Gorlin syndrome is a skeletal disorder caused by a gain of function mutation in Hedgehog (Hh) signaling. The Hh family comprises of many signaling mediators, which, through complex mechanisms, play several important roles in various stages of development. The Hh information pathway is essential for bone tissue development. It is also the major driver gene in the development of basal cell carcinoma and medulloblastoma. In this review, we first present the recent advances in Gorlin syndrome research, in particular, the signaling mediators of the Hh pathway and their functions at the genetic level. Then, we discuss the phenotypes of mutant mice and Hh signaling-related molecules in humans revealed by studies using induced pluripotent stem cells.
S. Serum parathyroid hormone-related protein concentrations in patients with hématologie malignancies or solid tumors. Acta EndocrinolThe clinical significance of parathyroid hormone-related protein in humoral hypercalcemia of malignancy was investigated by determining the serum parathyroid hormone-related protein concentrations in 167 normal subjects, 56 patients with hematologic malignancy and 144 patients with solid tumor. Serum parathyroid hormone-related protein was measured with a radioimmunoassay kit that recognizes the C-terminal portion of the molecule. The serum parathyroid hormone-related protein concentrations were 20.2\p=n-\50.8 pmol/l (mean\m=+-\2sd) in normal subjects, and were elevated in 80% of the patients with malignancies with hypercalcemia, including squamous cell carcinoma and adult T cell leukemia. Moreover, two cases of B cell non-Hodgkin's lymphoma with hypercalcemia had high serum parathyroid hormone-related protein concentrations, which varied in parallel with the tumor size during the clinical course. Of 136 patients with solid tumors with normocalcemia, the serum parathyroid hormone-related protein concentration was slightly elevated in only 5.1%, all of whom were at an advanced stage. These data indicate that determination of the serum parathyroid hormone\x=req-\ related protein concentration is useful for differential diagnosis of humoral hypercalcemia of malignancy and prediction of its development. In 1987, four groups (1-4) purified parathyroid hor¬ mone-related protein (PTHrP) and Suva et al. (5) cloned and sequenced the gene of this protein. In addition, immunoreactive PTHrP was demonstrated in an extract of a humoral hypercalcemia of malignancy tumor (6, 7) by radioimmunoassay (RIA). In 1990, Burtis et al. ( 8) developed an immunoradiometric assay (IRMA) for PTHrP (1-74) and an RIA for PTHrP (109-138). and reported that both their assays were useful in the differential diagnosis of hypercalcemia. The value of determining urinary PTHrP (127-141) was also reported (9). However, the serum PTHrP levels in normal subjects are difficult to measure by these assays, and there have been few reports on the relationship between the clinical course and serum PTHrP level.Recently, Kasahara et al. (10) developed an RIA kit for PTHrP (109-141) with which we could measure the serum PTHrP concentrations in normal subjects and in patients with various diseases. Here we report data on the serum PTHrP concentrations in patients with héma¬ tologie malignancies or solid tumors who had normal serum creatinine levels, and the relationship between the clinical course and change in serum PTHrP. Subjects and methods SubjectsThe subjects examined were 167 normal adults (92M, 75F) aged 20-60 years, 56 patients with hématologie malignancy and 144 patients with solid tumor.Serum calcium was measured using the O-cresolphthalein complexing method after an overnight fast. The serum calcium concentration was corrected by the equation, "corrected calcium = measured calcium (mg/ dl) + 4.0-albumin (g/dl)" and valu...
Background Basal cell carcinoma (BCC) is the most commonly occurring neoplasm in patients with Gorlin syndrome. It is widely accepted that multiple basal cell carcinomas simultaneously develop in middle-aged patients with this syndrome. However, the presence of driver genes other than the PTCH1 in Gorlin syndrome has not been explored. This study aimed to identify common gene mutations other than PTCH1 in simultaneously occurring basal cell carcinomas in patients with Gorlin syndrome via exome sequencing analysis. Methods Next-generation sequencing analysis was performed using four basal cell carcinoma samples, one dental keratinocyte sample, and two epidermoid cyst samples, which were surgically resected from one patient with Gorlin syndrome on the same day. Results Overall, 282 somatic mutations were identified in the neoplasms. No additional somatic mutations in PTCH1, PTCH2, TP53, and SMO were identified. However, enrichment analysis showed that multiple genes, such as IFT172 and KIFAP3, could regulate ciliary functions important for Hedgehog signaling. Conclusion The development of BCCs in patients with Gorlin syndrome may be triggered by mutations that cause substantial dysfunction of cilia.
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