Polymorphisms in Genes Involved in Osteoblast Differentiation and Function Are Associated with Anthropometric Phenotypes in Spanish Women

Much of the genetic variance associated with osteoporosis is still unknown. Bone mineral density (BMD) is the main predictor of osteoporosis risk, although other anthropometric phenotypes have recently gained importance. The aim of this study was to analyze the association of SNPs in genes involved in osteoblast differentiation and function with BMD, body mass index (BMI), and waist (WC) and hip (HC) circumferences. Four genes that affect osteoblast differentiation and/or function were selected from among the differentially expressed genes in fragility hip fracture (FOXC1, CTNNB1, MEF2C, and EBF2), and an association study of four single-nucleotide polymorphisms (SNPs) was conducted in a cohort of 1001 women. Possible allelic imbalance was also studied for SNP rs87939 of the CTNNB1 gene. We found significant associations of SNP rs87939 of the CTNNB1 gene with LS-sBMD, and of SNP rs1366594 of the MEF2C gene with BMI, after adjustment for confounding variables. The SNP of the MEF2C gene also showed a significant trend to association with FN-sBMD (p = 0.009). A possible allelic imbalance was ruled out as no differences for each allele were detected in CTNNB1 expression in primary osteoblasts obtained from homozygous women. In conclusion, we demonstrated that two SNPs in the MEF2C and CTNNB1 genes, both implicated in osteoblast differentiation and/or function, are associated with BMI and LS-sBMD, respectively.

No Evidence of Abnormal Expression of Beta-Catenin and Bcl-2 Proteins in Pilomatricoma as One Clinical Feature of Tetrasomy 9p Syndrome

Background. Little is currently known about the genetics of pilomatricoma. A number of studies have reported some evidence that this disease may have a genetic association with mutations of CTNNB1 gene or expression of the beta-catenin protein. In this study, we reviewed literatures involving 30 patients with various genetic syndromes that have been linked to pilomatricoma and found that somatic mutations of the CTNNB1 gene were reported in 67% of patients. Pilomatricoma has been reported in patients with chromosome 9 rearrangements, including 4 patients with tetrasomy 9p syndrome and one patient with partial trisomy 9. In addition to beta-catenin, the expression of bcl2 was observed in pilomatricoma. Objectives. To report an additional case of tetrasomy 9p syndrome with concurrent pilomatricoma and to examine whether abnormal protein expressions of the CTNNB1 and/or BCL2 genes were present. Methods. Cytogenetic analysis was carried out on peripheral blood, biopsied skin, and pilomatricoma tissue obtained from a patient with tetrasomy 9p syndrome. Immunohistochemical staining was performed on the pilomatricoma tissue, using beta-catenin and bcl2 monoclonal antibodies. Results. SNP microarray revealed nonmosaic gain of the short arm of chromosome 9. A nonmosaic isodicentric chromosome 9 was identified in the peripheral blood but this rearranged chromosome was detected in only 8.3% of the skin fibroblasts. Chromosomal abnormalities were not detected in the pilomatricoma nor expression of beta-catenin or bcl2 proteins in our patient. Conclusion. Pilomatricoma could be a new clinical feature associated with tetrasomy 9p syndrome; however, we found no evidence of tetrasomy 9p or abnormal beta-catenin or bcl2 proteins of the CTNNB1 and BCL2 genes in our pilomatricoma patient.

Pilomatrixoma: a common tumour of head and neck, but rarely reported

Pilomatrixoma is a benign subcutaneous tumour arising from the sebaceous glands. Mutation in the CTNNB1 gene is seen, suggesting beta-catenin misregulation may be the cause of pilomatrixoma. The preoperative diagnosis may be improved by the awareness of the fact that pilomatrixoma is a common and benign skin tumour of the head and neck region. It presents as a well-defined mass, which may be firm to hard in consistency, usually attached to the skin, but not to the underlying tissue. The colour of overlying skin appears a reddish-brown tinge, indicating that it could be a case of pilomatrixoma. Here, we report a case of pilomatrixoma of the cheek in a woman along with the CT findings and histopathological appearances. Dental surgeons should consider it as one of the differential diagnosis in superficial head and neck swelling with calcification.

Retraction: MiR-206 reduced the malignancy of hepatocellular carcinoma cells in vitro by inhibiting MET and CTNNB1 gene expressions

Retraction of ‘MiR-206 reduced the malignancy of hepatocellular carcinoma cells in vitro by inhibiting MET and CTNNB1 gene expressions’ by Qiang He et al., RSC Adv., 2019, 9, 1717–1725, DOI: 10.1039/C8RA09229J

RARE-63. CYST WALL OF ADAMANTINOMATOUS CRANIOPHARYNGIOMA CONTAINS TUMOR CELLS THAT COULD LEAD TO RECURRENCE AFTER SURGERY

BACKGROUND Adamantinomatous craniopharyngioma (ACP) is the primary subtype of craniopharyngioma in children, frequently with mutations in exon 3 of the CTNNB1 gene. Most ACP consists of both a solid tumor and one or more cysts. Despite surgical resection of the solid tumor followed by radiation, recurrence involving the cystic component is common, suggesting that the cyst wall contains tumor cells. We present here conclusive molecular pathology evidence of the presence of tumor cells in the cyst wall similar to those in the solid tumor. METHODS We used standard H&E staining and immunohistochemistry (IHC) to compare the histopathology characteristics between the matched cyst wall and solid tumor of 11 cases of ACP as well as their CTNNB1 expression and exon 3 mutation. RESULTS Samples of the cyst wall and solid tumor were collected separately during the operation of 11 cases of ACP through careful dissection. The cyst wall showed the nested cell clusters and peripheral palisading epithelium which are identical to those in the solid tumor. The cyst wall and solid tumor both showed Ki67 and nuclear β-catenin expression by IHC. There is no difference in the transcription level of CTNNB1 between the cyst wall and the solid tumor, both being significantly higher than that in normal brain tissue. Exon 3 mutations of the CTNNB1 gene of the cyst wall and the solid tumor are identical in each case. CONCLUSION Follow-up of clinical cases suggests that tumor cells in residual cyst wall may be the cause of recurrence after surgery.

RARE-07. THE LANDSCAPE OF GENOMIC ALTERATIONS IN ADAMANTINOMATOUS CRANIOPHARYNGIOMAS

INTRODUCTION Adamantinomatous craniopharyngiomas (ACPs) are characterized by activating mutations in the CTNNB1 gene. Here we perform a comprehensive genomic analysis of 23 ACPs to define the landscape of genomic alterations in this disease. METHODS We performed whole-genome sequencing of 24 ACPs and their matched normal tissues. We used Mutect 2.0 to detect mutations and indels in these samples and MutSig2CV to identify significant mutations. Copy numbers were called using the GATK4 pipeline and GISTIC 2.0 was applied to identify significant alterations. Finally, SvABA was applied to identify genome-wide structural variants and rearrangements. RESULTS 18/24 (75%) of the sequenced ACPs harbored activating mutations in exon 3 of CTNNB1 gene with an average variant allele fraction (VAF) of 0.4±0.1. These mutations have previously been shown to activate the WNT signaling pathway in these tumors. No other significantly recurrent mutations were detected in our samples. The ACPs were quiet with regard to copy number alterations and no recurrent amplifications or deletions were detected. 528 structural variations and rearrangements were detected in total in all 24 samples with an average of 22 variants per sample. Gene-Set Enrichment Analysis (GSEA) of the RNAseq data revealed upregulation of WNT/B-catenin (FDR q-value <0.25) in the CTNNB1 mutant samples compared to CTNNB1 WT samples. CONCLUSION Our study identified previously described activating CTNNB1 mutations in the majority of ACPs. In addition, we identified several rearrangements and structural variations in these tumors that could play an important role in the pathogenesis of the disease.