Gene Summary

Gene:FMR1; FMRP translational regulator 1
Summary:The protein encoded by this gene binds RNA and is associated with polysomes. The encoded protein may be involved in mRNA trafficking from the nucleus to the cytoplasm. A trinucleotide repeat (CGG) in the 5' UTR is normally found at 6-53 copies, but an expansion to 55-230 repeats is the cause of fragile X syndrome. Expansion of the trinucleotide repeat may also cause one form of premature ovarian failure (POF1). Multiple alternatively spliced transcript variants that encode different protein isoforms and which are located in different cellular locations have been described for this gene. [provided by RefSeq, May 2010]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:synaptic functional regulator FMR1
Source:NCBIAccessed: 29 August, 2019


What does this gene/protein do?
Show (11)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 29 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Ubiquitin-Protein Ligases
  • Fragile X Mental Retardation Protein
  • Polymerase Chain Reaction
  • FISH
  • Acute Lymphocytic Leukaemia
  • Translocation
  • Mutation
  • Gene Expression Profiling
  • Molecular Sequence Data
  • X Chromosome
  • Testis
  • Fragile X Syndrome
  • Ovarian Cancer
  • Genotype
  • Cell Differentiation
  • Messenger RNA
  • TOR Serine-Threonine Kinases
  • Teratoma
  • BRCA2 Protein
  • Tremor
  • Alleles
  • Transfection
  • Base Sequence
  • Cancer Gene Expression Regulation
  • Reproduction
  • Case-Control Studies
  • Liver Cancer
  • Brain Tumours
  • DNA Methylation
  • Nuclear Proteins
  • Breast Cancer
  • Genetic Predisposition
  • Nerve Tissue Proteins
  • Oligonucleotide Array Sequence Analysis
  • p53 Protein
  • RNA-Binding Proteins
  • Brain Tumours
  • Trinucleotide Repeats
  • Heterozygote
  • DNA-Binding Proteins
  • Amino Acid Sequence
Tag cloud generated 29 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: FMR1 (cancer-related)

Giorgenon TMV, Carrijo FT, Arruda MA, et al.
Preoperative detection of TERT promoter and BRAFV600E mutations in papillary thyroid carcinoma in high-risk thyroid nodules.
Arch Endocrinol Metab. 2019 Mar-Apr; 63(2):107-112 [PubMed] Related Publications
OBJECTIVES: This observational study analyzed telomerase reverse transcriptase (pTERT) mutations in 45 fine-needle aspiration (FNA) specimens obtained from thyroid nodules followed by postoperatively confirmation of papillary thyroid cancer (PTC) diagnosis, examining their relationship with clinicopathologic aspects and the BRAFV600E mutation.
SUBJECTS AND METHODS: Clinical information was collected from patients who presented to Ribeirao Preto University Hospital for surgical consultation regarding a thyroid nodule and who underwent molecular testing between January 2010 to October 2012. Tests included a DNA-based somatic detection of BRAFV600E and pTERT mutations.
RESULTS: We found coexistence of pTERTC228T and BRAFV600E mutations in 8.9% (4/45) of thyroid nodules. All nodules positive for pTERT mutations were BRAFV600E positives. There was a significant association between pTERTC228T/BRAFV600E with older age and advanced stage compared with the group negative for either mutation.
CONCLUSIONS: This series provides evidence that FNA is a reliable method for preoperative diagnosis of high-risk thyroid nodules. pTERTC228T/BRAFV600E mutations could be a marker of poor prognosis. Its use as a personalized molecular medicine tool to individualize treatment decisions and follow-up design needs to be further studied.

Wang XY, Qin YY
Long non-coding RNAs in biology and female reproductive disorders.
Front Biosci (Landmark Ed). 2019; 24:750-764 [PubMed] Related Publications
Accumulating data from large-scale transcriptome studies have identified a class of poorly understood non-protein-coding RNAs, including microRNAs, piwi-interacting RNAs (piRNAs), and long non-coding RNAs (lncRNAs), and a number of studies suggest that lncRNAs modulate the expression of protein-coding genes in a variety of tissues and organs by altering chromatin modification, transcription, mRNA decay, protein subcellular localization, and other key processes. Although much work still remains to identify the roles of lncRNAs in reproduction-related systems, they are likely to exert widespread effects during these processes. In this review, we highlight our emerging understanding of how lncRNAs regulate gene expression, and we discuss the physiological role of this new class of molecular regulators in neurobiology, cardiology, endocrinology, metabolism, muscle biology, and female reproductive disorders.

Li W, Zhang L, Guo B, et al.
Exosomal FMR1-AS1 facilitates maintaining cancer stem-like cell dynamic equilibrium via TLR7/NFκB/c-Myc signaling in female esophageal carcinoma.
Mol Cancer. 2019; 18(1):22 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Though esophageal cancer is three to four times more common among males than females worldwide, this type of cancer still ranks in the top incidence among women, even more than the female specific cancer types. The occurrence is currently attributed to extrinsic factors, including tobacco use and alcohol consumption. However, limited attention has been given to gender-specific intrinsic genetic factors, especially in female.
METHODS: We re-annotated a large cohort of microarrays on 179 ESCC patients and identified female-specific differently expressed lncRNAs. The associations between FMR1-AS1 and the risk and prognosis of ESCC were examined in 206 diagnosed patients from eastern China and validated in 188 additional patients from southern China. The effects of FMR1-AS1 on the malignant phenotypes on female ESCC cells were detected in vitro and in vivo. ChIRP-MS, reporter gene assays and EMSA were conducted to identify the interaction and regulation among FMR1-AS1, TLR7 and NFκB.
RESULTS: We found FMR1-AS1 expression is exclusively altered and closely associated with the level of sXCI in female ESCC patients, and its overexpression may correlate to poor clinical outcome. ChIRP-MS data indicate that FMR1-AS1 could be packaged into exosomes and released into tumor microenvironment. Functional studies demonstrated that FMR1-AS1 could bind to endosomal toll-like receptor 7 (TLR7) and activate downstream TLR7-NFκB signaling, promoting the c-Myc expression, thus inducing ESCC cell proliferation, anti-apoptosis and invasion ability. Exosome incubation and co-xenograft assay indicate that FMR1-AS1 exosomes may secreted from ESCC CSCs, transferring stemness phenotypes to recipient non-CSCs in tumor microenvironment. Furthermore, we also found a correlation between the serum levels of FMR1-AS1 and the overall survival (OS) of the female ESCC patients.
CONCLUSIONS: Our results highlighted exosomal FMR1-AS1 in maintaining CSC dynamic interconversion state through the mechanism of activating TLR7-NFκB signaling, upregulating c-Myc level in recipient cells, which may be taken as an attractive target approach for advancing current precision cancer therapeutics in female patients.

Darrigo Júnior LG, Lira RCP, Fedatto PF, et al.
MicroRNA profile of pediatric pilocytic astrocytomas identifies two tumor-specific signatures when compared to non-neoplastic white matter.
J Neurooncol. 2019; 141(2):373-382 [PubMed] Related Publications
PURPOSES: Pilocytic astrocytoma (PA) is a low-grade neoplasm frequently found in childhood. PA is characterized by slow growth and a relatively good prognosis. Genetic mechanisms such as activation of MAPK, BRAF gene deregulation and neurofibromatosis type 1 (NF1) syndrome have been associated with PA development. Epigenetic signature and miRNA expression profile are providing new insights about different types of tumor, including PAs.
METHODS: In the present study we evaluated global miRNA expression in 16 microdissected pediatric PA specimens, three NF1-associated PAs and 11 cerebral white matter (WM) samples by the microarray method. An additional cohort of 20 PAs was used to validate by qRT-PCR the expression of six miRNAs differentially expressed in the microarray data.
RESULTS: Unsupervised hierarchical clustering analysis distinguished one cluster with nine PAs, including all NF1 cases and a second group consisting of the WM samples and seven PAs. Among 88 differentially expressed miRNAs between PAs and WM samples, the most underexpressed ones regulate classical pathways of tumorigenesis, while the most overexpressed miRNAs are related to pathways such as focal adhesion, P53 signaling pathway and gliomagenesis. The PAs/NF1 presented a subset of underexpressed miRNAs, which was also associated with known deregulated pathways in cancer such as cell cycle and hippo pathway.
CONCLUSIONS: In summary, our data demonstrate that PA harbors at least two distinct miRNA signatures, including a subgroup of patients with NF1/PA lesions.

Peterson JF, Pitel BA, Smoley SA, et al.
Constitutional chromosome rearrangements that mimic the 2017 world health organization "acute myeloid leukemia with recurrent genetic abnormalities": A study of three cases and review of the literature.
Cancer Genet. 2019; 230:37-46 [PubMed] Related Publications
OBJECTIVES: To identify and characterize constitutional chromosomal rearrangements that mimic recurrent genetic abnormalities in acute myeloid leukemia (AML).
METHODS: Bone marrow and blood chromosome studies were reviewed to identify constitutional rearrangements that resemble those designated by the 2017 revised World Health Organization (WHO) "AML with recurrent genetic abnormalities". Mate-pair sequencing (MPseq) was performed on cases with constitutional chromosome mimics of recurrent AML abnormalities to further define the rearrangement breakpoints.
RESULTS: Three cases with constitutional rearrangements were identified, including t(6;9)(p23;q34), inv(16)(p13.1q22), and t(9;22)(q34.1;q12.2). Two cases were bone marrow specimens being evaluated for hematologic neoplasms, while one case was a blood specimen being evaluated for primary ovarian insufficiency. MPseq provided high-resolution and precise rearrangement breakpoints, and resolved the atypical FISH results generated with each rearrangement.
CONCLUSIONS: Our findings illustrate that constitutional rearrangements can mimic recurrent genetic abnormalities observed in AML, and we emphasize the importance of correlating genetic data with clinical and hematopathologic information.

Ivell R, Anand-Ivell R
Insulin-like peptide 3 (INSL3) is a major regulator of female reproductive physiology.
Hum Reprod Update. 2018; 24(6):639-651 [PubMed] Related Publications
BACKGROUND: Insulin-like peptide 3 (INSL3) is a member of the relaxin family of neohormones which has evolved to address specifically mammalian aspects of reproduction related to viviparity and internal fertilization. It was originally identified as a major product of testicular Leydig cells and has proved to be an important biomarker of Leydig cell functional capacity. However, INSL3 is also produced by theca interna cells of growing antral follicles and is secreted into the bloodstream in phases corresponding to the number and health of the follicles. Moreover, gene silencing experiments have shown that INSL3 is essentially required for androstenedione synthesis, which is the major steroid precursor for the granulosa cells of antral follicles to produce oestrogens. Knockout studies in mice confirm that loss of INSL3 or its receptor in females leads to partial infertility, with reduced follicle numbers, ovulations and litter size. Circulating INSL3 concentration corresponds to the reproductive lifespan, beginning with puberty and declining at the menopause, and thus may contribute to the physiology of other organ systems, particularly those relevant for hormone replacement strategies.
SEARCH METHODS: A literature review was carried out by exhaustive searching of literature databases (PubMed and Google Scholar) with the search terms INSL3, RLF, Ley-IL and RXFP2.
OBJECTIVE AND RATIONALE: We present the first comprehensive review of INSL3 and its specific receptor RXFP2, and their roles in the context of female reproductive physiology. Moreover, we highlight the potential involvement of INSL3 in female reproductive pathology, such as PCOS, its clinical application as a valuable biomarker of reproductive processes, and its potential for therapeutic interventions.
OUTCOMES: In the female mammal, INSL3 is largely produced by the theca interna cells of growing antral follicles during the follicular phase of the menstrual (oestrous) cycle. Within the follicle, INSL3 acts via its G-protein-coupled receptor, RXFP2, in an autocrine/paracrine manner to orchestrate and drive the production of the major steroid precursor androstenedione and its conversion by granulosa cells into oestrogens. These in turn create a positive feedback loop promoting the expression of more theca cell INSL3. This is countered by the follicular production of bone morphogenetic proteins and by the LH surge. Thus, the activity of the theca cell INSL3-RXFP2 system effectively determines the production of estradiol within an antral follicle through the follicular phase. INSL3 is also secreted into the circulation where it acts as a valuable biomarker to monitor the growth of antral follicles; it is consequently increased in PCOS and decreased in women with premature ovarian failure (POF). As an endocrine factor, INSL3 may also influence bone metabolism and kidney function. Additionally, INSL3 or its analogues may prove valuable as an adjunct in hormone replacement therapy or to monitor or influence IVF protocols.
WIDER IMPLICATIONS: The INSL3-RXFP2 system represents a new regulatory pathway essential for the proper functioning of growing antral follicles. We still know very little about its involvement in pathologies such as PCOS or POF, and its role as a new biomarker of female function needs to be explored more widely to improve diagnosis and treatment of ovarian dysfunction. We need to examine how INSL3 might be used to improve IVF protocols and outcomes. Opportunities should also be investigated in regard to the systemic application of INSL3 as a rejuvenant therapy, with positive effects on bone or kidney function, and possibly also for fertility regulation. Most research to date has involved animal models; this now needs to be extended to include more human studies.

Al Argan R, Saskin A, Yang JW, et al.
Glucocorticoid resistance syndrome caused by a novel NR3C1 point mutation.
Endocr J. 2018; 65(11):1139-1146 [PubMed] Related Publications
Glucocorticoid resistance syndrome (GRS) is a rare genetic disorder caused by inactivating mutations of the NR3C1 gene which encodes the glucocorticoid receptor. The phenotypic spectrum is broad but typically include symptoms of adrenal insufficiency, mineralocorticoid excess and hyperandrogenism. We report a new case associated with a novel NR3C1 mutation. A 55-year-old woman with lifelong history of low body weight, hyperandrogenism and anxiety was seen at the endocrine clinic after left adrenalectomy and salpingoophorectomy for lesions suspicious of ovarian cancer and adrenal metastasis. The tumors turned out to be a 3.5 cm benign ovarian serous adenofibroma and a 3.5 cm multinodular adrenal mass. She complained of worsened fatigue and inability to recover weight lost with surgery. Pre-operative serum and urinary cortisol were elevated, but she had no stigma of Cushing's syndrome. Plasma ACTH was elevated and a 1-mcg cosyntropin stimulation test was normal. Her fatigue persisted over ensuing years and ACTH-dependent hypercortisolemia remained stable. Low dose oral dexamethasone failed to suppress endogenous cortisol. A pituitary MRI was normal but revealed incidental brain aneurysms. Bone densitometry showed profound osteoporosis. On the bases of this contradictory clinical picture, glucocorticoid resistance syndrome (GRS) was suspected. Using next generation sequencing technology, a novel heterozygous pathogenic variant in the NR3C1 gene was detected. We speculate that vascular malformations and profound osteoporosis, findings associated to cortisol excess, reflect in our patient a variable tissue sensitivity to glucocorticoids. In conclusion, in patients with clinically unexpected ACTH-dependent hypercortisolemia, primary glucocorticoid resistance (GRS) should be considered.

Maas K, Mirabal S, Penzias A, et al.
Hippo signaling in the ovary and polycystic ovarian syndrome.
J Assist Reprod Genet. 2018; 35(10):1763-1771 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
PURPOSE: To provide a commentary on our understanding of the role that the Hippo signaling pathway may play in patients with polycystic ovarian syndrome (PCOS) and how this understanding may impact the diagnosis of PCOS.
METHODS: We assessed publications discussing the role of the Hippo signaling pathway in the ovary. In particular, we discuss how Hippo signaling disruption after ovarian fragmentation, combined with treating ovarian fragments with phosphatase and tensin homolog (PTEN) inhibitors and phosphoinositide-3-kinase stimulators to augment AKT signaling, has been used in treatment of patients with primary ovarian insufficiency. Furthermore, we discuss our own data on variations in Hippo signaling pathway gene expression in cumulus cells isolated from women undergoing IVF with a previous diagnosis of PCOS.
RESULTS AND CONCLUSIONS: Aberrant Hippo signaling in PCOS patients is likely a contributing mechanism to the multifactorial etiology of the disease. Given the challenge of discerning the underlying etiology of oligo-ovulation in some patients, especially those with normal body mass indices, and the need for customized stimulation protocols for PCOS patients who have an increased risk of over-response and higher percentage of immature oocyte yield, it is important to identify these patients prior to treatment. Hippo gene expression fingerprints could potentially be used to more accurately define patients with PCOS. Additionally, targeting this pathway with pharmacologic agents could lead to non-surgical therapeutic options for PCOS.

Ernst EH, Lykke-Hartmann K
Transcripts encoding free radical scavengers in human granulosa cells from primordial and primary ovarian follicles.
J Assist Reprod Genet. 2018; 35(10):1787-1798 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
PURPOSE: To study the presence and distribution of genes encoding free radical scavengers in human granulosa cells from primordial and primary ovarian follicles.
METHODS: A class comparison study on existing granulosa cell transcriptome from primordial (n = 539 follicles) and primary (n = 261) follicles donated by three women having ovarian tissue cryopreserved before chemotherapy was performed and interrogated.
RESULTS: In granulosa cells from primordial follicles, 30 genes were annotated 'mitochondrial dysfunction' including transcripts (PRDX5, TXN2) encoding enzymatic free radical scavengers peroxiredoxin 5 and thioredoxin 2. Several apoptosis regulation genes were noted (BCL2, CAS8, CAS9, AIFM1). In granulosa cells from primary follicles, mitochondrial dysfunction signalling pathway was annotated. High expression of transcripts encoding the free radical scavenger peroxiredoxin 3, as well as anti-apoptotic enzyme BCL2, was found. Interestingly, PARK7 encoding the deglycase (DJ-1) protein was expressed in granulosa cells from primary follicles. DJ-1 is implicated in oxidative defence and functions as a positive regulator of the androgen receptor and as a negative regulator of the phosphatidylinositol 3-kinase (PI3K)/phosphatase and tensin homolog (PTEN)/serine-threonine protein kinase (AKT) signalling pathway suppressor PTEN.
CONCLUSIONS: The results indicate extensive energy production and free radical scavenging in the granulosa cells of primordial follicles with potential implications for ovarian ageing, cigarette smoking, premature ovarian failure and polycystic ovarian syndrome. Furthermore, DJ-1 may be involved in androgen responsiveness and the regulation of follicle growth via PI3K/PTEN/AKT signalling pathway regulation in the granulosa cells of primary follicles. The involvement of mitochondrial free radical production in the age-related decline of competent oocytes is becoming apparent.

Baroni M, Marie SKN, Fedatto PF, et al.
Distinct response to GDF15 knockdown in pediatric and adult glioblastoma cell lines.
J Neurooncol. 2018; 139(1):51-60 [PubMed] Related Publications
INTRODUCTION: Glioblastoma (GBM) is the most common malignant primary brain tumor affecting adults. In pediatric patients, GBM exhibits genetic variations distinct from those identified in the adult GBM phenotype. This tumor exhibits complex genetic changes leading to malignant progression and resistance to standard therapies including radiotherapy and temozolomide treatment. The GDF15 gene codes for a growth factor whose expression is altered in the presence of inflammations and malignancies. GDF15 is associated with a poor prognosis and with radio- and chemoresistance in a variety of tumors. The aim of this study was to compare the response to GDF15 knockdown in adult (U343) and pediatric (KNS42) GBM cell line models.
METHODS: The expression of the GDF15 gene was investigated by qRT-PCR and overexpression was identified in both GBM cell lines. The KNS42 and U343 cell lines were submitted to lentiviral transduction with shRNA of GDF15 and validated at the protein level. To understand the difference between cell lines, RNAseq was performed after GDF15 knockdown.
RESULTS: The data obtained demonstrated that the pathways were differentially expressed in adult GBM and pediatric GBM cell lines. This was confirmed by functional assays perfomed after independent treatments (radiotherapy and TMZ).
CONCLUSION: These results demonstrated that GBM cell lines had distinct responses to GDF15 knockdown, a fact that can be explained by the different molecular profile of pediatric and adult GBM.

Li L, Zeng Q, Bhutkar A, et al.
GKAP Acts as a Genetic Modulator of NMDAR Signaling to Govern Invasive Tumor Growth.
Cancer Cell. 2018; 33(4):736-751.e5 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Genetic linkage analysis previously suggested that GKAP, a scaffold protein of the N-methyl-D-aspartate receptor (NMDAR), was a potential modifier of invasion in a mouse model of pancreatic neuroendocrine tumor (PanNET). Here, we establish that GKAP governs invasive growth and treatment response to NMDAR inhibitors of PanNET via its pivotal role in regulating NMDAR pathway activity. Combining genetic knockdown of GKAP and pharmacological inhibition of NMDAR, we implicate as downstream effectors FMRP and HSF1, which along with GKAP demonstrably support invasiveness of PanNET and pancreatic ductal adenocarcinoma cancer cells. Furthermore, we distilled genome-wide expression profiles orchestrated by the NMDAR-GKAP signaling axis, identifying transcriptome signatures in tumors with low/inhibited NMDAR activity that significantly associate with favorable patient prognosis in several cancer types.

Belli M, Shimasaki S
Molecular Aspects and Clinical Relevance of GDF9 and BMP15 in Ovarian Function.
Vitam Horm. 2018; 107:317-348 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Growth and differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) are oocyte-secreted factors with a leading role in the control of ovarian function in female reproduction, modulating both the cell fate of the somatic granulosa cells and the quality and developmental competence of the egg. This short review aims to consolidate the molecular aspects of GDF9 and BMP15 and their integral actions in female fertility to understand particularly their effects on oocyte quality and fetal growth. The significant consequences of mutations in the GDF9 and BMP15 genes in women with dizygotic twins as well as the clinical relevance of these oocyte factors in the pathogenesis of primary ovarian insufficiency and polycystic ovary syndrome are also addressed.

Shi X, Chen X, Li WC, et al.
Low expression of Cyfip1 may be a potential biomarker in nasopharyngeal carcinoma.
Neoplasma. 2018; 65(2):292-295 [PubMed] Related Publications
Cytoplasmic FMR1 interacting protein 1 (Cyfip1) is a new candidate tumor suppressor gene, which may play an impor- tant role in the occurrence and development of cancers. However, the role of Cyfip1 in nasopharyngeal carcinoma (NPC) remains poorly known. The aim of this study was to investigate the Cyfip1 mRNA expression in NPC and its association with clinicopathological features. The study population comprised 114 Chinese individuals, including 69 NPC tissues and 45 non-cancerous nasopharyngeal tissues. We used real-time fluorescent relatively quantitative PCR to evaluate the Cyfip1 mRNA expression in NPC tissues and non-cancerous nasopharyngeal tissues. The expression level of Cyfip1 mRNA was significantly lower in patients with NPC than in the control samples (p=0.001). Furthermore, low expression level of Cyfip1 mRNA was significantly associated with invasive range (T3-T4 vs T1-T2, p=0.001), lymph node metastasis (N1-N3 vs   N0, p=0.010), distant metastases (M1 vs M0, p=0.040) and clinical stage (III-IV vs I-II, p<0.001). Our results suggest the association between Cyfip1 mRNA expression and NPC. Detecting the expression of Cyfip1 may provide clinically useful information for diagnosis, progression and treatment methods in NPC.

Sundberg M, Tochitsky I, Buchholz DE, et al.
Purkinje cells derived from TSC patients display hypoexcitability and synaptic deficits associated with reduced FMRP levels and reversed by rapamycin.
Mol Psychiatry. 2018; 23(11):2167-2183 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Accumulating evidence suggests that cerebellar dysfunction early in life is associated with autism spectrum disorder (ASD), but the molecular mechanisms underlying the cerebellar deficits at the cellular level are unclear. Tuberous sclerosis complex (TSC) is a neurocutaneous disorder that often presents with ASD. Here, we developed a cerebellar Purkinje cell (PC) model of TSC with patient-derived human induced pluripotent stem cells (hiPSCs) to characterize the molecular mechanisms underlying cerebellar abnormalities in ASD and TSC. Our results show that hiPSC-derived PCs from patients with pathogenic TSC2 mutations displayed mTORC1 pathway hyperactivation, defects in neuronal differentiation and RNA regulation, hypoexcitability and reduced synaptic activity when compared with those derived from controls. Our gene expression analyses revealed downregulation of several components of fragile X mental retardation protein (FMRP) targets in TSC2-deficient hiPSC-PCs. We detected decreased expression of FMRP, glutamate receptor δ2 (GRID2), and pre- and post-synaptic markers such as synaptophysin and PSD95 in the TSC2-deficient hiPSC-PCs. The mTOR inhibitor rapamycin rescued the deficits in differentiation, synaptic dysfunction, and hypoexcitability of TSC2 mutant hiPSC-PCs in vitro. Our findings suggest that these gene expression changes and cellular abnormalities contribute to aberrant PC function during development in TSC affected individuals.

Brooke RJ, Im C, Wilson CL, et al.
A High-risk Haplotype for Premature Menopause in Childhood Cancer Survivors Exposed to Gonadotoxic Therapy.
J Natl Cancer Inst. 2018; 110(8):895-904 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Background: Childhood cancer survivors are at increased risk of therapy-related premature menopause (PM), with a cumulative incidence of 8.0%, but the contribution of genetic factors is unknown.
Methods: Genome-wide association analyses were conducted to identify single nucleotide polymorphisms (SNPs) associated with clinically diagnosed PM (menopause < 40 years) among 799 female survivors of childhood cancer participating in the St. Jude Lifetime Cohort Study (SJLIFE). Analyses were adjusted for cyclophosphamide equivalent dose of alkylating agents and ovarian radiotherapy (RT) dose (all P values two-sided). Replication was performed using self-reported PM in 1624 survivors participating in the Childhood Cancer Survivor Study (CCSS).
Results: PM was clinically diagnosed in 30 (3.8%) SJLIFE participants. Thirteen SNPs (70 kb region of chromosome 4q32.1) upstream of the Neuropeptide Receptor 2 gene (NPY2R) were associated with PM prevalence (minimum P = 3.3 × 10-7 for rs9999820, all P < 10-5). Being a homozygous carrier of a haplotype formed by four of the 13 SNPs (seen in one in seven in the general population but more than 50% of SJLIFE clinically diagnosed PM) was associated with markedly elevated PM prevalence among survivors exposed to ovarian RT (odds ratio [OR] = 25.89, 95% confidence interval [CI] = 6.18 to 138.31, P = 8.2 × 10-6); this finding was replicated in an independent second cohort of CCSS in spite of its use of self-reported PM (OR = 3.97, 95% CI = 1.67 to 9.41, P = .002). Evidence from bioinformatics data suggests that the haplotype alters the regulation of NPY2R transcription, possibly affecting PM risk through neuroendocrine pathways.
Conclusions: The haplotype captures the majority of clinically diagnosed PM cases and, with further validation, may have clinical application in identifying the highest-risk survivors for PM for possible intervention by cryopreservation.

Daniel DC, Johnson EM
PURA, the gene encoding Pur-alpha, member of an ancient nucleic acid-binding protein family with mammalian neurological functions.
Gene. 2018; 643:133-143 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
The PURA gene encodes Pur-alpha, a 322 amino acid protein with repeated nucleic acid binding domains that are highly conserved from bacteria through humans. PUR genes with a single copy of this domain have been detected so far in spirochetes and bacteroides. Lower eukaryotes possess one copy of the PUR gene, whereas chordates possess 1 to 4 PUR family members. Human PUR genes encode Pur-alpha (Pura), Pur-beta (Purb) and two forms of Pur-gamma (Purg). Pur-alpha is a protein that binds specific DNA and RNA sequence elements. Human PURA, located at chromosome band 5q31, is under complex control of three promoters. The entire protein coding sequence of PURA is contiguous within a single exon. Several studies have found that overexpression or microinjection of Pura inhibits anchorage-independent growth of oncogenically transformed cells and blocks proliferation at either G1-S or G2-M checkpoints. Effects on the cell cycle may be mediated by interaction of Pura with cellular proteins including Cyclin/Cdk complexes and the Rb tumor suppressor protein. PURA knockout mice die shortly after birth with effects on brain and hematopoietic development. In humans environmentally induced heterozygous deletions of PURA have been implicated in forms of myelodysplastic syndrome and progression to acute myelogenous leukemia. Pura plays a role in AIDS through association with the HIV-1 protein, Tat. In the brain Tat and Pura association in glial cells activates transcription and replication of JC polyomavirus, the agent causing the demyelination disease, progressive multifocal leukoencephalopathy. Tat and Pura also act to stimulate replication of the HIV-1 RNA genome. In neurons Pura accompanies mRNA transcripts to sites of translation in dendrites. Microdeletions in the PURA locus have been implicated in several neurological disorders. De novo PURA mutations have been related to a spectrum of phenotypes indicating a potential PURA syndrome. The nucleic acid, G-rich Pura binding element is amplified as expanded polynucleotide repeats in several brain diseases including fragile X syndrome and a familial form of amyotrophic lateral sclerosis/fronto-temporal dementia. Throughout evolution the Pura protein plays a critical role in survival, based on conservation of its nucleic acid binding properties. These Pura properties have been adapted in higher organisms to the as yet unfathomable development of the human brain.

Qie S, Majumder M, Mackiewicz K, et al.
Fbxo4-mediated degradation of Fxr1 suppresses tumorigenesis in head and neck squamous cell carcinoma.
Nat Commun. 2017; 8(1):1534 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
The Fbxo4 tumour suppressor is a component of an Skp1-Cul1-F-box E3 ligase for which two substrates are known. Here we show purification of SCF

Lesage C, Coupier I, Guillot B
A family with two cases of melanocytic tumors and fragile X syndrome.
Melanoma Res. 2017; 27(6):645-648 [PubMed] Related Publications
Fragile X syndrome (FXS), a leading cause of inherited intellectual disability, most commonly results from an expansion of the CGG trinucleotide repeat in the fragile X mental retardation 1 (FMR1) gene to more than 200 copies (full mutation). The FXS phenotype differs by sex and is associated with intellectual and cognitive impairment, characteristic physical features, epilepsy, and/or behavioral challenges including autism spectrum disorder. In this patient population, tumors involving blood cells, digestive organs, the central nervous system, and testes have been described, but melanocytic tumors have not been reported. Here, we describe two maternal cousins with FXS, one of whom has melanoma and the other has atypical nevus syndrome. We discuss possible mechanisms leading to this unusual or possibly coincidental association and the difficulties in the optimal treatment of FXS patients.

Adamsheck HC, Petty EM, Hong J, et al.
Is Low FMR1 CGG Repeat Length in Males Correlated with Family History of BRCA-Associated Cancers? An Exploratory Analysis of Medical Records.
J Genet Couns. 2017; 26(6):1401-1410 [PubMed] Related Publications
The FMR1 gene has been studied extensively with regard to expansions and premutations, but much less research has focused on potential effects of low CGG repeat length. Previous studies have demonstrated that BRCA1/2 positive women are more likely to have an FMR1 genotype with one low CGG allele, and that women with both FMR1 alleles in the low CGG repeat range are more likely to have had breast cancer compared to women with normal numbers of CGG repeats. However, there has been no research as to whether low CGG repeat length impacts cancer risks in men. Therefore, this study aimed to examine cancer incidence and related risk factors in men with low CGG repeat length in the FMR1 gene. We utilized subject data from the Marshfield Personalized Medicine Research Project to compare cancer-related diagnoses between 878 males with low CGG repeat length (< 24 repeats) and 368 male controls with CGG repeats in the normal range (24 to 40 repeats). We utilized ICD-9 codes to examine various cancer diagnoses, family histories of cancer, other non-malignant neoplasms, cancer surveillance, and genetic susceptibility. Men with low CGG repeats were identified to have significantly higher rates of family history of any cancer type (p = 0.011), family history of any BRCA-associated cancer (p = 0.002), and specifically, family history of prostate cancer (p = 0.007). The mean number of BRCA-associated cancer diagnoses (breast, prostate, pancreatic, and melanoma) per individual in the low CGG group was slightly higher than that of the control group, with this difference trending toward significance (p = 0.091). Additionally, men with low CGG repeats had significantly higher rates of connective/soft tissue neoplasms (p = 0.026). Additional research is needed to replicate the observations reported in this preliminary exploratory study, particularly including verification of ICD-9 codes and family history by a genetic counselor.

Trofimova T, Lizneva D, Suturina L, et al.
Genetic basis of eugonadal and hypogonadal female reproductive disorders.
Best Pract Res Clin Obstet Gynaecol. 2017; 44:3-14 [PubMed] Related Publications
This review discusses the current state of our understanding regarding the genetic basis of the most important reproductive disorders in women. For clarity, these disorders have been divided into eugonadal and hypogonadal types. Hypogonadal disorders have been further subdivided according to serum gonadotropin levels. Our review focuses on historical and recent data regarding the genetics of the hypothalamic-pituitary-gonadal axis dysfunction, as well as the development and etiology of eugonadal disorders including leiomyomata, endometriosis, spontaneous ovarian hyperstimulation syndrome, polycystic ovarian syndrome, mullerian aplasia, and steroid hormone resistance syndromes. We discuss the known genes most commonly involved in hypergonadotropic hypogonadism (Turner syndrome and premature ovarian failure) and hypogonadotrophic hypogonadism (Kallmann syndrome and normosmic types). In addition, we summarize the current clinical testing approaches and their utility in practical application.

Goedert L, Plaça JR, Fuziwara CS, et al.
Identification of Long Noncoding RNAs Deregulated in Papillary Thyroid Cancer and Correlated with BRAF
Sci Rep. 2017; 7(1):1662 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Papillary Thyroid Cancer (PTC) is an endocrine malignancy in which BRAF

You W, Chen B, Liu X, et al.
Farnesoid X receptor, a novel proto-oncogene in non-small cell lung cancer, promotes tumor growth via directly transactivating CCND1.
Sci Rep. 2017; 7(1):591 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Farnesoid X receptor (FXR), a nuclear receptor for maintaining bile acid homeostasis, has been recognized as a tumor suppressor in enterohepatic tissues. However, its expression and functional role in non-small cell lung cancer (NSCLC) remain unclear. We report that FXR is significantly increased in NSCLC and that it predicts poor clinical outcomes in NSCLC patients. FXR knockdown in NSCLC cells inhibited in vitro cell proliferation, blocked xenograft growth in nude mice, and delayed the G1/S transition of the cell cycle, whereas ectopic overexpression of FXR promoted NSCLC cell proliferation. Mechanistic analysis demonstrated that FXR could directly bind to an inverted repeat-0 sequence in the CCND1 promoter and activate its transcription. Cyclin D1 overexpression rescued NSCLC cells from the delayed G1/S transition and the impaired cell proliferation induced by FXR knockdown. Importantly, a positive correlation between the expression of FXR and cyclin D1 was confirmed in NSCLC samples, and patients with high expression of both FXR and cyclin D1 had the worst prognosis. In summary, our results suggest that FXR has oncogenic potential in NSCLC development, providing mechanistic insights that could be exploited for both prognostic and therapeutic purposes.

Xing Z, Zeng M, Hu H, et al.
Fragile X mental retardation protein promotes astrocytoma proliferation via the MEK/ERK signaling pathway.
Oncotarget. 2016; 7(46):75394-75406 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
OBJECTIVE: To examine the association between fragile X mental retardation protein (FMRP) expression and astrocytoma characteristics.
METHODS: Pathologic grade and expressions of glial fibrillary acidic protein (GFAP), Ki67 (proliferation marker), and FMRP were determined in astrocytoma specimens from 74 patients. Kaplan-Meier survival analysis was undertaken. Pathologic grade and protein levels of FMRP were determined in 24 additional patients with astrocytoma and 6 controls (cerebral trauma). In cultured U251 and U87 cell lines, the effects of FMRP knock-down on cell proliferation, AKT/mTOR/GSK-3β and MEK/ERK signaling were studied. The effects of FMRP knock-down on the volumes and weights of U251 cell-derived orthotopic tumors in mice were investigated.
RESULTS: In patients, FMRP expression was increased in grade IV (5.1-fold, P<0.01) and grade III (3.2-fold, P<0.05) astrocytoma, compared with controls. FMRP and Ki67 expressions were positively correlated (R2=0.877, P<0.001). Up-regulation of FMRP was associated with poorer survival among patients with FMRP integrated optical density >30 (P<0.01). In astrocytoma cell lines, FMRP knock-down slowed proliferation (P<0.05), inhibited total MEK levels P<0.05, and reduced phosphorylation of MEK (Ser217/221) and ERK (Thr202/Tyr204) (P<0.05). In mice with orthotopic tumors, FMRP knock-down decreased FMRP and Ki67 expressions, and reduced tumor volume and weight (36.3% or 61.5% on day 15, both P<0.01). Also, phosphorylation of MEK (Ser217/221) and ERK (Thr202/Tyr204), and total MEK in xenografts were decreased in sh-FMRP xenografts compared with non-transfected ones (all P<0.05).
CONCLUSION: Enhanced FMRP expression in astrocytoma may promote proliferation through activation of MEK/ERK signaling.

Bramham CR, Jensen KB, Proud CG
Tuning Specific Translation in Cancer Metastasis and Synaptic Memory: Control at the MNK-eIF4E Axis.
Trends Biochem Sci. 2016; 41(10):847-858 [PubMed] Related Publications
The eukaryotic translation initiation factor (eIF) 4E, which binds to the 5'-cap of mRNA, undergoes phosphorylation on a single conserved serine, executed by the mitogen-activated protein kinase (MAPK)-interacting kinases (MNKs). However, the functional consequences and physiological roles of MNK signalling have remained obscure. Now, new pharmacological and genetic tools have provided unprecedented insights into the function of MNKs and eIF4E phosphorylation. The studies suggest that MNKs control the translation of specific mRNAs in cancer metastasis and neuronal synaptic plasticity by a novel mechanism involving the regulation of the translational repressor, cytoplasmic fragile-X protein-interacting protein 1 (CYFIP1). These recent breakthroughs go a long way to resolving the longstanding enigma and controversy surrounding the function of the MNK-eIF4E axis in cancer cell biology and neurobiology.

Giordano S, Garrett-Mayer E, Mittal N, et al.
Association of BRCA1 Mutations with Impaired Ovarian Reserve: Connection Between Infertility and Breast/Ovarian Cancer Risk.
J Adolesc Young Adult Oncol. 2016; 5(4):337-343 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
PURPOSE: Mutations in the BRCA1/2 genes are associated with breast and ovarian cancer susceptibility. Recent studies have suggested that the BRCA mutation might be associated with occult primary ovarian insufficiency. To evaluate fertility, several studies have validated anti-Mullerian hormone (AMH) as a direct biomarker for ovarian aging and it is considered a quantitative marker of ovarian reserve. We hypothesize that BRCA1 gene mutations will be negatively associated with AMH levels.
METHODS: We evaluated 124 women aged 18-45 years participating in the Northwestern Ovarian Cancer Early Detection and Prevention Program. Patients with a history of cancer, ovarian surgery, or exposure to chemotherapy were excluded. Linear and logistic regression modeling were performed to evaluate the association between AMH levels, age, and BRCA1 mutation. In logistic models, the outcome 'low AMH' was defined as AMH <0.05 ng/mL. Logistic regression models were used to adjust for other factors, including body mass index (BMI), duration of birth control (BC), smoking, gravidity, and parity.
RESULTS: Women with the BRCA1 mutation had a significant decline in AMH with age (p = 0.0011). BRCA1-positive women >35 years had 10 times the odds of a low AMH (<0.5 ng/mL) compared with women ≤35 years. With adjustment for BMI, duration of BC, smoking, gravidity, parity, and age >35, BRCA1 was still strongly associated with a low AMH (p = 0.037).
CONCLUSION: Women >35 with the BRCA1 mutation have a lower AMH, and hence ovarian reserve, than women without a BRCA mutation. Therefore, young adults with the BRCA1 mutation should be counseled regarding this potential decrease in ovarian reserve.

Ruth KS, Murray A
Lessons from Genome-Wide Association Studies in Reproductive Medicine: Menopause.
Semin Reprod Med. 2016; 34(4):215-23 [PubMed] Related Publications
In recent years, common genetic variants have been identified by genome-wide association studies (GWASs) that have led to the detection of 44 genetic loci associated with approximately 6% of common variation in age at natural menopause. In the latest GWAS, doubling the sample size to approximately 70,000 women more than doubled the number of signals identified, from 17 to 56. In addition, low-frequency coding variants (< 5% minor allele frequency), with relatively large effect sizes, have been identified in two genes, by analyzing genome-wide exome data. GWAS has been very successful in identifying novel biological pathways involved in reproductive aging. Approximately two-thirds of the loci reported so far include genes involved in DNA damage response (DDR), highlighting the importance of this pathway in determining oocyte reserve. In addition, GWAS demonstrates that the hypothalamic-pituitary axis is involved in menopause timing as well as puberty timing, showing the first genetic link between timing of the start and end of reproductive life. Genetic variants have been used to explore the causal relationships between menopause timing and breast cancer. These studies demonstrate that for a 1 year increase in menopause age, there is a 6% increase in breast cancer risk, a value approximately double the estimate from epidemiological studies. Prolonged exposure to estrogen during reproductive life is the likely mechanism, rather than a direct effect of DDR variants on cancer risk. Further work is needed to determine the mechanism for the effect of each variant identified by GWAS and more variants will undoubtedly be discovered as sample sizes increase, denser single nucleotide polymorphism arrays and reference genomes are used, and populations from diverse ethnic groups are studied.

Poersch A, Grassi ML, Carvalho VP, et al.
A proteomic signature of ovarian cancer tumor fluid identified by highthroughput and verified by targeted proteomics.
J Proteomics. 2016; 145:226-236 [PubMed] Related Publications
UNLABELLED: Tumor fluid samples have emerged as a rich source for the identification of ovarian cancer in the context of proteomics studies. To uncover differences among benign and malignant ovarian samples, we performed a quantitative proteomic study consisting of albumin immunodepletion, isotope labeling with acrylamide and in-depth proteomic profiling by LC-MS/MS in a pool of 10 samples of each histological type. 1135 proteins were identified, corresponding to 505 gene products. 223 proteins presented associated quantification and the comparative analysis of histological types revealed 75 differentially abundant proteins. Based on this, we developed a panel for targeted proteomic analysis using the multiple reaction monitoring (MRM) method for validation of 51 proteins in individual samples of high-grade serous ovarian tumor fluids (malignant) and benign serous cystadenoma tumor fluids. This analysis showed concordant results in terms of average amounts of proteins, and APOE, SERPINF2, SERPING1, ADAM17, CD44 and OVGP1 were statistically significant between benign and malignant group. The results observed in the MRM for APOE were confirmed by western blotting, where APOE was more abundant in malignant samples. This molecular signature can contribute to improve tumor stratification and shall be investigated in combination with current biomarkers in larger cohorts to improve ovarian cancer diagnosis.
BIOLOGICAL SIGNIFICANCE: Despite advances in cancer research, ovarian cancer has a high mortality and remains a major challenge due to a number of particularities of the disease, especially late diagnosis caused by vague clinical symptoms, the cellular and molecular heterogeneity of tumors, and the lack of effective treatment. Thus, efforts are directed to better understand this neoplasia, its origin, development and, particularly the identification and validation of biomarkers for early detection of the disease in asymptomatic stage. In the present work, we confirmed by MRM method in individual ovarian tumor fluid samples the regulation of 27 proteins out of 33 identified in a highthroughput study. We speculate that the presence and/or differential abundance observed in tumor fluid is a cooperation primarily of high rates of secretion of such tumor proteins to extra tumor environment that will at the end accumulate in plasma, and also the accumulation of acute-phase proteins throughout the entire body. On top of that, consideration of physiological influences in the interpretation of expression observed, including age, menopause status, route-of-elimination kinetics and metabolism of the tumor marker, coexisting disease, hormonal imbalances, life-style influences (smoking, alcoholism, obesity), among others, are mandatory to enable the selection of good protein tumor marker candidates for extensive validation.

Peixoto Lira RC, Fedatto PF, Marco Antonio DS, et al.
IGF2 and IGF1R in pediatric adrenocortical tumors: roles in metastasis and steroidogenesis.
Endocr Relat Cancer. 2016; 23(6):481-93 [PubMed] Related Publications
Deregulation of the IGF system observed in human tumors indicates a role in malignant cell transformation and in tumor cell proliferation. Although overexpression of the IGF2 and IGF1R genes was described in adrenocortical tumors (ACTs), few studies reported their profiles in pediatric ACTs. In this study, the IGF2 and IGF1R expression was evaluated by RT-qPCR according to the patient's clinical/pathological features in 60 pediatric ACT samples, and IGF1R protein was investigated in 45 samples by immunohistochemistry (IHC). Whole transcriptome and functional assays were conducted after IGF1R inhibition with OSI-906 in NCI-H295A cell line. Significant IGF2 overexpression was found in tumor samples when compared with non-neoplastic samples (P<0.001), significantly higher levels of IGF1R in patients with relapse/metastasis (P=0.031) and moderate/strong IGF1R immunostaining in 62.2% of ACTs, but no other relationship with patient survival and clinical/pathological features was observed. OSI-906 treatment downregulated genes associated with MAPK activity, induced limited reduction of cell viability and increased the apoptosis rate. After 24h, the treatment also decreased the expression of genes related to the steroid biosynthetic process, the protein levels of the steroidogenic acute regulatory protein (STAR), and androgen secretion in cell medium, supporting the role of IGF1R in steroidogenesis of adrenocortical carcinoma cells. Our data showed that the IGF1R overexpression could be indicative of aggressive ACTs in children. However, in vitro treatments with high concentrations of OSI-906 (>1μM) showed limited reduction of cell viability, suggesting that OSI-906 alone could not be a suitable therapy to abolish carcinoma cell growth.

Scopim-Ribeiro R, Machado-Neto JA, de Melo Campos P, et al.
Low Ten-eleven-translocation 2 (TET2) transcript level is independent of TET2 mutation in patients with myeloid neoplasms.
Diagn Pathol. 2016; 11:28 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
BACKGROUND: New sequencing technologies have enabled the identification of mutations in Ten-eleven-translocation 2 (TET2), an enzyme that catalyzes the conversion of 5-methylcytosine into 5-hydroxymethylcytosine (5-hmC) in myeloid neoplasms. We have recently identified reduced TET2 mRNA expression in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), which is associated with a poor overall survival in MDS. We herein aimed to investigate TET2 mutations and their impact on TET2 expression in a cohort of patients with myeloid neoplasms, including MDS and AML patients.
FINDINGS: TET2 mutations were observed in 8 out of 19 patients (42 %) with myeloid neoplasms. The TET2 expression profile was similar between in wild type and in TET2 mutated patients.
CONCLUSION: Our results suggest that TET2 expression is reduced in MDS/AML patients, independently of mutational status.

Goldberg Y, Halpern N, Hubert A, et al.
Mutated MCM9 is associated with predisposition to hereditary mixed polyposis and colorectal cancer in addition to primary ovarian failure.
Cancer Genet. 2015; 208(12):621-4 [PubMed] Related Publications
Mutations in MCM9, which encodes DNA helicase, were recently shown to cause a clinical phenotype of primary ovarian failure and chromosomal instability. MCM9 plays an essential role in homologous recombination-mediated double-strand break repair. We describe a multiplex family with early colorectal carcinoma and mixed polyposis associated with primary hypergonadotropic hypogonadism. A combination of whole genome homozygosity mapping as well as exome sequencing and targeted gene sequencing identified a homozygous c.672_673delGGinsC mutation that predicts a truncated protein, p.Glu225Lysfs*4. Our data expand the phenotypic spectrum of MCM9 mutations and suggest a link between MCM9 and inherited predisposition to mixed polyposis and early-onset colorectal cancer.

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