas and indicate they could be restricted to a well-defined cytogenetic and clinical subgroup of menopausal women. Further studies in large series of patients are required to confirm our observations.

SUBMITTER: Tabernero M

PROVIDER: S-EPMC3818970 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Association between mutation of the NF2 gene and monosomy 22 in menopausal women with sporadic meningiomas.

Tabernero MariaDolores M Jara-Acevedo María M Nieto Ana B AB Caballero Arancha Rodríguez AR Otero Alvaro A Sousa Pablo P Gonçalves Jesús J Domingues Patricia H PH Orfao Alberto A

BMC medical genetics 20131030

<h4>Background</h4>Meningioma was the first solid tumor shown to contain a recurrent genetic alteration e.g. monosomy 22/del(22q), NF2 being the most relevant gene involved. Although monosomy 22/del(22q) is present in half of all meningiomas, and meningiomas frequently carry NF2 mutations, no study has been reported so far in which both alterations are simultaneously assessed and correlated with the features of the disease.<h4>Methods</h4>Here, we analyzed the frequency of both copy number chang ...[more]

PMID: 24171707

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Project description:BACKGROUND:Genomic studies of high-grade/progressive meningiomas have reported a heterogeneous mutation spectrum, identifying few recurrently mutated genes. Most studies have been underpowered to detect genomic subclasses of aggressive meningiomas due to relatively small number of available samples. Here, we present a genomic survey of one of the largest multi-institutional cohorts of high-grade/progressive meningiomas to date. METHODS:850 high-grade/progressive meningiomas, including 441 WHO grade 2 and 176 WHO grade 3 meningiomas and 220 progressive WHO grade 1 meningiomas, were tested as part of a clinical testing program by hybridization capture of 406 cancer-related genes to detect base substitutions, indels, amplifications, deletions, and rearrangements. Information from pathology reports, histopathology review, and patient clinical data was assessed. RESULTS:Genomic analyses converged to identify at least three distinct patterns of biologically-aggressive meningiomas. The first and most common contained NF2-mutant tumors (n?=?426, 50%), was associated with male sex (64.4% %, p?=?0.0001) and often harbored additional mutations in CDKN2A/B (24%), and the chromatin regulators ARID1A (9%), and KDM6A (6%). A second group (NF2-agnostic) featured TERT promoter (TERTp; n?=?56) or TP53 mutations (n?=?25) and were either NF2-mutant or wild-type, and displayed no association with either sex (p?=?0.39). The remaining group generally lacked NF2 mutations, and accounted for 40% of the cases-with three subgroups. One consistent primarily of grade 3 lesions harboring alterations in chromatin regulators BAP1 (n?=?22) or PBRM1 (n?=?16). A second subgroup contained AKT1 (n?=?26), PIK3CA (n?=?14) and SMO (n?=?7) mutant skull-based meningiomas, and a third mixed subgroup included 237 meningiomas with a heterogeneous spectrum of low frequency and non-recurrent alterations. CONCLUSIONS:Our findings indicate that the patterns of genomic alterations in high-grade/progressive meningiomas commonly group into three different categories. The most common NF2-associated canonical group frequently harbored CDKN2A/B alterations, which is potentially amenable to targeted therapies. An NF2-agnostic group harbored frequent TERTp and TP53 mutations. The final subclass, distinct from the canonical NF2 mutant associated pathway, was partly characterized by BAP1/PBRM1 alterations (rhabdoid/papillary histology) or skull-base disease. Overall, these data increase our understanding of the pathobiology of high-grade/progressive meningiomas and can guide the design of clinical trials. IRB APPROVAL STATUS:Reviewed and approved by Western IRB; Protocol No. 20152817.

Project description:BackgroundPhysical activity may be an effective way of preventing or attenuating menopause-related symptoms, and it has been shown to improve quality of life in menopausal women. However, there have been some inconsistencies regarding between exercise and menopausal symptoms, and study investigating this association has been scarce in Korea. In this study, the association between physical activity and menopausal symptoms in perimenopausal women in Korea was assessed.MethodsThis cross-sectional observational study was conducted between November 2012 and March 2013. In total, 2,204 healthy women aged 44-56 years were recruited from a healthcare center at the Kangbuk Samsung hospitals for investigating women's attitudes towards menopause. To investigate the influence of physical activity on perimenopause-associated symptoms, 631 perimenopausal women were selected for this study. Their physical activity levels were assessed using the International Physical Activity Questionnaire (IPAQ) short form. The Menopause-specific Quality of Life (MENQOL) questionnaire was used to assess menopause-related symptoms.ResultsThe study participants were, on average, 48.5?±?2.7 years old and had a mean body mass index of 22.8?±?3.1 kg/m2. The total MENQOL score and the psychosocial and physical subscores exhibited U-shaped trends in relation to the level of physical activity. Multiple linear regression analysis adjusted for confounding variables showed that perimenopausal women who performed moderate physical activity reported significantly lower psychosocial (??=?-0.413, P?=?0.012) and physical symptoms (??=?-0.445, P?=?0.002) than women who performed low physical activity. By contrast, a high level of physical activity did not influence the MENQOL total score and subscores relative to the low activity group. In addition, no associations were observed between physical activity and the vasomotor and sexual symptoms in any group.ConclusionsModerate level of physical activity was associated with reduced psychosocial and physical menopause symptoms in perimenopausal Korean women. Although these findings must be confirmed by prospective longitudinal studies, they suggest that physical activity may improve the symptoms of menopause, thereby increasing quality of life.

Project description:During the postpartum and menopausal periods of women's lives, there is a well-established and significant drop of circulating estrogens. This may be the reason why both these periods are associated with an increased risk for onset or exacerbation of psychiatric disorders. Whether symptoms are mainly affective or mainly psychotic, these disorders are frequently treated with antipsychotic medications, which calls for an examination of the relationship between hormone replacement and antipsychotic agents at these time periods. The aim of this narrative review is to summarize what is known about the association of hormones and antipsychotics in the postnatal period and at menopause. In the review, we focus on estrogen and oxytocin hormones and include, for the most part, only papers published within the last 10 years. Both estradiol and oxytocin have at various times been implicated in the etiology of postpartum disorders, and estrogens, sometimes combined with progesterone, have been tested as potential treatments for these conditions. The role of estradiol as an adjunct to antipsychotics in the prevention of postpartum relapses is currently controversial. With respect to oxytocin, studies are lacking. Psychosis in menopausal and postmenopausal women has been successfully treated with estrogens and selective estrogen-receptor modulators, mainly raloxifene, in addition to antipsychotics. Some symptoms appear to respond better than others. No oxytocin study has specifically targeted postmenopausal women. Because of feedback mechanisms, there is a theoretical danger of therapy with exogenous hormones interfering with endogenous secretion and disturbing the balance among inter-related hormones. When used with antipsychotics, hormones may also affect the metabolism and, hence, the brain level of specific antipsychotics. This makes treatment with antipsychotics plus hormones complicated. Dose, timing and route of intervention may all prove critical to efficacy. While much remains unknown, this literature review indicates that, within standard dose ranges, the combination of hormones and antipsychotics for postnatal and menopausal women suffering severe mental distress can be beneficial, and is safe.

Project description:BackgroundOsteocalcin is known to regulate energy metabolism. Recently, metabolic syndrome (MetS) has been found to be associated with reduced levels of osteocalcin in men, as well as in postmenopausal women. The aim of this study was to investigate the association between serum osteocalcin and MetS in premenopausal women, compared with that in postmenopausal women.MethodsThis cross-sectional study was based on 5,896 participants who completed a health screening examination. They were classified according to their menopausal status. Each group was subdivided into non-MetS and MetS groups according to the modified National Cholesterol Education Program-Adult Treatment Panel III criteria. Serum osteocalcin levels were measured using the electrochemiluminescence immunoassay.ResultsSerum osteocalcin level was significantly lower in women with MetS than in those without MetS, after adjusting for confounders (14.12 ± 0.04 vs. 13.17 ± 0.13 [P = 0.004] in premenopausal women, and 20.34 ± 0.09 vs. 19.62 ± 0.21 [P < 0.001] in postmenopausal women), regardless of their menopausal status. Serum osteocalcin levels decreased correspondingly with an increasing number of MetS elements (P for trend < 0.001). Multiple regression analysis demonstrated that waist circumference (β = -0.085 [P < 0.001] and β = -0.137 [P < 0.001]) and hemoglobin A1c (β = -0.09 [P < 0.001] and β = -0.145 [P < 0.001]) were independent predictors of osteocalcin in premenopausal and postmenopausal women. Triglyceride levels were also independently associated with osteocalcin levels in premenopausal women (β = -0.004 [P < 0.013]). The odds ratio (OR) for MetS was significantly higher in the lowest quartile than in the highest quartile of serum osteocalcin levels after adjusting for age, alkaline phosphatase, uric acid, high sensitivity C-reactive protein, and body mass index in all women (OR, 2.00; 95% confidence interval [CI], 1.49-2.68) as well as in premenopausal (OR, 2.23; 95% CI, 1.39-3.58) and postmenopausal (OR, 2.01; 95% CI, 1.26-3.23) subgroups.ConclusionLower serum osteocalcin concentrations were significantly associated with MetS in both premenopausal and postmenopausal women and were therefore independent of menopausal status.

Dataset Information

Association between mutation of the NF2 gene and monosomy 22 in menopausal women with sporadic meningiomas.

Publications

Association between mutation of the NF2 gene and monosomy 22 in menopausal women with sporadic meningiomas.

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