Editors' ChoiceCancer Genetics

The GRM Face of Chondromyxoid Fibroma

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Science Translational Medicine  09 Apr 2014:
Vol. 6, Issue 231, pp. 231ec62
DOI: 10.1126/scitranslmed.3009044

The traits that drive success are varied and enigmatic. The same can be said of rare tumors, which defy deep characterization because of their scarcity. But as technologies have become more intricate and sensitive, rare tumors have begun to reveal their secrets—for example, chondromyxoid fibroma. This rare benign cartilaginous tumor causes pain and limitations in movement and is treated with surgical resection. Recurrence rates are high, but we do not know why. Several groups have identified recurrent chromosome-6 rearrangements associated with these fibromas, but the precise molecular underpinnings that drive tumor development have remained elusive. Now, Nord and colleagues use an array of sophisticated molecular tools to identify the culprit gene responsible for driving tumorigenesis.

Using single-nucleotide polymorphism arrays, the authors first found—in tumors from two different patients—deletions in the long arm of chromosome 6, with a distal breakpoint immediately upstream of the gene that encodes metabotropic glutamate receptor 1 (GRM1). Subsequent whole-genome mate-pair sequencing detected genomic rearrangements around the GRM1 region in tumors from all four patients analyzed with this method. Invariably, these rearrangements recombined the complete coding region of GRM1 with a swapped promoter region of one of several partner genes, including COL12A1, TBL1XR1, and BCLAF1, which encode a collagen, a signaling protein, and a transcriptional repressor, respectively.

The investigators predicted that these rearrangments would lead to up-regulated expression of transcripts that include the rearranged coding region of GRM1. This hypothesis was confirmed by means of real-time quantitative polymerase chain reaction experiments that demonstrated a more than 100-fold increase in GRM1 expression (up to 1400-fold in some cases) in 18 of 20 chondromyxoid fibromas as compared with a control group of 174 mesenchmyal (non–chondromyxoid fibroma) tumors that were analyzed.

GRM1 belongs to a family of genes that encodes G protein–coupled glutamate receptors, all of which are well known to be involved in neurological and psychiatric disorders. This study provides direct evidence for the importance of abnormal glutamate signaling in the pathogenesis of non-neurological tumors and establishes GRM1 overexpression as a specific driver event in the formation of chondromyxoid fibromas. Whether metabotropic glutamate receptor 1 will serve as a biomarker or a therapeutic target for this disease remains an enigma to be unraveled.

K. H. Nord et al., GRM1 is upregulated through gene fusion and promoter swapping in chondromyxoid fibroma. Nat. Genet. 10.1038/ng.2927 (2014). [Abstract]

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