Disparities in incidence and survival for patients with Ewing sarcoma in Florida.

BACKGROUND: Ewing sarcoma (ES) is a malignant bone tumor most commonly affecting non-Hispanic White (NHW) adolescent males, though recognition among Hispanic individuals is rising. Prior population-based studies in the United States (US), utilizing Surveillance, Epidemiology, and End Results (SEER) have shown higher all-cause mortality among White Hispanics, Blacks, and those of low socioeconomic status (SES). Florida is not part of SEER but is home to unique Hispanic populations including Cubans, Puerto Ricans, South Americans that contrasts with the Mexican Hispanic majority in other US states. This study aimed to assess racial/ethnic disparities on incidence and survival outcomes among this diverse Florida patient population. METHODOLOGY: Our study examined all patients diagnosed with osseous ES (2005-2018) in Florida (n = 411) based on the state's population-based cancer registry dataset. Florida Age-adjusted Incidence Rates (AAIRs) were computed by sex and race-ethnicity and compared to the equivalent populations in SEER. Cause-specific survival disparities among Florida patients were examined using Kaplan-Meier analysis. Univariable and multivariable analyses using Cox regression were performed for race/ethnicity, with adjustment for age, sex, year of diagnosis, site of disease, staging, SES, and insurance type. RESULTS: There was a significantly higher incidence of osseous ES in Florida Hispanic males (AAIR 2.6/1,000,000); (95% CI: 2.0-3.2 per 1,000,000; n = 84) compared to the SEER Hispanic males (AAIR 1.2/1,000,000;1.1-1.4 per 1,000,000; n = 382). Older age, distant metastasis, lack of chemotherapy or surgical resection were statistically significant determinants of poor survival while SES, insurance status and race-ethnicity were not. However, among nonmetastatic ES, Florida Hispanics had an increased risk of death compared to Florida NHW (adjusted Hazard Ratio 2.32; 95%CI: 1.20-4.46; p = 0.012). CONCLUSIONS: Florida Hispanic males have a higher-than-expected incidence of osseous ES compared to the US. Hispanics of both sexes show remarkably worse survival for nonmetastatic disease compared to NHW. This disparity is likely multifactorial and requires further in-depth studies.

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.

Genome-wide association study identifies multiple new loci associated with Ewing sarcoma susceptibility.

Ewing sarcoma (EWS) is a pediatric cancer characterized by the EWSR1-FLI1 fusion. We performed a genome-wide association study of 733 EWS cases and 1346 unaffected individuals of European ancestry. Our study replicates previously reported susceptibility loci at 1p36.22, 10q21.3 and 15q15.1, and identifies new loci at 6p25.1, 20p11.22 and 20p11.23. Effect estimates exhibit odds ratios in excess of 1.7, which is high for cancer GWAS, and striking in light of the rarity of EWS cases in familial cancer syndromes. Expression quantitative trait locus (eQTL) analyses identify candidate genes at 6p25.1 (RREB1) and 20p11.23 (KIZ). The 20p11.22 locus is near NKX2-2, a highly overexpressed gene in EWS. Interestingly, most loci reside near GGAA repeat sequences and may disrupt binding of the EWSR1-FLI1 fusion protein. The high locus to case discovery ratio from 733 EWS cases suggests a genetic architecture in which moderate risk SNPs constitute a significant fraction of risk.

Comparison of Latino and non-Latino patients with Ewing sarcoma.

BACKGROUND: Ewing sarcoma (ES) is a malignancy of bone and soft tissue in children and adults. Previous registry-based studies indicate that Latino patients with ES have inferior outcomes compared to non-Latino patients, though an etiology for this difference could not be identified. To explore possible differences that might underlie this disparity, we conducted a retrospective study to compare clinical characteristics, tumor features, healthcare access, and treatment outcomes between Latino and non-Latino patients with ES. METHODS: Primary data for 218 ES patients treated at two academic medical centers between 1980 and 2010 were collected. Categorical data were compared using Fisher exact tests; Wilcoxon rank-sum tests were used for continuous variables. Survival was estimated using Kaplan-Meier analysis and compared using log-rank testing. RESULTS: Latino patients were diagnosed at a younger age (P = 0.014). All other clinical and histological data were similar between groups, including radiologic and histologic response to neoadjuvant chemotherapy. Latino patients had lower socioeconomic status (P = 0.001), were less likely to have insurance (P = 0.001), and were more likely to present to the emergency room at onset of symptoms (P = 0.031) rather than to primary care physicians. Five-year event free survival (EFS) and overall survival (OS) were similar between Latino and non-Latino patients (EFS: 60.5% vs. 50.9% P = 0.37; OS: 77.6% vs. 68.6% P = 0.54). CONCLUSION: Latino patients with ES present at a younger age, and have evidence of impaired access to healthcare. Response to initial therapy appears similar between Latino and non-Latino patients.

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.

Cytotoxic T-lymphocyte antigen-4 genetic variants and risk of Ewing's sarcoma.

Despite the knowledge of many genetic alterations present in Ewing's sarcoma (ES), the complexity of this disease precludes placing its biology into a simple conceptual framework. Cytotoxic T-lymphocyte antigen-4 (CTLA-4) can decrease T-cell activation and attenuate antitumor responses. Polymorphisms in the CTLA-4 gene have been shown to be associated with different diseases. Here, we investigated the association of four CTLA-4 gene polymorphisms, -1661A/G (rs4553808), -318C/T (rs5742909), +49G/A (rs231775), and CT60A/G (rs3087243), with ES in the Chinese population. A total of 308 ES cases and 362 healthy controls were recruited and CTLA-4 polymorphisms were tested by polymerase chain reaction-restriction fragment length polymorphism. Results showed that frequencies of the CTLA-4 gene +49AA genotype, +49A allele, and GTAG haplotype were significantly increased in ES patients compared to healthy controls (odds ratio [OR]=2.42, 95% confidence interval [CI] 1.43-4.09, p<0.001; OR 1.38, 95% CI 1.11-1.73, p=0.005, and OR=1.46, 95% CI 1.06-2.02, p=0.020, respectively). We further compared CTLA-4 polymorphisms in ES patients based on different clinical parameters and data revealed that ES patients with metastasis had higher numbers of the +49AA genotype than those without metastasis (p=0.004). These results indicated that the CTLA-4 polymorphism could be a risk factor for ES and suggested a potential role of CTLA-4 in the metastasis of this malignancy.

EWS/FLI-responsive GGAA microsatellites exhibit polymorphic differences between European and African populations.

The genetics of Ewing sarcoma development remain obscure. The incidence of Ewing sarcoma is ten-fold less in Africans as compared to Europeans, irrespective of geographic location, suggesting population-specific genetic influences. Since GGAA-containing microsatellites within key target genes are necessary for Ewing sarcoma-specific EWS/FLI DNA binding and gene activation, and gene expression is positively correlated with the number of repeat motifs in the promoter/enhancer region, we sought to determine if significant polymorphisms exist between African and European populations which might contribute to observed differences in Ewing sarcoma incidence and outcomes. GGAA microsatellites upstream of two critical EWS/FLI target genes, NR0B1 and CAV1, were sequenced from subjects of European and African descent. While the characteristics of the CAV1 promoter microsatellites were similar across both populations, the NR0B1 microsatellite in African subjects was significantly larger, harboring more repeat motifs, a greater number of repeat segments, and longer consecutive repeats, than in European subjects. These results are biologically intriguing as NR0B1 was the most highly enriched EWS/FLI bound gene in prior studies, and is absolutely necessary for oncogenic transformation in Ewing sarcoma. These data suggest that GGAA microsatellite polymorphisms in the NR0B1 gene might influence disease susceptibility and prognosis in Ewing sarcoma in unanticipated ways.

Common variants near TARDBP and EGR2 are associated with susceptibility to Ewing sarcoma.

Ewing sarcoma, a pediatric tumor characterized by EWSR1-ETS fusions, is predominantly observed in populations of European ancestry. We performed a genome-wide association study (GWAS) of 401 French individuals with Ewing sarcoma, 684 unaffected French individuals and 3,668 unaffected individuals of European descent and living in the United States. We identified candidate risk loci at 1p36.22, 10q21 and 15q15. We replicated these loci in two independent sets of cases and controls. Joint analysis identified associations with rs9430161 (P = 1.4 × 10(-20); odds ratio (OR) = 2.2) located 25 kb upstream of TARDBP, rs224278 (P = 4.0 × 10(-17); OR = 1.7) located 5 kb upstream of EGR2 and, to a lesser extent, rs4924410 at 15q15 (P = 6.6 × 10(-9); OR = 1.5). The major risk haplotypes were less prevalent in Africans, suggesting that these loci could contribute to geographical differences in Ewing sarcoma incidence. TARDBP shares structural similarities with EWSR1 and FUS, which encode RNA binding proteins, and EGR2 is a target gene of EWSR1-ETS. Variants at these loci were associated with expression levels of TARDBP, ADO (encoding cysteamine dioxygenase) and EGR2.

Predictors of acute chemotherapy-associated toxicity in patients with Ewing sarcoma.

BACKGROUND: Ewing sarcoma (ES) is a malignant tumor of bone and soft tissue of children and young adults. Patients with ES are treated with intensive chemotherapy regimens. We describe predictors of acute chemotherapy-associated toxicity in this population. PROCEDURE: In this retrospective cohort study, records of ES patients treated at two academic medical centers between 1980 and 2010 were reviewed. Grade 3 and 4 non-hematologic chemotherapy-associated toxicities during frontline therapy were recorded for each patient, along with potential clinical and demographic predictors of toxicity. Bivariate analyses were performed using the Fisher exact test. Multivariate analysis was performed using logistic regression. RESULTS: The cohort included 142 patients with ES and toxicity data. In bivariate analyses, age <12 years at diagnosis, Latino ethnicity, low family income, and treatment on a clinical trial were associated with higher incidence of toxicity (P < 0.01). Tumor size, site, stage, mode of local control, body mass index, overall chemotherapy exposure and dose-intensity were not associated with toxicity. In multivariate analysis, low income (odds ratio (OR) 4.97, 95% confidence interval (CI) 1.9-13.1), clinical trial enrollment (OR 3.67, 95% CI 1.2-10.9), pelvic tumor site (OR 3.88, 95% CI 1.17-12.88), and age <12 years (OR 2.8, 95% CI 1.0-7.5) were independent predictors of toxicity. CONCLUSION: ES patients who are younger, of Latino ethnicity, have pelvic tumors or low income have higher rates of toxicity that may require increased supportive care. Treatment on a clinical trial was also associated with higher rates of toxicity, though this finding may reflect better reporting in these patients.

Treatment outcome of Korean patients with localized Ewing sarcoma family of tumors: a single institution experience.

OBJECTIVE: Controversy exists about the treatment outcomes of the Ewing sarcoma family of tumors among low-incidence populations. We evaluated whether Korean Ewing sarcoma family of tumors patients have poorer outcomes than Euro-American patients. METHODS: We retrospectively analyzed the clinicopathologic characteristics and outcomes of patients with localized Ewing sarcoma family of tumors treated at Korea Cancer Center Hospital between 1986 and 2008. RESULTS: Seventy-six patients (48 male, 28 female) of median age 20 years (range: 1-69 years) were evaluated. Tumors were located in central-axial parts of the body in 33 cases (43.4%) and extremity in 43 cases (56.6%). Pelvis and femur were the most frequently involved sites. Histologic response to preoperative chemotherapy was analyzed in 48 cases and there were 32 (66.7%) good responders and 16 (33.3%) poor responders. For a median follow-up of 37.9 months (range: 0.9-260.6 months), 5-year overall survival and event-free survival rates were 58.9 ± 6.1 and 52.6 ± 6.1%, respectively. A poor histologic response to preoperative chemotherapy (P= 0.01) and a tumor location in a central-axial body region (P= 0.008) were found to be related to a poorer event-free survival. CONCLUSIONS: Survival of our Ewing sarcoma family of tumors patients was not inferior to those reported for Euro-American cases. Collaborative studies are necessary for further improvements of outcome and we believe that our data provide a basis for future studies targeting Ewing sarcoma family of tumors.

Racial differences in the incidence of mesenchymal tumors associated with EWSR1 translocation.

BACKGROUND: The incidence of Ewing sarcoma varies by race, with very low rates among persons of African and East Asian ancestry. The incidence by race of other mesenchymal tumors that also harbor EWSR1 translocations has not been studied. METHODS: The SEER database was queried to find cases of mesenchymal tumors associated with EWSR1 translocations: Ewing sarcoma; clear cell sarcoma; extraskeletal myxoid chondrosarcoma; myxoid liposarcoma; desmoplastic small round cell tumor; and myoepithelial tumor. Age-adjusted incidence rates were calculated for white, African American, and Asian/Native American populations and compared statistically. RESULTS: Ewing sarcoma was significantly less common in the African American and Asian/Native American populations compared with the white population, with incidence rate ratios of 0.12 (95% CI, 0.08-0.20; P<0.001) and 0.54 (95% CI, 0.41-0.69; P<0.001), respectively. Desmoplastic small round cell tumor was significantly more common in the African American population compared with the white population (incidence rate ratio=3.0; 95% CI, 1.62-5.49; P<0.001). Myxoid liposarcoma was significantly less common in the Asian/Native American population compared with the white population (incidence rate ratio=0.72; 95% CI, 0.56-0.92; P=0.006). The incidence rates for extraskeletal myxoid chondrosarcoma, myoepithelial tumors, and clear cell sarcoma did not differ significantly by race. CONCLUSIONS: Tumors associated with EWSR1 translocation are not uniformly more common in people of European ancestry. IMPACT: The relationship between race and EWSR1 somatic translocation is complex. Future studies investigating the genetic epidemiology of EWSR1 translocated tumors are required.

Analysis of prognostic factors in Ewing sarcoma using a population-based cancer registry.

BACKGROUND: Ewing sarcoma is a high-grade malignancy that most often occurs in children. Because its occurrence in adults has been historically low, few studies have been published on the epidemiology of Ewing sarcoma in this group of patients. By using data from a large, population-based cancer registry, the authors designed the present study to examine the outcome of children and adult patients with Ewing sarcoma and relevant prognostic factors. METHODS: A retrospective analysis of Ewing sarcoma patient cases in the California Cancer Registry database was performed to identify incident patient cases diagnosed between 1989-2007. Comparisons were made to examine differences in demographics, disease characteristics, treatment, and survival. Survival analyses were performed using Kaplan-Meier method with log-rank tests and Cox proportional hazards models. RESULTS: Seven hundred and twenty-five incident patient cases of Ewing sarcoma were identified, including 372 (51.3%) children and 353 (48.7%) adults. Hispanic race was associated with young age (P = .001) and lower socioeconomic status (SES; P = .0001). Pelvic involvement was associated with large tumor size (>8 cm; P < .0001), an increased incidence of metastasis (P < .0002), and poorer survival (P < .0001). After adjusting for clinically relevant factors, statistically significant decreased overall survival was seen with adults (hazard ratio [HR], 1.71; 95% confidence interval [CI], 1.35-2.17), Hispanics (HR, 1.33; 95% CI, 1.01-1.75), metastatic disease (HR, 2.74; 95% CI, 2.14-3.49), large tumor size (HR, 1.65; 95% CI, 1.17-2.34), no surgical treatment, and low SES. CONCLUSIONS: The authors determined that adult age, Hispanic race, metastatic disease, large tumor size, and low SES are poor prognostic factors for overall survival among Ewing sarcoma patient cases.

Ethnic and racial differences in patients with Ewing sarcoma.

BACKGROUND: Ewing sarcoma (ES) was a malignant tumor of bone or soft tissue. One of the few risk factors for developing ES is race, with a higher incidence noted in populations of European rather than African or Asian ancestry. The goal of the current study was to evaluate racial and ethnic differences in presentation and overall survival (OS) among patients diagnosed with ES before age 40 years. METHODS: Data from the Surveillance, Epidemiology, and End Results database identified 1715 patients aged <40 years who were diagnosed with ES between 1973 and 2005. Racial and ethnic group differences were compared using chi-square tests. OS was estimated by Kaplan-Meier analysis and compared using log-rank tests and Cox models. RESULTS: Black patients had significantly more soft-tissue tumors compared with white non-Hispanic patients (P <.0001). Asian and white Hispanic patients were found to have an intermediate frequency of soft-tissue tumors that also differed from white non-Hispanic patients (P <.0001). White Hispanic patients presented with a higher proportion of larger tumors compared with white non-Hispanic patients (P = .042). Black patients tended to be older than white non-Hispanic patients (P = .012). Sex, frequency of pelvic tumors, and metastatic status did not appear to differ by ethnicity or race. OS was found to differ according to race and ethnicity. Even after controlling for known confounders, OS was significantly worse for black, Asian, and white Hispanic patients compared with white non-Hispanic patients (P = .0031, P = .0182, and P = .0051, respectively). CONCLUSIONS: Ethnic and racial differences in characteristics and outcomes of patients with ES do exist. Understanding the etiology of these differences will require further study.

Ewing sarcoma demonstrates racial disparities in incidence-related and sex-related differences in outcome: an analysis of 1631 cases from the SEER database, 1973-2005.

BACKGROUND: Previous reports of Ewing sarcoma cohorts suggested that there is a difference in incidence according to racial origin. However, to the authors' knowledge, this finding has never been tested in a population-based database, and the impact of race on clinical outcome and the significance of known risk factors stratified to racial groups have not been reported. METHODS: Patients who had Ewing sarcoma diagnosed between 1973 and 2005 were identified in the Surveillance, Epidemiology, and End Results database. Patient demographic and clinical characteristics; incidence; year of diagnosis; tumor location, tumor size, and disease stage at diagnosis; treatment(s); cause of death; and survival were extracted. Kaplan-Meier, log-rank, and Cox regressions were used to analyze the significance of prognostic factors. RESULTS: Race-specific incidence indicated that Caucasians have the highest incidence (0.155), followed by Asians/Pacific Islanders (0.082), and African Americans (0.017). The difference in incidence between Caucasians and African Americans was 9-fold and significant (P<.001). The incidence of Ewing sarcoma increased over the past 3 decades among Caucasians (P<.05). Survival was not impacted by race. Local disease stage, primary tumor location in the appendicular skeleton, and tumor size

Clinical outcome of patients with Ewing sarcoma family of tumors of bone in Japan: the Japanese Musculoskeletal Oncology Group cooperative study.

BACKGROUND: Ewing sarcoma family of tumors (ESFT) of bone is extremely rare in Japan. The objectives of the current study were to assess the clinical outcome and prognostic factors of patients with ESFT of bone in Japan and to compare them between Euro-American and Japanese populations. METHODS: The authors conducted a retrospective analysis of 243 patients who were treated for ESFT of bone in Japan between 1981 and 2003. Local therapy was surgery in 35% of patients, surgery combined with radiotherapy in 40% of patients, radiotherapy alone in 22% of patients, and no local treatment in 3% of patients. All but 3 patients received various regimens of multidrug chemotherapy. RESULTS: The median patient age was 16 years. The primary disease sites were the trunk in 53% of patients and the extremities in 47% of patients. Forty-one patients had metastases at presentation. The median follow-up was 66 months. A univariate survival analysis demonstrated that patients who had metastases at presentation, primary site in the trunk, age >or=16 years, tumor size >or=10 cm, tumor that responded poorly to induction chemotherapy, and local treatment with radiotherapy alone had a significantly worse event-free survival (EFS). A multivariate analysis further verified that the former 3 factors were significant adverse prognostic factors. Of 201 patients with localized disease, 45 patients who received current chemotherapy regimens that included ifosfamide and etoposide had a significantly better 5-year EFS rate (67.6%) compared with other patients. CONCLUSIONS: The clinical outcome of patients with localized ESFT of bone in Japan has improved markedly with the use of current chemotherapy regimens that include ifosfamide and etoposide and has become comparable to the outcomes observed in other major series of Euro-American patients. The prognostic factors are also almost identical.

Population-based genetic alterations in Ewing's tumors from Japanese and European Caucasian patients.

BACKGROUND: The incidence of Ewing's tumors (ETs) is lower in Asians or African-Americans than in Caucasians. PATIENTS AND METHODS: Japanese ETs were available for analysis of chromosomal aberrations by comparative genomic hybridization (n = 16) and for expression of chimeric EWS transcripts by reverse-transcriptase polymerase chain reaction (n = 11). These results in Japanese patients were compared with those of 62 ETs in European Caucasian patients registered in the European Intergroup Cooperative Ewing's Sarcoma Study. RESULTS: Japanese patients with ET had lower overall survival (P = 0.0446) and relapse-free survival (P = 0.0371) compared with European Caucasian patients. Ten of 11 Japanese ETs and 31 of 62 European Caucasian ETs had type I (EWS exon 7 to FLI1 exon 6) fusion transcripts. In Japanese ETs, the median numbers of chromosomal aberrations were 2.0 and 6.0 in 11 primary tumors and five relapsed tumors, respectively. In European Caucasian ETs, the median number of changes were 2.5 and 5.0 in 52 primary and 10 relapsed tumors, respectively. Frequent gains were 8q (38%), 8p (31%) and 12q (25%) in Japanese ETs and 8q (52%), 8p (48%) and 12q (19%) in European Caucasian ETs. Frequent losses were 19q (44%), 19p (38%) and 17p (25%) in Japanese ETs and 16q (21%), 19q (18%) and 17p (15%) in European Caucasian ETs. The incidence of losses of 19p (P = 0.0215) and 19q (P = 0.0277) were significantly higher in Japanese ETs than in European Caucasian ETs. An amplification (1p33-p34) was observed in only one Japanese ET. CONCLUSIONS: Japanese patients with ET in this study had a worse prognosis than European Caucasian patients. In molecular genetic analyses, Japanese ETs had a higher frequency of loss of chromosome 19 than European Caucasian ETs. Different genetic aberrations may explain the different incidences and prognoses of ET between Caucasian and Japanese patients.

Interethnic polymorphism of EWS intron 6: genome plasticity mediated by Alu retroposition and recombination.

The EWS gene has been identified as being systematically translocated in Ewing's sarcoma. In order to ascertain the basis of a marked interethnic difference in the incidence of Ewing's sarcoma, intron 6 of EWS, which is located near the translocation breakpoint region (EWSR1), was characterized. Sequence analysis of the entire intron 6 region revealed a very high density of Alu elements. Most of these Alu sequences could be classified in previously described subfamilies, facilitating delineation of an evolutionary model that involves successive retroposition events. According to this model, the EWS intron 6 region progressively expanded until about 5 million years ago. More recently (10(5) years ago), in part of the human population, the size of this region decreased by over 50% as the result of a homeologous recombination between two Alu sequences, which removed 2480 bp. This rare allele has only been observed in individuals of African origin, a population that is characterized by the lowest incidence of Ewing's sarcoma.

Cancer incidence in young offspring of Jewish immigrants to Israel. A methodological study. I. Nasopharyngeal malignancies and Ewing sarcoma.

Differences in cancer incidence among various immigrant groups in Israel raised the question of persistence in their descendants. The methodological problems of identification of both parents and their origins, the choice of the denominator, and the long period of observation necessary for the rare childhood tumors have been examined. From 22-years data of the Israel Cancer Registry (ICR), three malignancies were chosen as examples: epithelial carcinoma of nasopharynx (31 cases), non-Hodgkin's lymphoma of nasopharynx (14 cases), and Ewing sarcoma (55 cases). The actual number of cases, in spite of the long period of incidence, is small and the computed significance must be accepted with reservation. There are two outstanding findings: the higher incidence in males as well as in females for nasopharynx carcinoma corresponds to that of their African-born parents; an increasing trend in the second 11-years period for Ewing sarcoma. Similar studies on leukemias, lymphomas, and others with a greater number of cases can be expected to have more reliable results. This survey relied on the majority of patients with immigrant parents, mostly of the same origin. In the following years, second and later generations of Israel-born and an increasing part of intermarriages will severely impede similar studies.