Effect of TIMP2/TIMP3 genes on the risk of osteosarcoma in Zhejiang population.

ABSTRACT: Osteosarcoma is a malignant tumor that develops from a mesenchymal cell line and is caused by gene-environment interactions. This study aimed to explore whether TIMP2/TIMP3 polymorphisms influenced the osteosarcoma risk.The expression of the TIMP2 and TIMP3 genes in osteosarcoma histiocytes was analyzed by immunohistochemistry. In this case-control study, which includes samples from 499 patients and 500 healthy controls, 10 single-nucleotide polymorphisms (SNPs) in TIMP2 and TIMP3 were selected. Furthermore, we used the Agena MassARRAY platform for genotyping. The statistical analysis was performed using χ2 test/Fisher exact test, and logistic regression analysis.The immunohistochemistry results showed that the expression of TIMP2 is obvious higher in osteosarcoma histiocytes than in the normal histiocytes. The association study indicated that the allele of rs2277698 and rs4789936 were protective SNPs reducing the risk of osteosarcoma (odds ratios  > 1, P < .05) by the χ2 test. In the genetic model, logistic regression analyses revealed that the rs2277698 and rs4789936 were associated with decreasing the risk of osteosarcoma under the codominant model, dominant model, and log-additive model. Stratification analysis revealed that 2 SNPs (rs2277698 and rs4789936) were significantly associated with a reduced risk of osteosarcoma in allele and genetic model after stratification by gender or age (P < .05). In addition, the haplotype "Trs2277698Crs2009169Crs7342880" of TIMP2 was associated with decreasing the osteosarcoma risk. The "Ars9609634Trs11547635" of TIMP3 was associated with reducing the osteosarcoma risk.This finding shed new light on the high expression of TIMP2 polymorphisms may contribute to decreasing the osteosarcoma risk in Zhejiang populations.

Kaposi's sarcoma herpesvirus is associated with osteosarcoma in Xinjiang populations.

Osteosarcoma is the most common malignant tumor of bone predominately affecting adolescents and young adults. Based on animal studies, a viral etiology of osteosarcoma was proposed more than a half-century ago, but no viral association with human osteosarcoma has been found. The Uyghur ethnic population in Xinjiang, China, has an unusually high prevalence of Kaposi's sarcoma-associated herpesvirus (KSHV) infection and elevated incidence of osteosarcoma. In the current study, we explored the possible association of KSHV infection and osteosarcoma occurrence. Our seroepidemiological study revealed that KSHV prevalence was significantly elevated in Uyghur osteosarcoma patients versus the general Uyghur population (OR, 10.23; 95%CI, 4.25, 18.89). The KSHV DNA genome and viral latent nuclear antigen LANA were detected in most osteosarcoma tumor cells. Gene expression profiling analysis showed that KSHV-positive osteosarcoma represents a distinct subtype of osteosarcomas with viral gene-activated signaling pathways important for osteosarcoma development. We conclude that KSHV infection is a risk factor for osteosarcoma, and KSHV is associated with some osteosarcomas, representing a newly identified viral-associated endemic cancer.

Socioeconomic Predictors of Surgical Resection and Survival for Patients With Osseous Spinal Neoplasms.

OF BACKGROUND DATA: Primary osseous spinal neoplasms (POSNs) include locally aggressive tumors such as osteosarcoma, chondrosarcoma, Ewing sarcoma, and chordoma. For such tumors, surgical resection is associated with improved survival for patients. Socioeconomic predictors of receiving surgery, however, have not been studied. OBJECTIVE: To examine the independent effect of race on receiving surgery and survival probability in patients with POSN. STUDY DESIGN: A total of 1904 patients from the SEER program at the National Cancer Institute database, all diagnosed with POSN of the spinal cord, vertebral column, pelvis, or sacrum from 2003 through 2012 were included in the study. Race was reported as white or nonwhite. Treatment included receiving surgery and no surgery. MATERIALS AND METHODS: Multivariable logistic regression was used to determine odds of receiving surgery based on race. Survival probability based on and race and surgery status was analyzed by Cox proportional hazards model and Kaplan-Meir curves. Results were adjusted for age at diagnosis, sex, socioeconomic status (composite index), tumor size, and tumor grade. Data were analyzed with SAS version 9.4. RESULTS: The study found that white patients were significantly more likely to receive surgery (odds ratio=3.076, P<0.01). Furthermore, nonwhite race was associated with significantly shorter survival time [hazard ratio (HR)=1.744, P<0.05]. Receiving surgery was associated with improved overall survival (HR=2.486, P<0.01). After adjusting for receiving surgery, white race remained significantly associated with higher survival probability (HR=2.061, P<0.05). CONCLUSIONS: This national study of patients with typically aggressive POSN found a significant correlation between race and the likelihood of receiving surgery. The study also found race to be a significant predictor of overall survival, regardless of receiving surgical treatment. These findings suggest an effect of race on receiving treatment and survival in patients with POSN, regardless of socioeconomic status. Further studies are required to understand reasons underlying these findings, and how they may be addressed.

Prognostic factors to survival of patients with chondroblastic osteosarcoma.

This study was aimed to reveal the changes in survival rates and prognostic factors to survival of chondroblastic osteosarcoma (COS).Patients from the Surveillance, Epidemiology, and End Results (SEER) database were retrieved. Kaplan-Meier survival analysis and Cox proportional hazard model were used during analysis.There were significant differences on overall survival between subtypes of osteosarcoma (P < .001*). Overall survival of COS did not change significantly during last forty years (P = .610), and cancer-specific survival increased to a plateau in 1980s and then remained stable (P = .058). Younger onset age, patients of white race, well and moderately differentiated tumors, and surgery independently predicted better overall (Hazard ratio [HR]: 1.034, P < .001*; HR: 0.538, P = .004*; HR: 0.240, P = .020* and HR: 0.350, P < .001*, respectively) and cancer-specific (HR: 1.031, P = .002*; HR: 0.592, P = .036*; HR: 0.098, P = .027* and HR: 0.253, P < .001*, respectively) survival. Metastasis at diagnosis independently predicted worse overall (HR: 3.108, P < .001*) and cancer-specific (HR: 4.26, P < .001*) survival compared to no metastasis.Younger onset age, white race, well and moderately differentiated tumors, no metastasis at diagnosis and surgical resection can independently predict better overall and cancer-specific survival of COS.

Strategies and challenges for communicating the diagnosis of cancer in cross-cultural clinical settings-Perspectives from South African healthcare professionals.

Communicating the diagnosis of cancer in cross-cultural clinical settings is a complex task. This qualitative research article describes the content and process of informing Zulu patients in South Africa of the diagnosis of cancer, using osteosarcoma as the index diagnosis. We used a descriptive research design with census sampling and focus group interviews. We used an iterative thematic data analysis process and Guba's model of trustworthiness to ensure scientific rigor. Our results reinforced the use of well-accepted strategies for communicating the diagnosis of cancer. In addition, new strategies emerged which may be useful in other cross-cultural settings. These strategies included using the stages of cancer to explain the disease and its progression and instilling hope using a multidisciplinary team care model. We identified several patients, professionals, and organizational factors that complicate cross-cultural communication. We conclude by recommending the development of protocols for communication in these cross-cultural clinical settings.

Vascular endothelial growth factor polymorphisms are associated with osteosarcoma susceptibility.

Polymorphisms in the vascular endothelial growth factor (VEGF) gene may contribute to osteosarcoma risk, but the results of previous studies have been inconsistent and inconclusive. We conducted a meta-analysis to assess this association more accurately. Relevant studies were collected systemically from three online English databases. Crude odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the associations of three VEGF gene polymorphisms (+936C/T, -634 G/C, +1612 G/A) with osteosarcoma risk. Seven case-control studies involving 1,350 cases and 1,706 controls were selected for the meta-analysis. The pooled OR indicated that the VEGF +936C/T polymorphism was associated with increased risk of osteosarcoma in a Chinese population (T vs. C: OR = 1.26, 95% CI = 1.12-1.42, P < 0.01; TT vs. CC: OR = 1.70, 95% CI = 1.29-2.24, P < 0.01; CT + TT vs. CC: OR = 1.23, 95% CI = 1.06-1.44, P < 0.01; TT vs. CC + CT: OR = 1.61, 95% CI = 1.23-2.10, P < 0.01). A significant association was also found between the -634 G/C polymorphism and osteosarcoma risk (C vs. G: OR = 0.81, 95% CI = 0.69-0.96, P = 0.01; CC vs. GG: OR = 0.66, 95% CI = 0.48-0.90, P < 0.01; GC + CC vs. GG: OR = 0.80, 95% CI = 0.67-0.96, P = 0.02; CC vs. GG + GC: OR = 0.72, 95% CI = 0.60-0.86, P < 0.01). In sum, our meta-analysis suggests VEGF polymorphisms are associated with osteosarcoma susceptibility in the Chinese population. However, further studies that include different ethnicities and larger populations are needed.

Genetic polymorphisms in MMP 2, 3 and 9 genes and the susceptibility of osteosarcoma in a Chinese Han population.

BACKGROUND: There are no data about the role of MMPs polymorphism in development of osteosarcoma. PATIENTS AND METHODS: Two-hundred fifty-one patients with osteosarcoma and 251 healthy controls were included to investigate the association between the MMP2, 3, 9 polymorphisms and the risk of osteosarcoma. RESULTS: Compared with the MMP2 SNP rs243865 homozygote CC, The heterozygous CT genotype was associated with significantly increased risk for osteosarcoma (OR = 1.86, 95% CI = 1.18-4.22, p = 0.014); the TT genotype was associated with increased risk for osteosarcoma (OR = 1.92, 95% CI = 1.21-3.52, p = 0.028). However, the genotype and allele frequencies of MMP3 rs3025058 and MMP9 rs3918242 polymorphisms were not significantly different. CONCLUSION: MMP2 rs243865 genotype was associated with increased risk for development of osteosarcoma in Chinese Han population.

Association between angiogenic growth factor genetic polymorphisms and the risk of osteosarcoma.

The aim of this study was to assess the role of the VEGF -2578C/A, +936C/T, and -460T/C gene polymorphisms in the development of osteosarcoma. A total of 182 patients with osteosarcoma and 182 age- and gender-matched healthy controls were enrolled into our study during January 2011 and December 2013. Genotype frequencies of the VEGF -2578C/A and -460T/C alleles in controls were found to be within the parameters of Hardy-Weinberg equilibrium, but the genotype frequencies of +936C/T alleles were not. By conditional regression analysis, we detected a statistically significantly increased risk of osteosarcoma in patients with the AA genotype (OR = 1.97; 95%CI = 1.02-3.83) and the CA+AA genotype (OR = 1.57; 95%CI = 1.01-2.44) of -2578C/A when compared with CC genotype. Therefore, our study showed that the AA and CA+AA genotypes of the VEGF -2578C/A polymorphism might modify the risk of osteosarcoma in a Chinese population.

Association of -308G/A and -238G/A polymorphisms of TNF-α and osteosarcoma risk.

OBJECTIVE: As a proinflammatory cytokine, TNF-α is associated with increased risk of osteosarcoma (OS). Our study aimed to explore the association of TNF-α polymorphisms and OS susceptibility in the Han Chinese population. METHODS: 80 OS patients and 99 healthy people, matched on the age and sex, participated in the study. Genotyping was conducted by the method of polymerase chain reaction-restricted fragment length polymorphisms (PCR-RFLP). Then logistic regression was used to evaluate the effects of TNF-α polymorphisms (-308 G/A and -238 G/A) on the pathology of OS. RESULTS: The frequency of AA genotype in -308 G/A locus in the cases was significantly higher than that of the healthy group (20.0% vs. 6.1%). Patients with OS were more likely to possess AA genotype of -308 G/A locus (OR=4.00, 95% CI=1.41-11.38). For the patients with A allele, the risk for OS increased 0.62 fold (OR=1.62, 95% CI=1.04-2.50). There was no remarkable relationship of -238 G/A polymorphisms and OS susceptibility. In addition, we found that patients with G-A and A-A haplotypes was much higher in the cases than that of control group (68.0% and 25.0%, 53.0% and 38.9%, respectively). A-G haplotype appeared to increase the risk for OS (OR=1.93, 95% CI=1.13-2.94). CONCLUSION: The AA genotype of -308 G/A locus of TNF-α gene was a risk factor for OS, however there was no correlation between -238 G/A of TNF-α and OS.

Pediatric osteosarcoma: a single institution's experience.

OBJECTIVES: The aim of the study was to evaluate outcomes with an examination of individual predictors influencing survival at a single institution. METHODS: This was a retrospective review of the 28 pediatric osteosarcoma patients diagnosed and studied from 2000 through 2012. Twenty-eight patient charts and imaging studies were reviewed for age, race, sex, location, extent of disease at presentation, imaging results, histology, treatment options, and overall survival. RESULTS: Of the 28 patients who were identified, the median age at diagnosis was 14 years. The majority of the patients were male African Americans with the tumor located in the lower long bones and most had conventional osteosarcoma histology. Four patients had metastasis at diagnosis. Of the 28 patients, 16 patients underwent limb salvage surgery, 6 underwent amputation, 4 had biopsy only, 1 had hip disarticulation, and 1 moved out of state and had no information available. All 28 patients received chemotherapy. Four patients received additional radiation therapy. On follow-up, 15 patients were still alive at last clinical contact and 13 died. Of the deceased, the median survival time was 2.3 years. The patient who lived the longest survived 8.3 years. Metastasis at diagnosis was associated with poorer outcome (P = 0.002). The 5-year overall survival rate was 40% (95% confidence interval 18-62) for our entire population of patients. CONCLUSIONS: Survival in our patient cohort tended to be at the lower end of the spectrum reported by other contemporary treatment centers of excellence or Surveillance, Epidemiology, and End Results databases probably because of the large number of African American patients with associated poor socioeconomic status. Future studies should be conducted to explore biological and nonbiological factors that may affect the prognosis in this disease.

Genetic polymorphisms of interleukin-1 beta and osteosarcoma risk.

PURPOSE: Osteosarcoma is the most common childhood bone cancer. Interleukin-1 beta (IL-1B) is crucially involved in osteosarcoma carcinogenesis. Whether genetic polymorphisms of IL-1B also influence osteosarcoma risk is unknown. The aim of this study was to investigate the association between IL-1B gene polymorphisms and osteosarcoma risk in Chinese Han patients. METHODS: A hospital-based case-control study involving 120 osteosarcoma patients and 120 controls was conducted. Polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) analysis was performed to detect three IL-1B gene polymorphisms (-31 T/C, -511 C/T and +3954 C/T) in these patients. RESULTS: Patients with osteosarcoma had a significantly lower frequency of -31 CC genotype [odds ratio (OR) = 0.40, 95% confidence interval (CI) = 0.17-0.92; P = 0.03] and -31 C allele (OR = 0.67, 95% CI = 0.46-0.99; P = 0.04) than controls. Patients with osteosarcoma had a significantly lower frequency of -511 TT genotype (OR = 0.40, 95% CI = 0.17-0.95; P = 0.04) than controls. The +3954 C/T gene polymorphisms were not associated with a risk of osteosarcoma. When stratified by Enneking stage, tumour location, histological type, tumour metastasis of osteosarcoma and family history of cancer, no statistically significant results were found. CONCLUSIONS: This is the first study to provide evidence for an association of IL-1B gene polymorphisms with osteosarcoma risk.

Characterization of localized osteosarcoma of the extremity in children, adolescents, and young adults from a single institution in South Texas.

BACKGROUND: Osteosarcoma is the most common bone malignancy in children, adolescents, and young adults. Most study cohorts have 10% to 15% Hispanic patients that encompass many different Hispanic backgrounds. This study characterizes the effect of mainly Mexican American ethnicity on the outcome of children, adolescents, and young adults with osteosarcoma. METHODS: A retrospective analysis of demographics, tumor characteristics, response to treatment, and survival outcome of all localized osteosarcoma of the extremity patients below 30 years of age was performed. A Kaplan-Meier estimates with log-rank tests and Cox proportional hazard regression models were used. RESULTS: Fifty patients (median age, 15; range, 2 to 28 y) with localized high-grade osteosarcoma of the extremity were diagnosed between January 2000 and December 2010. The cohort was 70% Mexican Americans. With a median follow-up of 39 months (range, 5 to 142 mo), patients had a 5-year overall survival and event-free survival of 65% and 48%, respectively. We observed a significantly decreased 5-year event-free survival in patients diagnosed before age 12 relative to patients diagnosed between ages 12 and 29 (11% vs. 57%, P<0.001). We also found that tumor necrosis was not predictive of outcome in our patients. CONCLUSIONS: The preadolescent patients of predominately Mexican American ethnicity had an increased rate of relapse when compared with previous studies. Tumor necrosis is not directly predictive of outcome in this population.

Significant association between cytotoxic T lymphocyte antigen 4 +49G>A polymorphism and risk of malignant bone tumors.

Cytotoxic T lymphocyte antigen 4 (CTLA-4) gene +49G>A polymorphism was implicated to be associated with risk of malignant bone tumors, but the finding was inconclusive owing to the limited sample of a single study. The objective of the current study was to conduct a pooled analysis of four previously published studies to investigate the association between CTLA-4 +49G>A polymorphism and the risk of malignant bone tumors. Data were extracted, and the pooled odds ratio (OR) with the corresponding 95% confidence interval (95% CI) was calculated to assess the association. Those four published studies included a total of 2,165 subjects. The pooled results indicated that CTLA-4 +49G>A polymorphism was significantly associated with risk of malignant bone tumors (AA versus GG: OR = 2.24, 95% CI 1.67-2.99, P < 0.001; AA/GA versus GG: OR = 1.35, 95% CI 1.14-1.61, P = 0.001; AA versus GG/GA: OR = 2.00, 95% CI 1.53-2.62, P < 0.001). Stratified analyses by tumor type showed that CTLA-4 +49G>A polymorphism was associated with risks of both osteosarcoma (AA versus GG: OR = 2.23, 95% CI 1.45-3.43, P < 0.001; AA/GA versus GG: OR = 1.35, 95% CI 1.04-1.75, P = 0.024; AA versus GG/GA: OR = 2.00, 95% CI 1.34-2.98, P = 0.001) and Ewing's sarcoma (AA versus GG: OR = 2.24, 95% CI 1.51-3.31, P < 0.001; AA/GA versus GG: OR = 1.36, 95% CI 1.07-1.72, P = 0.011; AA versus GG/GA: OR = 2.01, 95 % CI 1.39-2.89, P < 0.001). Therefore, results from the current pooled analysis suggest that CTLA-4 +49G>A polymorphism is associated with risk of malignant bone tumors, including osteosarcoma and Ewing's sarcoma.

Genome-wide association study identifies two susceptibility loci for osteosarcoma.

Osteosarcoma is the most common primary bone malignancy of adolescents and young adults. To better understand the genetic etiology of osteosarcoma, we performed a multistage genome-wide association study consisting of 941 individuals with osteosarcoma (cases) and 3,291 cancer-free adult controls of European ancestry. Two loci achieved genome-wide significance: a locus in the GRM4 gene at 6p21.3 (encoding glutamate receptor metabotropic 4; rs1906953; P = 8.1 × 10⁻9) and a locus in the gene desert at 2p25.2 (rs7591996 and rs10208273; P = 1.0 × 10⁻8 and 2.9 × 10⁻7, respectively). These two loci warrant further exploration to uncover the biological mechanisms underlying susceptibility to osteosarcoma.

Making a case for the socioeconomic determinacy of survival in osteosarcoma.

BACKGROUND: The literature on osteosarcoma survival generally focuses on tumor and treatment variables, although it is unclear whether and how ethnic and socioeconomic factors might influence survival. QUESTIONS/PURPOSES: We therefore investigated the relative contribution of socioeconomic influences together with more traditional tumor-specific factors on osteosarcoma survival. METHODS: We performed survival analyses on two national databases in two countries. Using multivariable analyses, we compared these with corresponding institution-specific survival to determine if socioeconomic factors might impact osteosarcoma survival. RESULTS: East Asian descent, state-specific treatment, female sex, treatment in the 1990s, low-grade disease, intracompartmental disease, small size, wide resections as opposed to forequarter or hindquarter amputations, and single primaries were good prognostic factors. Survival was better in the more affluent states. Males were affected at an older age than females. Blacks tended to have larger tumors, although their overall survival was similar to whites. East Asians were more likely to be treated in the 1990s with wide resections for smaller tumors and were located around states associated with good treatment. East Asians in Singapore and the United States had the same survival. Survival in East Asians in Singapore was similar to that of other races. The provision of health care for osteosarcoma varies greatly across the United States but is uniform in the socialized medical system in Singapore. Hence, the observed differences in the United States were likely the result of socioeconomic factors. CONCLUSIONS: Our analysis suggests ethnic and economic bias may influence survival in osteosarcoma and should receive greater attention in the collective literature on survival analyses. LEVEL OF EVIDENCE: Level II, prognostic study. See the Guidelines for Authors for a complete description of levels of evidence.

Demographic determinants of survival in osteosarcoma.

INTRODUCTION: Osteosarcoma treatment has experienced a renaissance in the last 3 decades with the institution of multimodality treatment involving multiagent chemotherapy and surgery. Yet globally, treatment success has stagnated at about 70% survival at 5 years in most single institution series. We performed survival analyses on 2 national databases in 2 countries and compared these with corresponding institution specific survival. MATERIALS AND METHODS: All patients with the diagnostic code of non-metastatic intramedullary osteosarcoma in the long bones of the upper and lower limbs less than 30 years of age were selected from the Surveillance Epidemiology and End Result (SEER) database to ensure uniformity with respect to disease and treatment. We studied the factors: ethnicity, gender, age, grade, histology, size, site, surgery, compartmentalisation, number of primaries and venue of treatment for their contribution to survival. In addition, the data were stratified into 3 decades (seventies, eighties and nineties) to account for variations due to the evolution of treatment paradigms and imaging modalities. RESULTS: Institution-specific survival was predictably better than national survival in the 4 databases. One thousand patients were selected from the SEER database. Oriental descent, state-specific treatment, female gender, treatment in the nineties, low-grade disease, intra-compartmental disease, small size, wide resections as opposed to forequarter or hindquarter amputations, and single primaries were good prognostic factors on univariate analysis as well as multivariate analysis (P <0.05). Survival was better in the more affluent states (P <0.05). Males were affected at an older age than females (P = 0.004). Blacks tended to have larger tumours although their overall survival was similar to whites. Orientals were more likely to be treated in the nineties with wide resections for smaller tumours and were located around states associated with good treatment. Orientals in Singapore and the United States had the same survival (P = 0.45). Survival in Orientals in Singapore was not significantly different from other races. The standard of healthcare for osteosarcoma varies greatly across the United States but is uniform in Singapore. Hence the observed differences in the United States were likely due to socioeconomic factors. CONCLUSION: This analysis confirms the importance of a number of prognostic variables in osteosarcoma and suggests the possibility of an ethnic and economic bias for good survival.

Osteogenic sarcoma of the maxillary region in a Mexican mestizo population.

BACKGROUND AND OBJECTIVES: This study analyzed maxillary osteosarcoma in a mestizo population, with particular emphasis on the type of treatment and disease-free and overall survival. METHODS: This is a retrospective study including all mestizo patients with osteosarcoma of the maxilla seen in a single cancer institution in Mexico during a 20-year period. RESULTS: There were 21 patients. Age ranged from 16 to 76 years (mean, 37.5 y). Mean evolution time to diagnosis was 13 months, with a mean tumor size of 7 × 6 cm2. Surgery was the initial treatment in 19 patients, 17 of whom received adjuvant treatment. Disease-free survival according to surgical margin and overall survival were not statistically significant. Disease-free survival was 29% at 5 years, and overall survival was 50% and 25% at 5 and 10 years, respectively. CONCLUSIONS: Osteosarcomas of the maxilla are infrequent lesions that merit early diagnosis and proper treatment because of their rapid evolution. Treatment is currently based on a well-planned surgery with free surgical margins plus adjuvant radiotherapy and/or chemotherapy.

Association between TGFBR1*6A and osteosarcoma: a Chinese case-control study.

BACKGROUND: TGFBR1*6A is a common hypomorphic variant of transforming growth factor beta receptor 1 (TGFBR1). TGFBR1*6A is associated with an increased cancer risk, but the association of this polymorphism with osteosarcoma remains unknown. We have measured the frequency of TGFBR1*6A variants in osteosarcoma cases and controls. METHODS: Our case-control study is based on 168 osteosarcoma patients and 168 age- and gender-matched controls. Blood samples were obtained and the TGFBR1*6A variant determined by PCR amplification and DNA sequencing. The odds ratio (OR) and 95% confidence interval (95% CI) for the TGFBR1*6A polymorphism were calculated by unconditional logistic regression, adjusted for both age and gender. Three models - dominant, additive and recessive - were used to analyze the contribution of the TGFBR1*6A variant to osteosarcoma susceptibility. RESULTS: Heterozygotic and homozygotic TGFBR1*6A variants represented 50.4% and 6.0% of the 168 cases, whereas the controls had 18. 5% and 1.3%, respectively. ORs for homozygosity and heterozygosity of the TGFBR1*6A allele were 4.6 [95% CI, 2.33-7.97] and 2.9 [95% CI, 1.59-5.34] in the additive model. There were significant increases in the TGFBR1*6A variants in osteosarcoma cases compared to control in all 3 models. Further analysis showed that TGFBR1*6A genotypes were not associated with gender, age, or tumor location. However, TGFBR1*6A was significantly associated with less metastasis. CONCLUSIONS: TGFBR1*6A, a dominant polymorphism of TGFBR1, is associated with increased susceptibility and metastasis spread of osteosarcoma.