MIA is a potential biomarker for tumour load in neurofibromatosis type 1

Abstract

BackgroundNeurofibromatosis type 1 (NF1) is a frequent genetic disease characterized by multiple benign tumours with increased risk for malignancy. There is currently no biomarker for tumour load in NF1 patients.MethodsIn situ hybridization and quantitative real-time polymerase reaction were applied to investigate expression of cartilage-specific genes in mice bearing conditional inactivation of NF1 in the developing limbs. These mice do not develop tumours but recapitulate aspects of NF1 bone dysplasia, including deregulation of cartilage differentiation. It has been recently shown that NF1 tumours require for their growth the master regulator of cartilage differentiation SOX9. We thus hypothesized that some of the cartilage-specific genes deregulated in an Nf1Prx1 mouse model might prove to be relevant biomarkers of NF1 tumours. We tested this hypothesis by analyzing expression of the SOX9 target gene product melanoma-inhibitory activity/cd-rap (MIA) in tumour and serum samples of NF1 patients.ResultsIncreased expression of Mia was found in Nf1-deficient cartilage in mice. In humans, MIA was expressed in all NF1-related tumours and its serum levels were significantly higher in NF1 patients than in healthy controls. Among NF1 patients, MIA serum levels were significantly higher in those with plexiform neurofibromas and in those with large number of cutaneous (> 1,000) or subcutaneous (> 100) neurofibromas than in patients without such tumours. Most notably, MIA serum levels correlated significantly with internal tumour burden.ConclusionsMIA is a potential serum biomarker of tumour load in NF1 patients which could be useful in following the disease course and monitoring the efficacy of therapies.

Serum biomarkers for neurofibromatosis type 1 and early detection of malignant peripheral nerve-sheath tumors

“…Recently, two studies identified MIA and ADM as potential NF1 tumor markers in cohorts of 42 and 32 patients, respectively [21,23]. There was also a trend towards correlation between ADM and MPNST, although the MPNST group was too small to show significance (n = 5).…”

“…Among such factors, serum levels for midkine and for stem cell factor were found to be significantly increased in a cohort of 39 patients with NF1, although no correlation with tumor load or MPNST was found [20]. Recently, we identified melanoma-inhibitory activity (MIA; also known as cartilage-derived retinoic acid-sensitive protein (CD-RAP)) as a marker for the internal tumor load in a cohort of 42 patients with NF1 [21]. MIA was shown previously to be a biomarker for malignant neuroectotermal tumors [22].…”

Plasma S100β is not a useful biomarker for tumor burden in neurofibromatosis

“…To date, no reliable circulating biomarkers have been validated for nerve sheath tumors although adrenomedullin, MIA, and SOX9 have been suggested for future Page 8 development [9][10][11]. Proteomic analysis of plasma samples from NF and non-NF patients may help identify candidate proteins that correlate with tumor burden.…”

Biallelic mutation in MYH7 and MYBPC3 leads to severe cardiomyopathy with left ventricular noncompaction phenotype

“…For histological analysis, ventricular heart biopsies were fixed in buffered 4% paraformaldehyde, dehydrated in subsequent ethanol steps and embedded in paraffin according to standard laboratory procedures (Kolanczyk et al, ). For histological assessment, 5 µm paraffin sections were stained with hematoxylin and eosin (overall tissue organization and cell morphology), sirius red (collagenous material accumulation), and periodic acid‐Schiff reaction (accumulation of carbohydrate macromolecules).…”