GTF2I Mutation in Thymomas: Independence From Racial-Ethnic Backgrounds. An Indian/German Comparative Study.

Thymomas are the most frequent adult mediastinal cancers. Their etiology is unknown and their pathogenesis poorly understood. Racial, ethnic and environmental factors influence tumorigenesis in many cancers, but their role in thymomas remains unclear to date. In this study that included pretreatment thymoma cases from India and Germany (n = 37 and n = 77, respectively) we compared i) the prevalence of the thymoma-specific chromosome 7 c.74146970T > A mutation of the GTF2I gene in type A and AB thymomas; ii) epidemiological features; and iii) the frequency of myasthenia gravis (MG). Due to a known predominance of GTF2I mutation in A and AB histotypes, we included only a marginal number of type B thymomas as a control group in both cohorts. While the distribution of histological types between the cohorts was similar (p = 0.1622), Indian patients were strikingly younger (p < 0.0001; median age 50 vs. 65 years) and showed significantly lower tumour stage (Masaoka-Koga stage I) at primary diagnosis (p = 0.0005) than the German patients. In patients with known MG status (n = 17 in Indian and n = 25 in German cohort), a clear trend towards more frequent MG was observed in the Indian group (p = 0.0504; 48 vs. 82%). The prevalence of the GTF2I mutation (analysed in n = 34 Indian and n = 77 German patients) was identical in the two cohorts. We conclude that racial-ethnic and environmental factors do not significantly influence the most common molecular feature of thymomas but may have an impact on the timing of clinical presentation.

Mutation analysis of the EGFR gene and its downstream signaling pathway in thymic carcinoma patients from a Chinese Han population.

INTRODUCTION: For thymic carcinoma (TC), which is a rare epithelial neoplasm of the thymus gland, median survival with current treatments is only 2 years. OBJECTIVES: Mutations in the epidermal growth factor receptor (EGFR) gene or its downstream effectors may cause constitutive activation that leads to cell proliferation and metastases. Thus, molecular profiling is essential for selecting TC patients who may respond to anti-EGFR therapies. METHODS: Genomic DNA was extracted from 61 histological samples of TCs. Real-time polymerase chain reaction (PCR) and direct sequencing were used to assess the mutations in the EGFR downstream pathway. RESULTS: Gene mutations were identified in seven patients (11.5%). In particular, the identified mutations included four mutations in the KRAS gene, one mutation in the BRAF gene, one mutation in the PIK3CA gene, and only one mutation in the EGFR gene itself. Gene mutations in the EGFR downstream pathway were associated with shorter survival time and were observed to be an independent prognostic factor for TC patients. CONCLUSION: Mutations in the EGFR downstream pathway are not rare in TCs. These data offer interesting possibilities for the future management of TCs, particularly in the era of new targeted therapies.

Effect of ethnic origin and gender on the clinical manifestations of myasthenia gravis among the Jewish population in Israel.

Reports on patients with myasthenia gravis (MG) of different ethnic origins demonstrated differences in weakness distribution and serological results. We studied MG characteristics in a cohort of Ashkenazi (ASH) and non-Ashkenazi (NASH) Jewish origin according to their ethnic origins and gender. The frequency of age of MG onset was distributed in a bi-modal fashion in the female patients and increased gradually over time, with a peak around 70years of age in the male patients. Ocular MG was more frequent in males and ASH patients. Unlike previous reports, our male patients had a higher proportion of positive serum anti-acetyl choline receptor (AChR) than female patients, with no ethnic-based differences in the rates of anti-AChR or anti-muscle specific kinase. Comorbidity with another autoimmune disease was more frequent among female patients with late-onset MG and NASH patients (mainly Israel-born). Male MG patients tended to have more malignant comorbidities than female MG patients. These results demonstrate the effect of ethnicity on clinical aspects of MG within the Jewish population in Israel, and reveal novel effects of gender-associated comorbidities in patients with MG.

Expression of mesothelin in thymic carcinoma and its potential therapeutic significance.

OBJECTIVES: Advanced thymic epithelial tumors (TETs) lack adequate treatment options in part due to absence of well characterized tumor-specific antigens. Mesothelin, a cell surface antigen, has been used successfully as a target for tumor-directed therapy. We sought to determine tumor expression and serum levels of mesothelin in patients with TETs. PATIENTS AND METHODS: Tissue samples were obtained from 71 patients with histologically confirmed, unresectable advanced TETs and evaluated for mesothelin expression by immunohistochemistry. The evaluation was blinded for clinical data and outcome. Mesothelin expression and its association with clinico-pathological parameters and survival were assessed. RESULTS: Thymic carcinoma, thymoma, and thymic neuroendocrine tumors (NETs) accounted for 34 (48%), 29 (41%), and 8 (11%) cases respectively. Mesothelin expression was seen in a significantly larger proportion of thymic carcinoma (27/34, 79%) than thymoma (3/29, 10%) (P<0.0001) and was absent in thymic NETs. Among thymic carcinomas 13/34 (38%) showed expression in nearly all tumor cells. Immunoreactivity was membranous, strong, and homogenous. Patients with thymic carcinoma and high mesothelin expression (in >50% of tumor cells) had significantly improved overall survival (median not reached, n=19) compared to patients with no or low mesothelin expression (1.60 years; 95% CI: 1.24-4.94 years; n=15; HR=4.46, 95% CI: 1.55-12.80; p=0.0026). CONCLUSION: Mesothelin expression is frequently observed in advanced thymic carcinomas, infrequently in thymomas and is absent in thymic NETs. Due to strong, membranous expression mesothelin is a potential therapeutic target in thymic carcinoma.

The association of HLA-DQA1*0401 and DQB1*0604 with thymomatous myasthenia gravis in northern Chinese patients.

Genetic analyses indicate that HLA complex genes can be involved in susceptibility to autoimmune myasthenia gravis (MG). Various HLA alleles serve as genetic elements that either predispose to or protect against MG. This study investigates the probable relationship between HLA-DQ allele polymorphisms and MG cases in northern China. The HLA-DQA1 and DQB1 alleles were determined by polymerase chain reaction/sequence-specific primers (PCR-SSP) in 84 MG patients, and the results were compared to 293 healthy controls. Our findings indicate that DQ A1*0401(P=0.008, OR: 2.5, 95%CI: 1.24-3.07) and B1*0301(P=0.000, OR: 2.29, 95%CI: 1.48-3.54) were the most frequent allele; the frequencies of DQA1*0103(P=0.000, OR:0.24, 95%CI 0.13-0.49) and DQB1*0601(P=0.001, OR:0.40, 95%CI 0.22-0.50) were significantly decreased in MG patients compared with healthy controls. Patients with thymomatous MG were positively associated with DQA1 *0401(P=0.011, OR:4.57, 95% CI 1.40-14.90) and DQB1 *0604 (P=0.001, OR:4.01, 95% CI 1.65-9.73) as compared to MG patients without thymoma. Different genetic mechanisms may exist between MG patients with thymoma and those without thymoma. The HLA-DQ associations in MG subgroups suggest that disease heterogeneity may be influenced by different genes or alleles.