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Cellular/intramuscular myxoma and grade I myxofibrosarcoma are characterized by distinct genetic alterations and specific composition of their extracellular matrix.

Willems SM, Mohseny AB, Balog C, Sewrajsing R, Briaire-de Bruijn IH, Knijnenburg J, Cleton-Jansen AM, Sciot R, Fletcher CD, Deelder AM, Szuhai K, Hensbergen PJ, Hogendoorn PC - J. Cell. Mol. Med. (2009)

Bottom Line: GNAS1-activating mutations were exclusively found in 50% of intramuscular myxoma.No mutations in KRAS codon 12/13 or in TP53 were detected.This was confirmed by immunohistochemistry and qPCR.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.

ABSTRACT
Cellular myxoma and grade I myxofibrosarcoma are mesenchymal tumours that are characterized by their abundant myxoid extracellular matrix (ECM). Despite their histological overlap, they differ clinically. Diagnosis is therefore difficult though important. We investigated their (cyto) genetics and ECM. GNAS1-activating mutations have been described in intramuscular myxoma, and lead to downstream activation of cFos. KRAS and TP53 mutations are commonly involved in sarcomagenesis whereby KRAS subsequently activates c-Fos. A well-documented series of intramuscular myxoma (three typical cases and seven cases of the more challenging cellular variant) and grade I myxofibrosarcoma (n = 10) cases were karyotyped, analyzed for GNAS1, KRAS and TP53 mutations and downstream activation of c-Fos mRNA and protein expression. ECM was studied by liquid chromatography mass spectrometry and expression of proteins identified was validated by immunohistochemistry and qPCR. Grade I myxofibrosarcoma showed variable, non-specific cyto-genetic aberrations in 83,5% of cases (n = 6) whereas karyotypes of intramuscular myxoma were all normal (n = 7). GNAS1-activating mutations were exclusively found in 50% of intramuscular myxoma. Both tumour types showed over-expression of c-Fos mRNA and protein. No mutations in KRAS codon 12/13 or in TP53 were detected. Liquid chromatography mass spectrometry revealed structural proteins (collagen types I, VI, XII, XIV and decorin) in grade I myxofibrosarcoma lacking in intramuscular myxoma. This was confirmed by immunohistochemistry and qPCR. Intramuscular/cellular myxoma and grade I myxofibrosarcoma show different molecular genetic aberrations and different composition of their ECM that probably contribute to their diverse clinical behaviour. GNAS1 mutation analysis can be helpful to distinguish intramuscular myxoma from grade I myxofibrosarcoma in selected cases.

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Box-plots showing qPCR results of structural ECM proteins. Abbreviations: IM, intramuscular myxoma; MFS, grade I myxofibrosar-coma. Intramuscular myx-oma showed significantly lower mRNA expression for decorin (P= 0.000), collagen I-A1 (P= 0.003), collagen VI-A1 (P= 0.023) and collagen XIV-A1 (P= 0.001).
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fig02: Box-plots showing qPCR results of structural ECM proteins. Abbreviations: IM, intramuscular myxoma; MFS, grade I myxofibrosar-coma. Intramuscular myx-oma showed significantly lower mRNA expression for decorin (P= 0.000), collagen I-A1 (P= 0.003), collagen VI-A1 (P= 0.023) and collagen XIV-A1 (P= 0.001).

Mentions: Results of relative mRNA expression are shown in Table 4 and box-plots in Fig. 2. qPCR showed that c-Fos RNA was over-expressed in all tumours compared with control tissue, but not significantly differently expressed between intramuscular myxoma and grade I myxofibrosarcoma. No significant differences were seen between typical intramuscular myxoma and cellular myxoma. Grade I myxofibrosarcoma showed significant expression of decorin mRNA, whereas decorin mRNA was barely detectable in intramuscular myxoma. Grade I myxofibrosarcoma clearly showed significant over-expression of mRNA expression for collagens I-A1, VI-A1 and XIV-A1 compared with intramuscular myxoma (including cellular myxoma).


Cellular/intramuscular myxoma and grade I myxofibrosarcoma are characterized by distinct genetic alterations and specific composition of their extracellular matrix.

Willems SM, Mohseny AB, Balog C, Sewrajsing R, Briaire-de Bruijn IH, Knijnenburg J, Cleton-Jansen AM, Sciot R, Fletcher CD, Deelder AM, Szuhai K, Hensbergen PJ, Hogendoorn PC - J. Cell. Mol. Med. (2009)

Box-plots showing qPCR results of structural ECM proteins. Abbreviations: IM, intramuscular myxoma; MFS, grade I myxofibrosar-coma. Intramuscular myx-oma showed significantly lower mRNA expression for decorin (P= 0.000), collagen I-A1 (P= 0.003), collagen VI-A1 (P= 0.023) and collagen XIV-A1 (P= 0.001).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4496143&req=5

fig02: Box-plots showing qPCR results of structural ECM proteins. Abbreviations: IM, intramuscular myxoma; MFS, grade I myxofibrosar-coma. Intramuscular myx-oma showed significantly lower mRNA expression for decorin (P= 0.000), collagen I-A1 (P= 0.003), collagen VI-A1 (P= 0.023) and collagen XIV-A1 (P= 0.001).
Mentions: Results of relative mRNA expression are shown in Table 4 and box-plots in Fig. 2. qPCR showed that c-Fos RNA was over-expressed in all tumours compared with control tissue, but not significantly differently expressed between intramuscular myxoma and grade I myxofibrosarcoma. No significant differences were seen between typical intramuscular myxoma and cellular myxoma. Grade I myxofibrosarcoma showed significant expression of decorin mRNA, whereas decorin mRNA was barely detectable in intramuscular myxoma. Grade I myxofibrosarcoma clearly showed significant over-expression of mRNA expression for collagens I-A1, VI-A1 and XIV-A1 compared with intramuscular myxoma (including cellular myxoma).

Bottom Line: GNAS1-activating mutations were exclusively found in 50% of intramuscular myxoma.No mutations in KRAS codon 12/13 or in TP53 were detected.This was confirmed by immunohistochemistry and qPCR.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.

ABSTRACT
Cellular myxoma and grade I myxofibrosarcoma are mesenchymal tumours that are characterized by their abundant myxoid extracellular matrix (ECM). Despite their histological overlap, they differ clinically. Diagnosis is therefore difficult though important. We investigated their (cyto) genetics and ECM. GNAS1-activating mutations have been described in intramuscular myxoma, and lead to downstream activation of cFos. KRAS and TP53 mutations are commonly involved in sarcomagenesis whereby KRAS subsequently activates c-Fos. A well-documented series of intramuscular myxoma (three typical cases and seven cases of the more challenging cellular variant) and grade I myxofibrosarcoma (n = 10) cases were karyotyped, analyzed for GNAS1, KRAS and TP53 mutations and downstream activation of c-Fos mRNA and protein expression. ECM was studied by liquid chromatography mass spectrometry and expression of proteins identified was validated by immunohistochemistry and qPCR. Grade I myxofibrosarcoma showed variable, non-specific cyto-genetic aberrations in 83,5% of cases (n = 6) whereas karyotypes of intramuscular myxoma were all normal (n = 7). GNAS1-activating mutations were exclusively found in 50% of intramuscular myxoma. Both tumour types showed over-expression of c-Fos mRNA and protein. No mutations in KRAS codon 12/13 or in TP53 were detected. Liquid chromatography mass spectrometry revealed structural proteins (collagen types I, VI, XII, XIV and decorin) in grade I myxofibrosarcoma lacking in intramuscular myxoma. This was confirmed by immunohistochemistry and qPCR. Intramuscular/cellular myxoma and grade I myxofibrosarcoma show different molecular genetic aberrations and different composition of their ECM that probably contribute to their diverse clinical behaviour. GNAS1 mutation analysis can be helpful to distinguish intramuscular myxoma from grade I myxofibrosarcoma in selected cases.

Show MeSH
Related in: MedlinePlus