GRM1 is upregulated through gene fusion and promoter swapping in chondromyxoid fibroma

Nord, Karolin Hansén; Lilljebjörn, Henrik; Vezzi, Francesco; Nilsson, Jenny; Magnusson, Linda; Tayebwa, Johnbosco; Jong, Daniëlle de; Bovée, Judith V.M.G.; Hogendoorn, Pancras C.W.; Szuhai, Károly

doi:10.1038/ng.2927

Cited by 80 publications

(61 citation statements)

References 27 publications

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“…15 The pituitary-specific over-expression of GPR101 may be due to a gene-dose effect (as described in many genomic disorders 23 ) or to an unknown promoter sequence created by the chromosomal rearrangement, although we did not identify any putative new promoter, or to perturbed chromatin regulation due to the genomic structural alteration from duplication CNVs. 24,25 On the basis of our data from transfection experiments, we cannot rule out a modest contribution of RBMX and ARHGEF6 coexpression to cell proliferation. However, unlike GPR101 , neither ARHGEF6 nor RBMX was overexpressed in the pituitary tumors from children with microduplications.…”

Section: Discussionmentioning

confidence: 89%

Gigantism and Acromegaly Due to Xq26 Microduplications and GPR101 Mutation

Trivellin¹,

Daly²,

Faucz³

et al. 2014

N Engl J Med

297

378

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BACKGROUND Increased secretion of growth hormone leads to gigantism in children and acromegaly in adults; the genetic causes of gigantism and acromegaly are poorly understood. METHODS We performed clinical and genetic studies of samples obtained from 43 patients with gigantism and then sequenced an implicated gene in samples from 248 patients with acromegaly. RESULTS We observed microduplication on chromosome Xq26.3 in samples from 13 patients with gigantism; of these samples, 4 were obtained from members of two unrelated kindreds, and 9 were from patients with sporadic cases. All the patients had disease onset during early childhood. Of the patients with gigantism who did not carry an Xq26.3 microduplication, none presented before the age of 5 years. Genomic characterization of the Xq26.3 region suggests that the microduplications are generated during chromosome replication and that they contain four protein-coding genes. Only one of these genes, GPR101, which encodes a G-protein–coupled receptor, was overexpressed in patients’ pituitary lesions. We identified a recurrent GPR101 mutation (p.E308D) in 11 of 248 patients with acromegaly, with the mutation found mostly in tumors. When the mutation was transfected into rat GH3 cells, it led to increased release of growth hormone and proliferation of growth hormone–producing cells. CONCLUSIONS We describe a pediatric disorder (which we have termed X-linked acrogigantism [X-LAG]) that is caused by an Xq26.3 genomic duplication and is characterized by early-onset gigantism resulting from an excess of growth hormone. Duplication of GPR101 probably causes X-LAG. We also found a recurrent mutation in GPR101 in some adults with acromegaly. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others.)

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Section: Discussionmentioning

confidence: 89%

Gigantism and Acromegaly Due to Xq26 Microduplications and GPR101 Mutation

Trivellin¹,

Daly²,

Faucz³

et al. 2014

N Engl J Med

297

378

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“…A known mechanism for gene activation by SVs is the swapping of strong and weak promoters in the context of gene fusions. This is described for many individual genes, both with and without alteration of the protein-coding region (6,27,28), but it remains unclear to what extent such events have a measurable global influence on tumor expression profiles.…”

Section: Resultsmentioning

confidence: 99%

Global analysis of somatic structural genomic alterations and their impact on gene expression in diverse human cancers

Alaei-Mahabadi

Bhadury

Karlsson

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Tumor genomes are mosaics of somatic structural variants (SVs) that may contribute to the activation of oncogenes or inactivation of tumor suppressors, for example, by altering gene copy number amplitude. However, there are multiple other ways in which SVs can modulate transcription, but the general impact of such events on tumor transcriptional output has not been systematically determined. Here we use whole-genome sequencing data to map SVs across 600 tumors and 18 cancers, and investigate the relationship between SVs, copy number alterations (CNAs), and mRNA expression. We find that 34% of CNA breakpoints can be clarified structurally and that most amplifications are due to tandem duplications. We observe frequent swapping of strong and weak promoters in the context of gene fusions, and find that this has a measurable global impact on mRNA levels. Interestingly, several long noncoding RNAs were strongly activated by this mechanism. Additionally, SVs were confirmed in telomere reverse transcriptase (TERT) upstream regions in several cancers, associated with elevatedTERTmRNA levels. We also highlight high-confidence gene fusions supported by both genomic and transcriptomic evidence, including a previously undescribed paired box 8 (PAX8)–nuclear factor, erythroid 2 like 2 (NFE2L2) fusion in thyroid carcinoma. In summary, we combine SV, CNA, and expression data to provide insights into the structural basis of CNAs as well as the impact of SVs on gene expression in tumors.

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“…It has been postulated that transcriptional upregulation due to the genomic rearrangement can induce tumor formation (20). Similarly complex rearrangements, which involve regulatory sequences upstream of the coding sequence, have been described recently in chondromyxoid fibromas (27).…”

Section: Discussionmentioning

confidence: 99%