Clinicopathological features and outcome of gastroenteropancreatic high-grade (WHO G3) neuroendocrine tumors: a study of 60 cases / 中华病理学杂志

Objective@#To investigate the clinicopathological features and outcome of gastroenteropancreatic high-grade neuroendocrine tumors.@*Methods@#A total of 60 gastroenteropancreatic high-grade neuroendocrine tumors were collected from January 1st, 2013 to December 31th, 2018 at Fudan University Shanghai Cancer Center, with available pathology databases and clinic follow-up information. At the same time, 157 cases of gastrointestinal pancreatic neuroendocrine neoplasm (NEN) diagnosed at the hospital in 2018 were collected and the incidence of NEN at all grades was compared.@*Results@#There were 32 males and 28 females, aged 13-80 years (mean 54 years). Pancreas primary was the most common (48%, 29/60). Nodal metastatic rate was 9/16 and distant metastatic rate was 41%(18/44). Liver was the most common site of metastasis. Among all the gastroenteropancreatic neuroendocrine neoplasms diagnosed in the hospital in 2018, the incidence of high-grade neuroendocrine tumors was the lowest (7%, 11/157). High-grade neuroendocrine tumors had typical pathologic features of well-differentiated/moderate neuroendocrine tumors, but with significant differences in mitotic rates. By immunohistochemical staining, most of the tumors expressed neuroendocrine markers and somatostatin receptor 2 was positive in 60% (12/20) of the cases. The average Ki-67 index was 30%-40%, and there was significant difference between cases (18%-80%). The overall survival of high-grade neuroendocrine tumors was 43 months, and the disease-free survival was 12 months.@*Conclusions@#High-grade neuroendocrine tumor is a rare group of neuroendocrine tumors, with unique clinicopathological features and good prognosis. Pathological classification and grading of gastroenteropancreatic neuroendocrine neoplasms can help clinicians to select appropriate treatment and accurately evaluate prognosis.

Small cell carcinoma of ovary, hypercalcemic type: analysis of clinicopathologic characteristics and the diagnostic utility of loss expression of SMARCA4 protein / 中华病理学杂志

<p><b>OBJECTIVE</b>To study the clinicopathologic features of small cell carcinoma of ovary, hypercalcemic type (SCCOHT) and to evaluate the diagnostic significance of loss of SMARCA4 expression.</p><p><b>METHODS</b>The clinicopathologic characteristics of 5 cases of SCCOHT were reviewed. The expression of SMARCA4 protein was detected by immunohistochemistry in the cases of SCCOHT and 240 cases of other primary malignant tumors of ovary and peritoneum.</p><p><b>RESULTS</b>The mean and medium age of these patients was 30 years and 28 years, respectively. The presenting symptoms included abdominal pain, distention and a pelvic mass. Hypercalcemia was found in 3 patients. The maximum diameter of tumors ranged from 13.5 to 22.0 cm. Extraovarian spread was demonstrated in all of the patients on presentation. Histologically, the tumors were composed of closely packed small round cells with scanty cytoplasm, hyperchromatic nuclei and irregular chromatin clumps. The tumor cells grew in sheets, nests, cords or trabecular pattern. Follicle-like spaces were observed in 4 cases. Three of the tumors contained large cells with abundant eosinophilic cytoplasm. Spindle cell morphology was found in 1 case. There were 2 cases with myxoid or hyaline stroma. Four out of five of SCCOHT cases showed loss of SMARCA4 protein while only 6.3% (15/240) of the other primary malignant tumors of ovary and peritoneum , including undifferentiated carcinoma (1/5), high-grade serous carcinoma (4.6%, 5/109), endometrioid carcinoma (7.7%, 2/26), clear cell carcinoma (1/9), mucinous carcinoma (1/5), mixed carcinoma (4.9%, 3/61), carcinosarcoma (1/9) and high-grade serous carcinoma of peritoneum (1/9), were negative.</p><p><b>CONCLUSIONS</b>SCCOHT is a rare malignant tumor and often misdiagnosed as other types of ovarian small cell tumor. Loss expression of SMARCA4 protein is characteristic and facilitates the diagnosis and differential diagnosis of SCCOHT.</p>

Relationship between Line 1 methylation and clinical data of non-small cell lung cancer / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To explore the impact of Line-1 methylation on clinical features of non-small cell lung cancer and its connection with smoking and other living habits.</p><p><b>METHODS</b>Pyrosequencing was used to determine the extent of Line-1 methylation in cancer and adjacent tissues derived from 197 patients with primary non-small cell lung cancer. Non-conditional logistic regression analysis was performed to correlate the level of Line-1 methylation with clinical features and living habits of the patients.</p><p><b>RESULTS</b>Line-1 methylation for cancer tissue and adjacent tissue has measured 68.20±11.63 and 78.90±2.09, respectively (P < 0.01), and has been associated with TNM staging, smoking history and histopathological types.</p><p><b>CONCLUSION</b>Lung cancer tissue Line-1 methylation level is closely related with clinical features and smoking. There is also a correlation between histopathological types of lung cancer and relative hypomethylation of Line-1.</p>

Evaluation of K-ras status concordance between primary colorectal cancer and related metastatic sites / 中国癌症杂志

Background and purpose:Metastatic colorectal cancer (mCRC) patients with K-ras mutation won’t benefit in the anti-epidermal growth factor receptor (EGFR) treatments. Thus K-ras mutation analysis is mandatory before this treatment. There is controversy that K-ras mutation analysis should be performed on primaries or related metastases. The aim of our study was to evaluate the concordance of K-ras status between primary and related metastases tumors, thus investigate the validity and rigorousness of clinical K-ras testing. Methods:Seventy-six patients with confirmed mCRC treated in Fudan University Shanghai Cancer Center were enrolled. After DNA extraction and PCR amplification, tumor specimens with paired primary tumors and related metastatic sites were put into sequencing analysis. And the K-ras mutation status in exon 2 was assessed. Results: K-ras mutation was detected in 31 out of 76 primary tumours (40.8%) and also 40.8%of the metastatic sites. But discordance was found between primary tumor and metastasis in 15 cases (19.7%):8 primary tumors had a K-ras mutation with a wild-type metastasis, meanwhile 7 primary tumors were wild type with a K-ras-mutated metastasis. Conclusion:Our study indicated that quite a few mCRC cases have different K-ras status between primary tumors and related metastatic sites, and it’s not very rigorous to choose the anti-EGFR treatments merely according to the primary tumor-K-ras mutation.Further study and consultation are needed on this problem.

Effects of CYP1A1 and GSTM1 gene polymorphisms and BPDE-DNA adducts on lung cancer / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To investigate the effect of CYP1A1 and GSTM1 genetic polymorphisms and BPDE-DNA adducts on lung tumorigenesis.</p><p><b>METHODS</b>The case control study has included 200 cases of lung cancer and 200 controls. DNA was extracted from blood samples of all subjects. The genotype of both CYP1A1 and GSTM1 were detected with PCR-based restriction fragment length polymorphisms (PCR-RELP). BPDE-DNA adducts were detected with competitive ELISA.</p><p><b>RESULTS</b>CYP1A1 mutant genotype and GSTM1 null genotype with smoke has increased the risk of lung cancer, with OR being 2.406(1.321-4.382), 2.755(1.470-5.163), respectively. The level of BPDE-DNA adducts in patients was greater than control, and the adduct level in ever smokers was higher than never smokers, the difference was statistically significant (P= 0.0252). GSTM1 null genotype individuals with BPDE-DNA level higher than 5 adducts/10(8) nucleotide have increased risk of lung cancer (OR= 1.988, 95%CI: 1.011-3.912). Compared with never smokers with CYP1A1 wild genotype, smokers with CYP1A1 mutation genotype had an increased risk of forming a higher level of DNA adducts (P= 0.0459). Smokers with GSTM1 null genotype formed more DNA adducts compared with never smokers with GSTM1 functional genotype (OR = 2.432, 95% CI: 1.072-4.517).</p><p><b>CONCLUSION</b>GSTM1 null genotype with higher level DNA adducts may increase the risk of lung cancer. DNA adducts form easier in smokers with CYP1A1 mutation genotype and GSTM1 null genotype, which in turn may influence lung tumorigenesis.</p>

Correlation between RARbeta gene promoter methylation and P53 gene mutations in non-small cell lung cancer / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To investigate the correlation between RARbeta gene promoter methylation and P53 gene mutations in non-small cell lung cancer (NSCLC).</p><p><b>METHODS</b>Promoter methylation of RARbeta and P53 mutations of exons 5 through 9 in 198 resected primary NSCLC tissues were determined by methylation-specific PCR and direct sequencing.</p><p><b>RESULTS</b>RARbeta gene promoter methylation and P53 mutation were detected in 58.1% and 36.4% of tumors, respectively. Both were higher in males than in females and in smokers than in nonsmokers. A higher prevalence of RARbeta promoter methylation was found in patients with advanced stage tumors than those with TNM stage I. P53 gene mutations were more frequent in squamous cell carcinoma and adeno-squamous carcinoma than adenocarcinoma. All such differences were statistically significant (P< 0.05). Frequencies of P53 mutations, including G:C>T:A mutations, transversions and missense mutations were significantly higher in tumors with RARbeta methylation than in those without (P< 0.05). A significantly higher prevalence of RARbeta methylation was found in tumors with only G:C>T:A mutation in P53 gene than those without P53 mutations (P< 0.05). This difference (OR=3.737, 95%CI: 1.414-9.873) was still statistically significant (P< 0.05) in smokers (OR=4.020, 95%CI: 1.263-12.800), squamous cell carcinomas (OR=5.480, 95%CI: 1.400-21.446) or patients with advanced tumors (OR=3.446, 95%CI: 1.054-11.267) after adjusting for age and sex.</p><p><b>CONCLUSION</b>RARbeta methylation is associated with G:C>T:A mutations in P53 gene in NSCLC.</p>

Relationship between promoter methylation of p16, DAPK and RAR beta genes and the clinical data of non-small cell lung cancer / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To investigate the effects of promoter methylation of p16, death-associated protein kinase (DAPK) and retinoic acid receptor-beta (RAR beta) genes on clinical data in non-small cell lung cancers, and to study the effect of smoking on the risk of gene methylation.</p><p><b>METHODS</b>The promoter methylation of p16, DAPK and RAR beta genes in 200 primary non-small cell lung cancers and the corresponding nonmalignant lung tissues were determined by methylation-specific PCR.</p><p><b>RESULTS</b>Methylation in the tumor tissues was detected in 51.0% for p16, 60.0% for DAPK, and 58.0% for RAR beta gene, with significant differences (P < 0.05) when compared with those in the corresponding nonmalignant tissues(12.5%, 11.5% and 15.0%) respectively. p16 gene methylation in tumor tissue was associated with age significantly in unconditional logistic regression analysis (P < 0.01) and histologic type (P < 0.05). DAPK gene methylation in tumor tissue was associated significantly with age (P < 0.05), gender (P < 0.05) and clinical type (P < 0.05). RAR beta gene methylation in tumor tissue was associated with clinical type (P < 0.05) and tumor stage (P < 0.05) significantly. The interaction odds ratio (OR) for the gene-gene interaction in tumor tissue between p16 and DAPK was 1.987 (95%CI:1.055-3.743). The results of the gene-smoking analyses revealed that a relationship existed between cigarette smoking and p16 gene methylation (OR = 3.139, 95%CI: 1.046-9.419), the OR for the relationship of DAPK gene methylation and cigarette smoking was 3.585(95%CI: 1.270-10.123) in tumor tissue. The RAR beta gene methylation did not differ based on the smoking status of patients in tumor tissue.</p><p><b>CONCLUSION</b>The p16, DAPK and RAR beta genes methylation are strongly associated with clinical data of non-small cell lung cancer, and methylation of p16 and DAPK genes are associated with tobacco smoking.</p>

Current progress in research on epigenetic effects of air pollution / 浙江大学学报·医学版

Air pollution is associated with numerous diseases. In recent years,researches have increasingly showed that epigenetic modifications usually occur at the early stage of diseases, and make greater contributions to the occurrence and development of diseases compared to genetic abnormalities. Thus, researches on epigenetic effects of air pollution would serve for better understanding the interaction between air pollutants and genome in the pathogenesis of disease. Meanwhile, in order to reduce the exposure to air pollution and diminish the adverse effects related, further studies are needed to identify epigenetic biomarkers of air pollution so that we can take timely and effective measures in disease prevention.

Study on the relationship between nitric oxide synthase gene G894T polymorphism and hypertension related risk factors in patients with essential hypertension in Chongqing city / 中华流行病学杂志

<p><b>OBJECTIVE</b>To explore the relationship between genetic anomaly and risk factors in hypertension, a polymorphism at position G894T of the gene encoding the endothelial nitric oxide synthase (eNOS) together with hypertension related risk factors were observed in patients with essential hypertension (EH) in Chongqing city.</p><p><b>METHODS</b>Two hundred and twenty-six patients with EH and matched controls were selected. Genotypes of polymorphisms were determined by polymerase chain reaction (PCR), while PCR products were digested by restriction endonuclease (BanII). Questionnaire referred to life style, dietary, smoking, alcohol consumption, psychological and mental state, waist-to-hip ratio (WHR), etc was administered.</p><p><b>RESULTS</b>There was no significant difference noticed in genotype distribution for the eNOS gene G894T genotype between hypertensive groups and controls, but difference was found among certain related risk factors, such as salt intake, snoring and WHR, etc. Logistic regression analysis showed no association between 894T allele and hypertension.</p><p><b>CONCLUSION</b>Although the polymorphism of eNOS gene G894T did not seem to play an important and direct role in the pathogenesis of EH it might have indirect effects through certain risk factors.</p>