Chondromyxoid fibroma (CMF) is a rare benign bone tumour. While CMF located entirely on the surface of a bone (i.e. juxtacortical CMF) has been well characterised, CMF has not so far been ...convincingly documented to arise in soft tissues without connection to an underlying bone.
We report a subcutaneous CMF in a 34-year-old male, located on the distal medial aspect of the right thigh without any connection with the femur. The tumour measured 15 mm, it was well-circumscribed and displayed typical morphological features of a CMF. At the periphery, there was a small area of metaplastic bone. Immunohistochemically, the tumour cells were diffusely positive for smooth muscle actin and GRM1, and negative for S100 protein, desmin and cytokeratin AE1AE3. Whole transcriptome sequencing revealed a novel
PNISR
::
GRM1
gene fusion.
Our case indicates that CMF should be included in the differential diagnosis of soft tissue (including subcutaneous) tumours composed of spindle/ovoid cells, with a lobular architecture and chondromyxoid matrix. The diagnosis of CMF arising in soft tissues can be confirmed by identifying a
GRM1
gene fusion or GRM1 expression by immunohistochemistry.
Activating mutations in GNAQ, GNA11, CYSLTR2, and PLCB4 genes are regarded as the main oncogenic drivers of blue nevi (BN) and blue malignant melanocytic tumors. Here we report 4 cases of blue ...melanocytic neoplasms devoid of these mutations but harboring GRM1 gene fusions. In this short series, there was no gender predominance (sex ratio, 1). The mean age at diagnosis was 40 years (range, 12-72). Tumors were located on the face (n = 2), forearm (n = 1), and dorsum of the foot (n = 1). Clinically, a plaque-like pre-existing BN was found in 2 cases, including a deep location; another case presented as an Ota nevus. Two cases were diagnosed as melanoma ex-BN, one as an atypical BN, and one as a plaque-like BN. Microscopic examination revealed a dermal proliferation of dendritic melanocytes in a sclerotic stroma. A dermal cellular nodule with atypia and mitotic activity was observed in 3 cases. Genetic investigation by whole exome RNA sequencing revealed MYO10::GRM1 (n = 2) and ZEB2::GRM1 (n = 1) fusions. A GRM1 rearrangement was identified by fluorescence in situ hybridization in the remaining case. SF3B1 comutations were present in the 2 melanomas, and both had a MYO10::GRM1 fusion. Array comparative genomic hybridization was feasible for 3 cases and displayed multiple copy number alterations in the 2 melanomas and limited copy number alterations in the atypical BN, all genomic profiles compatible with those of classical blue lesions. GRM1 was overexpressed in all cases compared with a control group of blue lesions with other typical mutations. Both melanomas rapidly developed visceral metastases following diagnosis, with a fatal outcome in one case and tumor progression under palliative care in the other. These data suggest that GRM1 gene fusions could represent an additional rare oncogenic driver in the setting of BN, mutually exclusive of classical canonical mutations, especially in plaque-type or Ota subtypes.
Metabotropic glutamate receptor 1 (mGluR1) plays a crucial role in slow excitatory postsynaptic conductance, synapse formation, synaptic plasticity, and motor control. The
gene is expressed mainly in ...the brain, with the highest expression in the cerebellum. Mutations in the
gene have previously been known to cause autosomal recessive and autosomal dominant spinocerebellar ataxias. In this study, whole-exome sequencing of a patient from a family of Azerbaijani origin with a diagnosis of congenital cerebellar ataxia was performed, and a new homozygous missense mutation in the
gene was identified. The mutation leads to the homozygous amino acid substitution of p.Thr824Arg in an evolutionarily highly conserved region encoding the transmembrane domain 7, which is critical for ligand binding and modulating of receptor activity. This is the first report in which a mutation has been identified in the last transmembrane domain of the mGluR1, causing a congenital autosomal recessive form of cerebellar ataxia with no obvious intellectual disability. Additionally, we summarized all known presumable pathogenic genetic variants in the
gene to date. We demonstrated that multiple rare variants in the
underlie a broad diversity of clinical neurological and behavioral phenotypes depending on the nature and protein topology of the mutation.
Litter size is one of the important economic traits of livestock. Seasonal oestrus, ovulation and lambing of sheep have severely restricted the development of sheep farming in Xinjiang, China. The ...purpose of this study was to investigate the polymorphisms and genetic correlation between GRM1, GNAQ and HCRTR1 genes and the seasonal reproduction and litter size in three sheep breeds. The DNA mixed pool sequencing and PCR‐SSCP methods were used to detect single nucleotide polymorphisms (SNPs) of GRM1, GNAQ and HCRTR1 genes in seasonal oestrous (Kazakh and Chinese Merino Xinjiang Junken type) and perennial oestrous (Hu) sheep breeds. The association between genetic polymorphism and litter size was also analysed. The results showed that T945C in exon 2 of GRM1 gene, C589T in exon 2 of HCRTR1 gene and A191G in exon 2 of GNAQ gene were identified by Sanger sequencing, and three genotypes were existed in each SNP site, which all belonged to the synonymous mutation. GRM1 (CC), GNAQ (GA) and HCRTR1 (TC) were the dominant genotypes of seasonal reproduction and litter size in Kazakh sheep and Chinese Merino sheep, respectively, while, in perennial oestrous Hu sheep populations, the dominant genotypes were GRM1 (TC), GNAQ (GA) and HCRTR1 (TC), respectively, and association analysis also confirmed the results. The above results implied that GRM1, GNAQ and HCRTR1 genes are significantly associated with lambing traits in Kazakh, Chinese Merino and Hu sheep. Among them, the locus of GRM1 (T945C), GNAQ (A191G) and HCRTR1 (C589T) might be considered as a potential molecular marker, which controls seasonal reproduction and litter size in sheep.
Chondromyxoid fibroma (CMF) is a rare benign bone neoplasm that manifests histologically as a lobular proliferation of stellate to spindle-shaped cells in a myxoid background, exhibiting morphologic ...overlap with other cartilaginous and myxoid tumors of bone. CMF is characterized by recurrent genetic rearrangements that place the glutamate receptor gene GRM1 under the regulatory control of a constitutively active promoter, leading to increased gene expression. Here, we explore the diagnostic utility of GRM1 immunohistochemistry as a surrogate marker for GRM1 rearrangement using a commercially available monoclonal antibody in a study of 230 tumors, including 30 CMF cases represented by 35 specimens. GRM1 was positive by immunohistochemistry in 97% of CMF specimens (34/35), exhibiting moderate to strong staining in more than 50% of neoplastic cells; staining was diffuse (>95% of cells) in 25 specimens (71%). Among the 9 CMF specimens with documented exposure to acid decalcification, 4 (44%) exhibited diffuse immunoreactivity (>95%) for GRM1, whereas all 15 CMF specimens (100%) with lack of exposure to decalcification reagents were diffusely immunoreactive ( P =0.003). High GRM1 expression at the RNA level was previously observed by quantitative reverse transcription polymerase chain reaction in 9 CMF cases that were also positive by immunohistochemistry; low GRM1 expression was observed by quantitative reverse transcription polymerase chain reaction in the single case of CMF that was negative by immunohistochemistry. GRM1 immunohistochemistry was negative (<5%) in histologic mimics of CMF, including conventional chondrosarcoma, enchondroma, chondroblastoma, clear cell chondrosarcoma, giant cell tumor of the bone, fibrous dysplasia, chondroblastic osteosarcoma, myoepithelial tumor, primary aneurysmal bone cyst, brown tumor, phosphaturic mesenchymal tumor, CMF-like osteosarcoma, and extraskeletal myxoid chondrosarcoma. These results indicate that GRM1 immunohistochemistry may have utility in distinguishing CMF from its histologic mimics.
Background and objectives: Autosomal recessive spinocerebellar ataxia-13 (SCAR13) is an ultra-rare disorder characterized by slowly progressive cerebellar ataxia, cognitive deficiencies, and skeletal ...and oculomotor abnormalities. The objective of this case report is to expand the clinical and molecular spectrum of SCAR13. Methods: We investigated a consanguineous Pakistani family with four patients partially presenting with clinical features of SCAR13 using whole exome sequencing. Segregation analysis was performed by Sanger sequencing in all the available individuals of the family. Results: Patients presented with quadrupedal gait, delayed developmental milestones, non-progressive peripheral neuropathy, and cognitive impairment. Whole exome sequencing identified a novel pathogenic nonsense homozygous variant, Gly240*, in the gene GRM1 as a cause of SCAR13 that segregates with the recessive disease. Discussion: We report a novel homozygous nonsense variant in the GRM1 gene in four Pakistani patients presenting with clinical features that partially overlap with the already reported phenotype of SCAR13. In addition, the family presented quadrupedal gait and non-progressive symptoms, manifestations which have not been recognized previously. So far, only four variants in GRM1 have been reported, in families of Roma, Iranian, and Tunisian origins. The current study adds to the mutation spectrum of GRM1 and provides a rare presentation of SCAR13, the first from the Pakistani population.
The clinical, radiological, and histopathological features of chondromyxoid fibroma can sometimes resemble those of other benign or malignant tumors. Recently, recurrent
rearrangements have been ...identified in chondromyxoid fibroma, and GRM1 positivity by immunohistochemistry has emerged as a dependable surrogate marker for this molecular alteration. Phosphaturic mesenchymal tumor is a rare tumor that often exhibits overexpression of fibroblastic growth factor 23 (FGF23) through various mechanisms. In this report, we present a case of
-rearranged chondromyxoid fibroma that also exhibited FGF23 expression via in situ hybridization, posing significant diagnostic challenges during workup of the initial core biopsy. We hope that this case can serve as an educational resource, shedding light on a rare diagnostic pitfall.
Our laboratory previously showed that ectopic expression of Grm1 is sufficient to induce spontaneous melanoma formation with 100% penetrance in transgenic mouse model, TG-3, which harbors wild-type ...BRaf. Studies identified Grm1 expression in human melanoma cell lines and primary to secondary metastatic melanoma biopsies having wild-type or mutated BRaf, but not in normal melanocytes or benign nevi. Grm1 expression was detected in tissues from mice genetically engineered with inducible melanocyte-specific BRaf
. Additionally, stable clones derived from introduction of exogenous BRaf
in mouse melanocytes also showed Grm1 expression, which was not detected in the parental or empty vector-derived cells, suggesting that expression of BRaf
could activate Grm1 expression. Despite aberrant Grm1 expression in the inducible, melanocyte-specific BRaf
mice, no tumors formed. However, in older mice, the melanocytes underwent senescence, as demonstrated previously by others. It was proposed that upregulated p15 and TGFβ contributed to the senescence phenotype. In contrast, in older TG-3 mice the levels of p15 and TGFβ remained the same or lower. Taken together, these results suggest the temporal regulation on the expression of "oncogenes" such as Grm1 or BRaf
is critical in the future fate of the cells. If BRaf
is turned on first, Grm1 expression can be induced, but this is not sufficient to result in development of melanoma; the cells undergo senescence. In contrast, if ectopic expression of Grm1 is turned on first, then regardless of wild-type or mutated BRaf in the melanocytes melanoma development is the consequence.
PDF
