bluuebunny/crossref_metadata_2025_split huggingface dataset:
A new PMS2 gene variant of unknown significance: How pathogenic is it?
Authors: Picanço-Albuquerque Clarissa Gondim , Bezerra Maria Júlia Barbosa , Silva Paulo Goberlanio de Barros , Sant'Ana Rosane Oliveira , Luciano Maria Claudia dos Santos , Silva-Fernandes Isabelle Joyce de Lima , Lima Marcos Venicio Alves 
Published: May 2020

e13532 Background: The Lynch syndrome (LS) is the most common inherited syndrome associated with colorectal cancer (CRC). The hallmark of LS is DNA mismatch repair deficiency. The amount of variants of uncertain significance (VUS) in suspected LS confounds diagnosis, requiring surveillance of variant reclassifications. In this paper we describe a new and most likely pathogenic VUS in PMS2. Methods: Patient screened for personal and familial cancer and evaluated with NGS gene panels for 31 genes. The protein structure was analyzed with the software Pymol. Results: A woman diagnosed with breast cancer (BC) at 60 years and CRC at 65 years was investigated due to her extensive family history of cancer (21 maternal relatives), including 6/9 siblings [gastric n = 1, lung n = 1, BC n = 4 (one of whom with BC, endometrium and CRC)], 8/12 aunts and uncles, all of whom died of cancer (gastric n = 4, CRC n = 1, CNS n = 1, BC n = 1; uterus/gallbladder n = 1), and 7 cousins (CNS n = 3, lung n = 1, gastric n = 2, suspected ovary n = 1). The new PMS2 gene variant c.134A > G(p.Asn45Ser), which was also detected in two sisters with CRC submitted to segregation analysis, occupied the same locus as a known pathogenic variant, c.134A > C(p.Asn45Thr). The structural analysis showed that the mutated locus encodes a serine instead of an asparagine in position 45 at the enzyme’s active site. Asn 45 is a conserved amino acid that binds to ATP in protein structure (PDB = 1EA6). Interestingly, this is close to position 42-44, for which another potentially pathogenic VUS (p.Leu42_Glu44del) has been described. Conclusions: Based on our patient’s personal and family history and on the locus variant and protein structure analysis, the new PMS2 gene variant described in this paper is most likely pathogenic.
The landscape of POLE variants in colorectal and endometrial tumors: Correlation with microsatellite instability (MSI) and tumor mutation burden (TMB).
Authors: Arora Sanjeevani , Xiu Joanne , Sohal Davendra , Lou Emil , Goldberg Richard M. , Weinberg Benjamin A. , Grothey Axel , Korn W. Michael , Khushman Mohd , Shields Anthony Frank , Marshall John , Hall Michael J. 
Published: May 2020

e13538 Background: Polymerase epsilon (POLE) is a major replicative DNA polymerase. Somatic POLE pathogenic variants (PV) are prevalent in endometrial cancer (EC) and in germline predispose to colorectal cancer (CRC), EC, and possibly other cancers (CA). PVs in the exonuclease domain (ExoD) [amino acid (AA) 268-471] lead to CAs with exceptionally high TMB. PV and uncertain variants (VUS) outside ExoD are sometimes concurrent with an ExoD PV and/or MSI. We hypothesized that the presence of non-ExoD variants may further increase POLE-associated mutation rate and tumor mutational burden. Methods: We retrospectively examined 1870 CRC and 4481 EC genomic profiles conducted by Caris Life Sciences (6/2016-6/2019). All patients had a 592-targeted gene somatic panel. Profiles with a POLE variant (PV or VUS) were analyzed. Median TMB (TMB, in mutations/megabase) was dichotomized to low/intermed ( < 17) vs high (>17). Tumors were grouped by: single ExoD PV, ExoD PV plus another variant (PV or VUS), or no ExoD PV. Known CRC/EC ExoD PV drivers were identified (Campbell et al, Cell 2017): D275G, P286R, S297F/Y, F367C/L/V, V411L, L424F, P436R/S/Y, M444K/L, A456P, S459F/Y, S461L/P, A465V. Kruskal-Wallis and chi-square tests were used. Results: Overall 4.5% CRC (80/1870) and 6.5% EC (303/4481) samples had POLE variants (Table). High TMB was seen in 56.3% CRC and 53.3% EC. In both CRC/ECs, TMB was higher in tumors with an ExoD PV and a 2nd variant compared to those with a solitary ExoD PV or no ExoD PV (both p < 0.001). MSI was more prevalent in CRC and EC with high TMB but no ExoD PV vs those with either high TMB and an ExoD PV, or low/intermed TMB and no ExoD PV (both p < 0.001). In both CRC/ECs, several ExoD PV associated with very high TMB when non-ExoD regions of POLE contained recurrent variant clusters: AA 1906 (TMB 225); AA 1826-7 (TMB 243); AA 1380-2 (TMB 229). Conclusions: In CRC/ECs, POLE ExoD PV and MSI appear to drive TMB in distinct and largely non-overlapping ways. Non-ExoD POLE variants may synergize with ExoD PVs to further increase mutation rates. [Table: see text]
HBV-human DNA integration in non-hepatic tumors.
Authors: Liu Lei , Liu Ming , Huang Tanxiao , Liao Wenting , Fu Mimi , Duan Jingxian , Chen Shifu 
Published: May 2020

e13544 Background: Hepatitis B virus (HBV) infection in hepatocytes may induce chronic liver damage, which further leads to hepatocellular carcinoma. HBV infection was also reported in other cell types including peripheral blood mononuclear cells (PBMCs). Moreover, epidemiological evidence suggested that HBV infection was associated with various types of cancers. In this study, we investigated whether HBV DNA integration was observed in extrahepatic tumor cells. Methods: The study enrolled thousands of Chinese patients with different types of cancers. Peripheral blood and tumor tissue samples were collected, plasma cfDNA, PBMC gDNA and tumor tissue DNA were extracted. By targeted capture and next-generation sequencing, we sequenced the cancer-related genes and identified HBV DNA integration events in these samples. Moreover, the subtype of HBV captured in the host genome was verified, and the ratio of reads mapped to the HBV genome was calculated. Results: Samples with more than 0.1% of the sequencing reads mapped to the HBV genome were identified as HBV positive cases. Thirty-two liver cancer patients were subtype-b HBV positive, among which 8 tumor samples exhibited HBV genome integration. Three colorectal cancer patients were infected by subtype-c HBV, only one tumor sample carried HBV DNA integration. Two lung cancer patients were shown to be HBV positive; one was infected by subtype-b HBV and the other carried subtype-c HBV. Subtype-b and-c HBV genome was observed in the tumor sample of two cholangiocarcinoma patients, whereas subtype-b HBV DNA was identified in the PBMC of one gastrointestinal stromal cancer patient. Conclusions: HBV genome integration was identified in the tumor cells of lung, colorectal, biliary ducts, and gastrointestinal stromal cancer. The mechanisms by which the HBV genome integrates into these tissues requires further investigation.
Community-based practice of early lung cancer screening with low-dose spiral computed tomography in Jiaxing city from Zhejiang Province.
Authors: Zhu You-cai , Wang Wen xian , Xu Chunwei , Lan Gang , Chen Huafei , Li Xiaofeng , Zhai Zhanqiang , Huang Lichao , Du Kaiqi , Fang Meiyu 
Published: May 2020

e13557 Background: As one of the most frequent malignant tumors in China, the morbidity and mortality of lung cancer remain high. Early diagnosis and normative treatment is the key to improve the prognosis of lung cancer. The aim of this study is to explore the practice of early lung cancer screening with low-dose spiral computed tomography (CT) based on the current situation in community health service, with integration of superior resources of medical institutions at all levels in Jiaxing City from Zhejiang Province. Methods: From Jan. 2017 to Dec. 2019, we screened 13491 (male 8783, female 4708) individuals high-risk population in selected communities of Nanhu District, Pinghu County and Haiyan County, Zhejiang Province, for early diagnosis of lung cancer with low-dose spiral CT combined with multidisciplinary comprehensive treatment models including minimally invasive surgery, exploring the medical service network covering prevention, diagnosis, treatment, rehabilitation and follow-up. Results: Screening resulted in a diagnosis of cancer in 27 participants. Of these participants, 24 cases of primary lung cancer, 1 case of lung metastasis, 1 case of breast cancer, 1 case of thyroid cancer. The morbidity of primary lung cancer is 224.53×10-5. There were 20 cases of Stage 0-Ⅰlung cancer accounting for 83.33% of all diagnosed primary lung cancer. Conclusions: Based on community health service, screening with LDCT could improve the early diagnosis rate of lung cancer in both smokers and nonsmokers with feasibility and validity, which could be applicable in qualified eligible medical centers and communities in China. It is not reasonable to exclude nonsmokers from screening with LDCT.
Proteomic screening of saturated fatty acid-induced hepatocytes-derived exosomes.
Authors: Liu Yi-Ting , Huang Jee-Fu , Yu Ming-Lung , Wang Shu-Chi 
Published: May 2020

e13568 Background: Most countries continuously westernize and industrialize, the prevalence of NAFLD is expected to increase, which will greatly increase social and economic burden. Meanwhile, the trend that NAFLD acts as a main stream of liver diseases will be much emphasized with the eradication and/or effective control of viral hepatitis in the future. There are many studies indicated that lipotoxicity of hepatocyte plays an important role in the inflammation and hepatic injury during the progression of liver steatohepatitis and HCC. However, the extracellular vesicles (EVs) participate in intercellular signaling, tissue injury and repair, and matrix remodeling still unclear. Methods: In this research, we used hepatitis liver cells (Huh 7.5.1 and Hep-G2) and LX-2 cell lines (liver stellate cells, HSCs) with palmitic acid (PA) to study the cell inflammation/fibrosis response and exosome contents. Results: The Oil red lipid droplet cell stain result found the liver cells has produced higher fatty oil droplet than HSCs cells in the same PA dose. However, the inflammation cytokines (IL-6, TNF-α, and IL-1β) and fibrosis-related protein (α-SMA and COL1A1) only significant increasing in HSCs cells but not in liver cells after the PA treatment. Isolation of exosomes from PA-treated hepatocytes presenting the same effect on the activation of HSCs, which lead to significant expression of fibrosis markerα-SMA and COL1A1. Based on the finding, we further analyzed the exosomes from PA-treated hepatocytes by LC-MS analysis and found 6 proteins (CFHR-4, A2M, HBG, APOB, IG, DCTN1) presenting compare to un-treated liver cells. Conclusions: This study provide the released Hep-EVs have important roles in hepatocyte-to-HSC communication.
Highly accurate NGS-based multi-gene testing in the diagnosis of thyroid nodules with indeterminate cytology.
Authors: Song Yuntao , Zhang Bin , Ma Tonghui 
Published: May 2020

e13579 Background: Thyroid nodules are highly prevalent, Fine-needle aspiration (FNA) is the standard pre-operative tool for diagnosis. However, some of the samples are classified as indeterminate, which leads to unnecessary surgery. BRAF V600E mutation is often used as a diagnostic marker for thyroid cancer, and it is highly specific for papillary thyroid carcinoma (PTC). But BRAF mutation is rarely occurred in thyroid nodules with indeterminate cytology. To diagnose the indeterminate thyroid nodules precisely, some NGS-based multi-gene testing panel has been developed and clinically used in America and Europe, but rare research was reported in China. In this study, we evaluated the value of a next-generation sequencing (NGS) panel to cancer diagnosis in indeterminate thyroid nodules. Methods: From February 2018 to September 2018, 360 patients with thyroid nodules who underwent FNA at Peking University Cancer Hospital were enrolled. And the FNA samples with indeterminate cytology were evaluated using a next-generation sequencing (NGS) assay, including 16 genes analyzed for point mutations and 26 types of gene fusions. Diagnostic performance of this multi-gene testing panel was compared with BRAF V600E single gene mutation analysis. Results: 141 nodules were cytologically indeterminate among 360 patients on FNA biopsy, 72 of which were resected and analyzed by NGS successfully. Histologic analysis after surgery revealed 41 (56.9%) cancers in these 72 patients. The multi-gene testing assay could classify 30/41 cancers correctly, showing a sensitivity of 73.2%, specificity of 96.8%, positive predictive value of 96.8%, and negative predictive value of 73.2%. The diagnostic accuracy of the multi-gene testing was significantly higher than the BRAF V600E mutation analysis (83.3% vs 73.6%, x2= 31.588, p < 0.01). Conclusions: Our study demonstrated that the multi-gene testing provided both high sensitivity and high specificity for cancer detection in thyroid nodules with indeterminate cytology, and its accuracy was much higher than BRAF V600E mutation test.
Overview of obesity and breast cancer in Brazil: 24 year of follow up.
Authors: Pereira Andrea Z , Pitito Bianca de Almeida , do Prado Rogério Ruscitto , Mattar Andre , Hegg Roberto , Shida Jorge Yoshinori , Gebrim Luiz Henrique 
Published: May 2020

e13580 Background: Obesity is one of the major public health challenges of the 21st century. The prevalence of obesity is growing exponentially across all age groups and on all continents and it is associated with morbidities such as cardiovascular disease, diabetes mellitus type 2, dyslipidemia, hypertension and cancer. There is a higher risk of developing breast cancer in postmenopausal obese women, and with worse outcome for women of all ages. Objectives: To evaluate obesity prevalence in breast cancer patients and its association with recovering, survival, death, age, Human Epidermal Growth Factor Receptor 2 (HER2) and anti-human KI67 antibody(KI67). Methods: A retrospective cohort study was performed between 1994 and 2018 at the Breast Cancer Department, São Paulo State Government Women's Health Reference Center (Perola Byington Hospital), São Paulo, Brazil with 8824 breast cancer patients. From those, 2899 patients were excluded because they did not have description of weight and/or Body Mass Index (BMI). Survival analysis was performed according to BMI groups. Results: The participants had mean (SD) age of 54 (12.0) years and weight of 70 (15.0) kg. There were 769 (13%) deaths and the mean survival was 20 (2.0) years. 1787 (30%) participants were stratified in obese (BMI≥30Kg/m2) and 4138 (70%) non-obese Obese were older (p < 0,001) and had a higher frequency of HER2 negative (p < 0,04) than non-obese women. There were not a significant difference in frequencies of KI67, recovering and survival between groups. The prevalence of obesity was not different over 24 years. Conclusions: There was a relevant prevalence of obesity in breast cancer patients, which was associated with HER2 negative and age, but not with recovering or survival.
A nomogram to predict the probability of breast intraductal tumors in patients with nipple discharge: A report based on our 13-year clinical experience.
Authors: Jiang Siyuan , Wang Bin , Zhu Lizhe , Yu Shibo , Ren Yu 
Published: May 2020

e13582 Background: Nipple discharge is a common symptom of breast disease. Our aim was to perform a descriptive statistical analysis of the cases we collected and to establish a model to predict intraductal tumors. Methods: We conducted a retrospective study of patients from 2007 to 2019. The variables were analyzed by the c2 test. Univariate binary logistic regression was used to analyze the relationship between clinical features of patients. Receiver operating characteristics (ROC) were used to assess the sensitivity and specificity of the predictive ability of the model. Results: Patients with spontaneous, single duct, bloody discharge and smooth ductal wall were more likely to diagnose with tumor by ductoscopy. A model was established based on seven variables: age, side of discharge, spontaneous or not, duration of discharge, ductal wall and characteristics of discharge. It was subsequently validated in 178 patients with complete data on variables in the validation cohort. The area under ROC curve (AUC) were calculated to be 0.7024 indicating a good predictive ability. Conclusions: Patients with clinical characteristics of unilateral, bloody, single duct, spontaneous discharge and smooth ductal wall were more likely to have intraductal tumors by ductoscopy. Our nomogram can effectively predict intraductal tumors in patients with nipple discharge.
Statin use is associated with a lower risk of diffuse large B-cell lymphoma: A systematic review and meta-analysis.
Authors: Ponvilawan Ben , Charoenngam Nipith , Ungprasert Patompong 
Published: May 2020

e13585 Background: Statin use is associated with decreased risk of several types of cancer such as hepatocellular carcinoma, colorectal cancer and hematologic malignancy, although the data on diffuse large B-cell lymphoma (DLBCL) is still inconclusive. The current systematic review and meta-analysis was conducted to summarize all available data on this association. Methods: A systematic review was performed using EMBASE and MEDLINE database from inception to October 2019 with search strategy that included terms for “statin” and “DLBCL”. Eligible studies could be either cohort or case-control studies that reported the association between statin use and risk of DLBCL. Eligible cohort studies must include patients with history of statin use and comparators with no history of statin use, then follow them for incident DLBCL and report the relative risk, hazard risk ratio, or standardized incidence ratio and associated 95% confidence intervals (CI) comparing the incidence of DLBCL between the two groups. Eligible case-control studies must include cases with DLBCL and controls without DLBCL, then search for prior statin use and report the odds ratio and associated 95% CI for this association. Point estimates along with standard errors were extracted and combined together for the calculation of the pooled effect estimate using the random effect, generic inverse variance method. Results: A total of 1,139 articles were identified using the search strategy. Six studies satisfied the inclusion criteria and were included into the meta-analysis. Statin use was associated with a significantly reduced risk of DLBCL with the pooled relative risk of 0.70 (95% CI, 0.56 – 0.88; I2 = 70%). Funnel plot was fairly symmetric and was not suggestive of presence of publication bias. Conclusions: This systematic review and meta-analysis found that patients with history of statin use had a significantly lower risk of DLBCL compared to individuals without history of statin use.
The contribution of hereditary cancer-related germline mutations to lung cancer susceptibility.
Authors: Song Lele , Liu Mengyuan , Liu Xinyi , Peisu Suo , Huang Tanxiao , Chen Yaru , Zhou Yanqing , Liu Guifeng , Yao Jianfei , Chen Shifu , Xu Mingyan 
Published: May 2020

e13594 Background: Germline variations may contribute to lung cancer susceptibility besides environmental factors. The susceptibility of germline mutations and their correlation with somatic mutations has not been systematically investigated in lung cancer patients. Methods: Germline mutations from 1090 lung cancer patients were analyzed with a 58-gene NGS panel containing known hereditary cancer-related genes, and were categorized based on ACMG guidelines in pathogenicity, and the corresponding somatic mutations were analyzed using a 605-gene NGS panel containing known cancer-related genes. Results: Genetic susceptibility was found in 4.5% of lung cancer patients, in which 14 patients with pathogenic mutations and 35 patients with likely-pathogenic mutations were identified. Significantly stronger family history was found with the pathogenic group than other groups. Pathogenic mutations fell most commonly in BRCA2 (6/14), followed by CHEK2 (3/14) and ATM (2/14). Likely-pathogenic mutations fell most commonly in NTRK1 mutations (4/35) and EXT2 mutations (4/35), followed by BRIP1 (3/35) and PALB2 (3/35). These genes are involved in DNA repair (BRCA1 and BRCA2, BLM, RAD50, BRIP1, MLH3), cell cycle regulation (such as CHEK2, ATM, NTRK1 and EPCAM) and tumor suppressor (such as PALB2). The overall odds ratio (OR) value of the pathogenic group was 17.93 (95% CI: 9.74 to 33.01), and was 15.86 (95% CI: 5.999 to 133.2) for the likely-pathogenic group, suggesting that the pathogenic or the likely-pathogenic germline mutations as a whole were risk factors for lung cancer. Somatic mutation analysis revealed no significant difference in TMB among the groups, although a trend of lower TMB in the pathogenic group was found. The SNV/INDEL mutation rate of TP53 in the pathogenic group was significantly lower. Pathway enrichment analysis found no significant difference in aberrant pathways among the groups. Conclusions: 4.5% of patients carrying germline variants may be linked to increased susceptibility to lung cancer. The susceptibility is mainly reflected in family history and morbidity risk without significant influence on aberrant pathways.
Marital status and survival analysis of patients with pure mucinous breast carcinoma: A SEER population-based retrospective study.
Authors: Tang Fan , Wei Xiaoqing , Dian Li ping , Zhou Qu zhi , Xu Rui , Ren Liping , Zhang Yuzhu , Chen Qianjun 
Published: May 2020

e13598 Background: The present study was conducted to investigate the influence of marital status on survival of pure mucinous breast carcinoma(PMBC) based on surveillance, epidemiology, and end results (SEER) databases. Methods: Data were extracted from the SEER database on eligible patients diagnosed with pure mucinous breast carcinoma between 1998 and 2015. Patients were divided into married groups (including common law) and not married groups (including single[never married]/unmarried or domestic Partner、Divorced、Separated、Widowed). Survival curves were generated using the kaplan-meier method, and survival differences were estimated using the log-rank test. Multivariate Cox proportional risk models were used to assess independent risk factors for survival. Results: A total of 14972 eligible pure mucinous breast carcinoma patients were enrolled from the SEER database, including 7462(49.84%) married and 7510(50.16%) not married patients. The OS and CSS were significantly greater in married patients than not married patients (79.27 vs 62.49% for OS and 96.07 vs 93.34% for CSS, both P =0.000). Married patients were more likely to be more younger (aged≥75) (21.5% vs. 44.1%), cancer stage were even lower(stage I)(69.6% vs. 62.6%), (stage II)(28.6% vs. 33.9%), (stage III)(0.6% vs. 0.9%), (stage IV)(1.3% vs. 2.5%), more patients received breast conserving surgery(67.4% vs. 62.9%), chemotherapy(15.3% vs. 11.0%) and radiation therapy(54.3% vs. 43.1%), also no recurrent lymph node metastasis was observed(82.8% vs. 74.6%) compared to unmarried group(All P =0.000). The multivariate Cox proportional hazards model showed that marriage is an independent protective factor for OS (HR = 1.356, 95% CI: 1.271-1.446, P =0.000) and CSS (HR = 1.942, 95% CI: 1.681–2.644, P =0.000). Conclusions: Marital status was an independent prognostic indicator in PMBC patients. Research data showed that married pure mucinous breast carcinoma patients can obtain better OS and CSS than unmarried patients.