Adolescent ; Humans ; Male ; Werner Syndrome

Osteosarcoma is a primary malignant bone tumor that accounts for 5% of childhood cancers. Despite the use of chemotherapy, long-term survival has reached a plateau, and this figure has not changed for almost 20 years. Therefore, there is a need for understanding of the basic biology and pathogenesis of osteosarcoma in order to develop more therapeutic strategies and ultimately improve survival. This article reviews current state of knowledge about several aspects of osteosarcoma biology with regard to host genetic predispositions, cytogenetics and molecular markers. Genetic conditions with a predisposition to osteosarcoma include hereditary retinoblastoma, Li-Fraumeni syndrome, Rothmund-Thomson syndrome and Werner syndrome. Although most of osteosarcomas are sporadic, these syndromes may provide important clues to the pathogenesis of sporadic osteosarcomas. A multitude of cytogenetic abnormalities have been detected, but no specific abnormalities that can serve as markers of osteosarcoma have been found. Areas of molecular aberrations include tumor suppressor pathway (RB and p53), oncogenes (Her-2), telomere maintenance, angiogenesis (VEGF), chemokines (CXCR4), cytoskeletons (Ezrin), matrix metalloproteinases and adhesion molecules (CD44). Understanding the contributions of the different cytogenetic and molecular aberrations will aid in discovering predictors of outcome and in devising therapies for osteosarcoma.
Biomarkers* ; Biology ; Chemokines ; Chromosome Aberrations ; Cytogenetics ; Cytoskeleton ; Drug Therapy ; Genetic Predisposition to Disease ; Li-Fraumeni Syndrome ; Matrix Metalloproteinases ; Oncogenes ; Osteosarcoma* ; Retinoblastoma ; Rothmund-Thomson Syndrome ; Telomere ; Werner Syndrome

Werner syndrome is a rare autosomal recessive, hereditary disease that demonstrates progeroid features and has characteristic WRN gene mutations. Atypical Werner syndrome refers to a small subset of individuals who produce the normal WRN protein, but show some signs and symptoms that sufficiently overlap with Werner syndrome. Recently, we experienced a case of atypical Werner syndrome. A 43-year-old woman was admitted to our hospital due to being severely underweight. She had an operative history of cataracts in both eyes and had suffered from multiple skin ulcers, deafness, and vision loss. Physical examination revealed short stature, low body weight, flat feet, and a scleroderma-like skin change. Laboratory and clinical tests showed that the patient had diabetes mellitus, osteoporosis, and premature atherosclerotic features. Her clinical presentation and laboratory findings were consistent with Werner syndrome. We performed a WRN, LMNA gene sequence analysis, but no mutations were detected. The patient was diagnosed with atypical Werner syndrome.
Adult ; Body Weight ; Cataract ; Deafness ; Diabetes Mellitus ; Eye ; Female ; Flatfoot ; Genetic Diseases, Inborn ; Humans ; Osteoporosis ; Physical Examination ; Sequence Analysis ; Skin ; Skin Ulcer ; Thinness ; Vision, Ocular ; Werner Syndrome

OBJECTIVETo explore the relationship between SULF2 and WRN promoter methylation and chemosensitivity to irinotecan, and also the clinicopathological features in patients with gastric cancer.

METHODSThe chemosensitivity to irinotecan was tested by MTT assay. The methylation of SULF2 and WRN promoter in the fresh gastric cancer tissues was detected by methylation specific PCR. The differences of chemosensitivity and clinicopathological features of the methylation group were compared with that of the non-methylation group. The tumor growth in nude mice bearing human gastric cancer xenografts treated with CPT-11was also observed.

RESULTSThe methylation rates of SULF2 and WRN were 28.4% (29/102) and 23.5% (24/102), respectively. There were no significant association between promoter methylation and clinicopathological features of patients including age, gender, histologic type, lymphatic invasion, and TNM Stage. In all the 102 cases, there were 30 cases of irrinotecan-sensitive group, and 72 cases of the irrinotecan-resistant group. The SULF2 methylation rate was 46.7% (14/30)in the sensitive group, and 20.8% (15/72) in the resistant group (P = 0.008),The WRN methylation rate was 33.3% (10/30) in the sensitive group, and 19.4% (14/72) in the resistant group (P = 0.214). Gastric cancer tissues were more sensitive to irrinotecan when both the genes were methylated. The nude mice bearing human gastric cancer xenografts with SULF2 methylation were more sensitive to irrinotecan.

CONCLUSIONSThe detection of SULF2 and WRN promoter methylation may provide evidence for screening and targeting the most sensitive gastric cancer subpopulation suitable for personalized irrinotecan chemotherapy.

Antineoplastic Agents, Phytogenic ; pharmacology ; Camptothecin ; analogs & derivatives ; pharmacology ; DNA Methylation ; Exodeoxyribonucleases ; metabolism ; Humans ; Methylation ; Promoter Regions, Genetic ; RecQ Helicases ; metabolism ; Stomach Neoplasms ; metabolism ; Sulfotransferases ; metabolism ; Werner Syndrome Helicase

Werner syndrome (WRN), or adult progeria, is a very rare, autosomal recessive disorder characterized by the appearance of accelerated aging, including cataracts, gray hair, skin atrophy, and atherosclerosis. This syndrome is caused by mutations in the WRN gene and had a high risk of a spectrum of rare neoplasms including: i) non-epithelial malignant or pre-malignant tumors/conditions, osteosarcomas and soft tissue sarcomas, malignant melanomas, myeloid leukemia and myelodysplastic syndrome; ii) an epithelial neoplasm, thyroid carcinoma, and iii) meningiomas. Recently, authors experienced a case of Werner syndrome complicated by bone metastasis of rhabdomyosarcoma in a 20-year old Korean man. The patient revealed a painful mass on his right knee and progeroid features, short stature, scalp alopecia, abnormal dentition, craniofacial disproportion, hypothyroidsm, cataracts and osteoporosis. The onset of symptoms of Werner syndrome generally precedes any later symptoms of associated conditions, such as malignant tumor. Therefore, early recognition of Werner syndrome is important to assist identification of malignant tumors at an early stage in this patient group.
Aging ; Alopecia ; Atherosclerosis ; Atrophy ; Cataract ; Dentition ; Hair ; Humans ; Knee ; Leukemia, Myeloid ; Melanoma ; Meningioma ; Neoplasm Metastasis ; Neoplasms, Glandular and Epithelial ; Osteoporosis ; Osteosarcoma ; Rhabdomyosarcoma ; Sarcoma ; Scalp ; Skin ; Thyroid Neoplasms ; Werner Syndrome

Hutchinson-Gilford progeria syndrome (HGPS) and Werner's syndrome are representative types of progeroid syndrome. LMNA (Lamin A/C) gene mutation with atypical Werner's syndrome have recently been reported. Atypical Werner's syndrome with the severe metabolic complications, the extent of the lipodystrophy is associated with A133L mutation in the LMNA gene and these patients present with phenotypically heterogeneous disorders. We experienced a 15-yr-old Korean female with progeroid features, generalized lipodystrophy, hypertriglyceridemia, fatty liver, steatohepatitis, and type 2 diabetes mellitus. Skin fibroblasts from the patient showed marked abnormal nuclear morphology, compared with that from normal persons. Gene analysis revealed that this patient had T506del of exon 2 in the LMNA gene. We report here the first case of atypical Werner's syndrome with frameshift mutation that was caused by T506del.
Adolescent ; DNA/*genetics ; Exons ; Female ; Genetic Predisposition to Disease ; Humans ; Lamin Type A/*genetics/metabolism ; Lipodystrophy ; *Mutation ; Sequence Analysis, DNA ; Skin/metabolism/pathology ; Werner Syndrome/diagnosis/*genetics/metabolism

Hutchinson-Gilford progeria syndrome (HGPS) and Werner syndrome (WS) are two of the best characterized human progeroid syndromes. HGPS is caused by a point mutation in lamin A (LMNA) gene, resulting in the production of a truncated protein product-progerin. WS is caused by mutations in WRN gene, encoding a loss-of-function RecQ DNA helicase. Here, by gene editing we created isogenic human embryonic stem cells (ESCs) with heterozygous (G608G/+) or homozygous (G608G/G608G) LMNA mutation and biallelic WRN knockout, for modeling HGPS and WS pathogenesis, respectively. While ESCs and endothelial cells (ECs) did not present any features of premature senescence, HGPS- and WS-mesenchymal stem cells (MSCs) showed aging-associated phenotypes with different kinetics. WS-MSCs had early-onset mild premature aging phenotypes while HGPS-MSCs exhibited late-onset acute premature aging characterisitcs. Taken together, our study compares and contrasts the distinct pathologies underpinning the two premature aging disorders, and provides reliable stem-cell based models to identify new therapeutic strategies for pathological and physiological aging.
Aging ; genetics ; physiology ; DNA Helicases ; genetics ; Human Embryonic Stem Cells ; metabolism ; physiology ; Humans ; Kinetics ; Lamin Type A ; genetics ; Mesenchymal Stem Cells ; metabolism ; physiology ; Mutation ; Progeria ; genetics ; physiopathology ; Werner Syndrome ; genetics ; physiopathology

Werner syndrome (WS) is a premature aging disorder that mainly affects tissues derived from mesoderm. We have recently developed a novel human WS model using WRN-deficient human mesenchymal stem cells (MSCs). This model recapitulates many phenotypic features of WS. Based on a screen of a number of chemicals, here we found that Vitamin C exerts most efficient rescue for many features in premature aging as shown in WRN-deficient MSCs, including cell growth arrest, increased reactive oxygen species levels, telomere attrition, excessive secretion of inflammatory factors, as well as disorganization of nuclear lamina and heterochromatin. Moreover, Vitamin C restores in vivo viability of MSCs in a mouse model. RNA sequencing analysis indicates that Vitamin C alters the expression of a series of genes involved in chromatin condensation, cell cycle regulation, DNA replication, and DNA damage repair pathways in WRN-deficient MSCs. Our results identify Vitamin C as a rejuvenating factor for WS MSCs, which holds the potential of being applied as a novel type of treatment of WS.
Animals ; Ascorbic Acid ; pharmacology ; Cell Cycle Checkpoints ; drug effects ; Cell Line ; Cellular Senescence ; drug effects ; DNA Damage ; DNA Repair ; drug effects ; DNA Replication ; drug effects ; Disease Models, Animal ; Heterochromatin ; metabolism ; pathology ; Humans ; Mesenchymal Stem Cells ; metabolism ; pathology ; Mice ; Nuclear Lamina ; metabolism ; pathology ; Reactive Oxygen Species ; metabolism ; Telomere Homeostasis ; drug effects ; Werner Syndrome ; drug therapy ; genetics ; metabolism