bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genomic characterization of sub-centimeter pulmonary nodules.
Authors: Peng Muyun , Xing Guanlan , Zhang Bingyu , Xu Yaping , Yu Fenglei 
Published: May 2020

e13530 Background: There has been a dramatic increase in the detection of indeterminate pulmonary nodules (IPNs), many of which are 10 mm or less in diameter. The management of subcentimeter pulmonary nodules remains controversial. Deciphering the genomic landscape of subcentimeter pulmonary nodules will provide critical insights to the mechanisms of carcinogenesis and pave the way for the early prevention and interception of lung cancer. Methods: We subjected 439 IPN samples including 249 subcentimeter pulmonary nodules (≤10 mm in diameter) and 190 larger pulmonary nodules (>10 and ≤30mm in diameter) to deep next generation sequencing by using customized panels of 1021 genes. Clinical parameters of these IPNs were collected. The genomic landscape of subcentimeter pulmonary nodules and differences from that of larger pulmonary nodules were defined. Results: The proportions of atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and invasive adenocarcinoma (ADC) in the subcentimeter group and the larger nodule group were 2.81% vs 0.00%, 13.25% vs 0.80%, 28.92% vs 4.82% and 55.02% vs 70.68%, respectively. The most commonly mutated genes in subcentimeter group were in EGFR, ERBB2, BRAF, MED12 and MAP2K1. Compared with the larger nodule group, the subcentimeter nodule group had lower TMB ( p< 0.0001), lower mutation frequencies in EGFR, TP53, RBM10, and SMARCA4 ( p< 0.05), but higher mutation frequencies in ERBB2, BRAF, MAP2K1, and TSC1 ( p< 0.05). In the subset of ADC, the subcentimeter nodule group had lower TMB ( p< 0.0001), lower mutation frequencies in EGFR, TP53, RBM10, and PIK3CA ( p< 0.05), but higher mutation frequencies in ERBB2, BRAF ( p< 0.05). Clonal index analysis of driver genes in lung adenocarcinoma showed that the larger nodule group had more driver mutations, but the clonality index of BRAF was higher in the subcentimeter group ( p= 0.0014). Furthermore, in the subcentimeter nodule group, the mutation frequency of BRAF was significantly higher in pre-invasive group (AAH/AIS) than that in the invasive group (IAC). And BRAF and EGFR were significantly mutually exclusive ( q< 0.001) in subcentimeter nodules, which showed the subgroup with BRAF mutations was a special subtype. Conclusions: Our results provided the distinct mutation pattern of subcentimeter nodules and showed that BRAF could play different roles in early phase of lung carcinogenesis. It would be helpful for understanding the genomic evolution mechanisms underlying the progression and invasiveness of early lung adenocarcinoma.
Expression profile and co-expression analysis of ADH1A in human solid tumors.
Authors: Huang Wenqi , Yang Mi , Wu Xixi , Yuan Lu , Wu Yuting , Hwang Jihong , Guan Jian , Liu Laiyu 
Published: May 2020

e13533 Background: The human alcohol dehydrogenase (ADH) gene family is associated with various solid cancers. It seems that the ADH1 gene cluster plays an important role in various solid tumors, so it aroused our interest in studying these genes to find out their functions and biological process within different solid tumors. Methods: Paired tumor and normal tissues gathered from 38 tumor patients, and 5 male BALB/c mice tissues were collected and Immunohistochemistry (IHC) assay was performed. The expression of ADH1A at RNA level in normal tissues and pan-solid tumors and the main functions of ADH1A in different solid tumors were analyzed by Bioinformatics mining. Results: At the RNA level, ADH1A was highly expressed in normal hepatocytes and was expressed lower in the tumor tissues than in the adjacent normal tissues or the corresponding normal tissues, suggesting the At the protein level, ADH1A was expressed to varying degrees in human alveoli, kidney, stomach, colon, and rectum. We predicted three major conserved functions of ADH1A, including angiogenesis, cell adhesion, and leukocyte migration function which might influence the prognosis of the immunotherapy and the immune response, and constructed an upstream regulation network of ADH1A and a downstream protein network. Besides, we also explored the functional differences of ADH1A in lung adenocarcinoma and lung squamous cell carcinoma and its effect on overall survival. And for investigating ADH1A, the BALB/c mice might be an option to consider in constructing an animal model of gastric cancer (GC), esophageal carcinoma (ESCA), liver hepatocellular carcinoma (LIHC), and pancreatic adenocarcinoma (PAAD). Conclusions: ADH1A has potential diagnostic and prognostic value in various solid tumors. Our findings highlight new avenues for further investigation of ADH1A biology process and provide a novel potential prognostic biomarker of immunotherapy.
Enrichment of circulating tumor DNA from cell-free DNA of hematopoietic origin.
Authors: Terrell Jason , Van den Ackerveken Priscilla , Lobbens Alison , Eccleston Mark , Hannart Clotilde , Deglasse Jean-Philippe , Turatsinze Jean-Valery , Herzog Marielle , Micallef Jake 
Published: May 2020

e13534 Background: In liquid biopsy, circulating tumor DNA (ctDNA) is more fragmented than background cell free DNA, peaking at 147bp (equivalent to a mono-nucleosome) instead of 165bp (nucleosome with an additional 20bp of linker DNA). Isolation of these shorter cell free DNA fragments from longer, extracted cell-free DNA improves detection of ctDNA as demonstrated by enrichment of tumor specific mutations. Nuclease protection of the additional 20bp of linker DNA, conferred by bound linker proteins such as Histone 1, would account for the 165bp peak in host background DNA. We hypothesised that extracting intact nucleosomes with linker DNA using a novel, H1 antigen based, immunocapture approach would enrich the ctDNA fraction in the remaining nucleosomes. Methods: We expressed H1.0 protein in E. coli and following extraction, purification and chemically immobilised it to tosyl-activated magnetic beads. The beads were first used to immunodeplete mono-nucleosomes from HeLa cell digests and the level of immunocaptured nucleosomes was determined by immunoassay targeting intact nucleosomes. The level of nucleosome levels determined before and after depletion was further determined by ELISA targeting H3.1 containing intact nucleosomes. DNA was extracted from the H1 immunocaptured “long” nucleosomes and size profiles compared with the remaining nucleosomes in the supernatant by BioAnalyzer. Then, the method was applied to clinical plasma samples and the size distribution of NGS Libraries (Illumina system) prepared from five colorectal cancer and three healthy samples, their immune depleted supernatants and the immunocaptured nucleosomes were then compared. Enrichment of specific genomic regions was also evaluated. Results: We observed relative enrichment of nucleosomes with short DNA in supernatants following H1 immuno-depletion of the cancer samples as evidenced by a change in size distribution by Bioanalyzer and NGS-sequencing. We also observed potential enrichment of TSS is the H1 immunocaptured nucleosomes consistent with linker DNA positioning of TF binding sites. Conclusions: Histone 1.0 has the highest affinity of H1 mammalian isoforms and successfully immunodepleted plasma samples containing cell free circulating nucleosomes with DNA longer that 147bp. Immobilized H1.0 effectively formed a pseudo-chromatosome by binding to free linker DNA or displacing endogenous H1 and other linker associated proteins. H1 antigen based immuno-depletion offers a simple way to enrich tumour derived nucleosomes and thus cell free DNA.
A discrete choice experiment (DCE) study evaluating preferences of Asian adults for inherited cancer risk testing.
Authors: Tay Ru Jin , Zhao Pan , Chen Hao , Tan Min-Han , Chong Josephine Shuk Ching 
Published: May 2020

e13550 Background: Inherited cancer genetic testing (CGT) is increasingly recommended in a wide range of settings to better evaluate and manage personal and/or family cancer risks. For individuals at risk, identification of monogenic risk factors by inherited CGT allows more appropriate advice, surveillance and targeted prevention. For cancer patients, inherited CGT provides guidance for the selection of targeted therapy treatment options. Little is known about the views of non-Western global communities, which can impact cancer prevention. We designed a DCE study to evaluate four key attributes to better target educational and policy interventions in an urban Asian community. Methods: We recruited healthy adults in the community aged between 21-60 in Singapore. Participants received basic information about cancer and cancer genetic testing, then completed a 16-task DCE survey that examined preferences for four attributes of cancer genetic testing for targeted prevention including: accuracy, waiting time for result, out-of-pocket cost and insurance claims. A conditional logit regression model was used to examine the main effect parameter, assuming all attributes have an independent influence on the participants’ preferences. Results: 93 adults were enrolled (71% female, 29% male). Attributes influencing decision to undergo inherited CGT in decreasing order of concern were accuracy (37%), out-of-pocket costs (22%), insurance claim (21%) and waiting time for result (20%). Increased out-of-pocket cost reduces the likelihood of people to go for testing (coef: -6.579e−04, p < 0.01). The impact of financial cost is less important for participants with increased monthly household income (coef: 1.791e−04, p < 0.01). Conclusions: With inherited cancer genetic testing becoming more common and relevant in terms of personal and/or family risk managements and guiding treatment options, this DCE study is helpful to guide clinicians tailor of individualized genetic counseling for non-Western communities, who may have different concerns from Western populations. Targeted policy intervention and education on these concerns may lead to greater accessibility for inherited CGT.
DNA methylation profile in unknown cancer origin identification: A multi-class classification model.
Authors: Yu Jianing , Hong Yuanyuan , Zhihua Pei , Han Tiancheng , Xiaofeng Song , Song Xue , Xiaoqing Wang , Zhuo Zhang , Chen Weizhi , He Ji ,   Too
Published: May 2020

e13554 Background: Approximately 3-5% of human cancers are cancer of unknown primary (CUP). Treatment of a cancer patient is largely dependent on the tumor origin. Therefore, identification of the tumor origin can improve the survival of patients with CUP. We developed a multi-class classification model using DNA methylation profile as biomarker to determine the primary site of CUP. Methods: We split 7,082 primary tumor samples of 19 cancers and 679 normal samples of 15 tissues from TCGA into a 75% training set and a 25% testing set to develop the classification model. We started with multiple support vector machine (SVM) models, and then combined them into an optimal multi-class ensemble model. Predictors included tumor-specific markers and tissue-specific markers, which were filtered by comparing between groups. Only the training samples were used for feature selection and model development. A validation dataset consisting of 150 primary tissues, 54 metastasis tissues, 105 plasma samples with known cancer site origins from 12 classes was generated in house by a self-designed panel. Performance was measured by area under the curve (AUC) using the one-vs-all approach. Results: 7,453 tumor-specific and 1,533 tissue-specific markers were selected for model construction. AUCs of all cancer types were high in TCGA training and testing set (AUC≥0.96 for all classes). In our validation tissues, esophageal cancer, pancreatic cancer, colorectal cancer, lung adenocarcinoma, breast cancer and liver cancer achieved high AUC in both primary (0.83, 0.83, 0.82, 0.82, 0.80 and 0.79 respectively) and metastasis (0.74, 0.92, 0.86, 0.61, 0.92 and 0.65 respectively). Lung adenocarcinoma, colorectal cancer, liver cancer, breast cancer and esophageal cancer even achieved high AUC in the plasmas. Conclusions: Performance of our model in tissue and plasma samples indicated the potential clinical application of DNA methylation profile in unknown cancer origin identification.
Early cancer detection using multi-omic approach including epigenetic signal from ultra-small fragments.
Authors: Wu Johnny , Li Xin-Xing , Zhou Huabang , Liu Wendi , Wang Fenfen , Yao Qianqian , Lu Dongsheng , Lu Huiqi , Wang Hongyan , Wittkop Tobias , Tang Paul , Hu Heping , Cheng Xiaodong , Hu Zhiqian , Faham Malek , Weng Li 
Published: May 2020

e13561 Background: Genetic and epigenetic signals from plasma cell-free DNA (cfDNA) as well as proteins have been shown to detect cancer early. We have previously developed Circular Ligation and Amplification (CLAmp-seq) to detect mutations very sensitively and demonstrated higher performance than molecular barcode-based methods. The same single strand based technology yielded a much larger proportion of small fragments ( < 100 bp) than traditional methods typically relying on double stranded ligation, allowing us to investigate epigenetic signature of cancer in ultra-short fragments. We sought to measure the performance using a multi-omics approach of these genetic and epigenetic changes as well as proteins in detecting colorectal cancer (CRC), ovarian cancer (OC) and hepatocellular carcinoma (HCC). Methods: A healthy and a late stage cancer sample were assessed by whole genome sequencing (WGS) using CLAmp-seq. Then we analyzed cfDNA from plasma samples of 731 patients, including 69 CRC, 57 HCC, 49 OC patients and 556 age-matched healthy individuals. Out of the diseased samples, the numbers for stages I-IV are 49, 39, 71, and 16, respectively. CLAmp-seq WGS was performed on 58 healthy and 66 cancer samples to discover cancer epigenetic signature. In addition, all the samples were analyzed for a panel of proteins and a CLAmp-seq targeted panel that includes known mutation sites. Results: Using CLAmp-Seq in late stage cancer showed 33% of its fragments as smaller than 100 bp compared to 15% in healthy and < 1% in late stage by double stranded library prep. In addition, the difference in fragment size between late stage cancer and healthy was 29bp using CLAmp-Seq and 12bp using traditional double stranded prep. This focused our attention to detect epigenetic signature specific to cancer on the small fragments using CLAmp-Seq. Using data from whole genome analysis we demonstrated a performance using the epigenetic signature alone of 50% sensitivity at 97% specificity. Combined with mutations and proteins, we obtained at specificity of 97% sensitivities of 50%, 88%, 88%, and 100% in stage I, II, III, and IV, respectively. At the same 97% specificity we obtained the sensitivities of 73%, 100%, and 85% in CRC, OC, and HCC, respectively. Conclusions: We have demonstrated that CLAmp-Seq detects small fragments that are enriched in cancer. We have found predictive epigenetic signature in these small fragments. When combined with mutations and proteins we obtained a performance of 80% sensitivity at 97% specificity.
Mammographic screening and socio-epidemiological profile of Amerindian riverside women in the Amazon forest.
Authors: Chaves Juliana Ramos , Zemero Maria Isabel , dos Reis Matheus Dinelly Ribeiro , Puty Taynah Cascaes , Fernandes Bruno Melo , Martins Junior Rodnei Jose Macambira , Lima Lorena Lira Tavares dos Santos de , Werneck De Carvalho Luis Eduardo 
Published: May 2020

e13573 Background: Breast cancer still represents the most common tumor among women in the world and in Brazil. Screening coverage in Brazil is much lower than what is recommended by the World Health Organization (WHO), which makes it difficult to perform an early diagnosis. Thus, the current work aims to carry out mammographic screening and the socio-epidemiological profile of Amerindian riverside women in the Amazon region. Methods: This study is characterized as sectional and the sample consists of 260 female patients, living riverside, from the communities of the Amazon Forest, Xingu and Tapajos rivers, interviewed after the mammography screening in a task force promoted by the Brazilian Navy. Results: The median patients age was 49 years (p25-75: 45-58), menarche was around 13 years (p25-75: 12-14), menopause was 48 years (p25-75: 43-50) and the median of pregnancies was four (p25-75: 2-6). Most patients were classified as BIRADS 1 (41.32%), 4 of the 8 suspected and highly suspected cases were confirmed as breast cancer, and these patients had no complaints (82.98%), did not use therapy hormonal (97.15%), and did not use oral contraceptives (60.57%) and breastfed during pregnancy (97.52%). Conclusions: There is a high prevalence of protective factors against cancer, related to lifestyle and local culture. However, these communities have minimal access to health services, which demonstrates actual need of public policies to assist Amerindian riverside women, in order to promote better health care and, thus, reduce one of the most prevalent diseases in the Amazon region. [Table: see text]
Subsequent pregnancy and long-term safety from breast cancer patients.
Authors: Kim Yunyeong , Kang Minsun , Jung Jaehun , Cho Eun Kyung , Park Heung Kyu , Chun Yong-Soon 
Published: May 2020

e13575 Background: Long-term safety of pregnancy after breast cancer still remained controversial, especially according to tumor subtypes. Prior results of other studies have limitations of short follow-up periods or small groups. Methods: We analyzed a population-based retrospective cohort data extracted from a random sample of 50% of women aged between 20 and 60 years who were diagnosed with breast cancer from 2002 to 2017 in the Korean National Health Insurance Service database. Propensity score matching analysis for age and Charlson Comorbidity Index (CCI) variables was performed for pregnant groups and non-pregnant groups with the same type of hormone therapy, chemotherapy and surgery. Study population was categorized to 4 biologic subgroups by the combination of hormone therapy, chemotherapy and target therapy. In this observational study, 1,566 patients with pregnancy after breast cancer were matched (1:2) to 2,462 non-pregnant patients of similar characteristics, adjusting for guaranteed bias. The matched patients were followed up to 7 years, or disease and mortality occurrence after the diagnosis of breast cancer. Survival estimates were calculated using the Kaplan-Meier analysis, groups were compared with the log-rank test. Results: Mean time from diagnosis to pregnancy was 3.4 years in study population. At a follow-up of 7 years after pregnancy, no inferiority in disease-free survival and overall survival was observed in pregnant patients factoring in treatment bias. In sub-analysis according to tumor subtypes, no difference in disease-free survival was observed between pregnant and non-pregnant patients in HR-positive and triple negative subgroup ( p= 0.088, p= 0.048, respectively). Likewise, no overall survival difference was observed in ER-positive patients and triple negative patients ( p= 0.05∼0.73, p= 0.03∼0.09, respectively). Conclusions: Our observational data provides reassuring evidence on long-term safety of pregnancy in young breast cancer patients, regardless of tumor subtypes.
The relationship between leptin, leptin receptor, and FGFR1 in primary human breast tumors.
Authors: Shoemaker Wyatt , Paithankar Shreya , Benham Vanessa , Chen Bin , Bernard Jamie 
Published: May 2020

e13578 Background: General/overall obesity and visceral/central obesity are associated with increased breast cancer risk and poorer cancer outcomes; however, the precise etiology of these observations is not fully known. Our previous research suggests that adipose tissue-derived fibroblast growth factor 2 (FGF2) promotes malignant transformation of mammary epithelial cells through the activation of its primary receptor, fibroblast growth factor receptor 1 (FGFR1). Both FGF2 and leptin have been shown to be elevated in the serum in obesity (body mass index (BMI) > 25kg/m2). It is well established that elevated sera leptin promotes breast cancer through multiple mechanisms. Therefore, we hypothesized that tumors that express elevated FGFR1 and leptin receptor (LepR) may have a poorer prognosis in obese patients. Methods: Databases that house gene-sequenced breast cancer tumors and normal breast tissue were analyzed to discern relationships between gene copy number and mRNA levels of leptin, leptin receptor, FGFR1 and janus kinase 2 (Jak2), as Jak2 was shown to be a common downstream mediator of both FGFR1 and leptin receptor activation by Cytoscape network analysis. Furthermore, we tested the efficacy of Jak2 inhibitors for preventing mammary epithelial cell malignant transformation using our well-established models of adipose tissue-stimulated growth in soft agar. The anchorage-independent growth in soft agar is a surrogate marker for malignant transformation. Results: A much stronger significant relationship exists between FGFR1 mRNA and leptin mRNA in primary breast cancer (p = 3.17*10−9) compared with normal breast epithelium (p = 0.0013). In primary breast tumors, gene copy number of FGFR1 positively correlates with leptin copy number (p = 8.956*10−8, r = 0.19). Moreover, two separate Jak2 inhibitors attenuated both leptin+FGF2-stimulated and mouse adipose tissue-stimulated MCF-10A cell transformation. Conclusions: Taken together, these results suggest that elevated sera FGF2 and leptin in obese patients may promote breast tumorigenesis in tumors that express elevated FGFR1 and LepR and that Jak2 inhibitors may be a novel therapeutic option for adiposity-driven breast cancers. Future work will examine the relationship between FGFR1/leptin receptor expression and survival and how these relationships are influenced by BMI status.
Is there an association between air pollution levels and lung cancer incidence?
Authors: Patel Seema , Chagpar Anees B. 
Published: May 2020

e13584 Background: PM2.5 particles are an indicator of air pollution levels associated with various respiratory illnesses. We sought to determine the association between air pollution levels and lung cancer incidence across different countries. Methods: Country-specific data for median PM2.5 levels and age-standardized lung cancer incidence rates (ASLCIR) were collected for the year 2016 from the World Health Organization and the Global Cancer Observatory, respectively. Country-specific data for median age and proportion of smokers were collected from the Central Intelligence Agency and Our World in Data, respectively. Statistical analyses were performed using SPSS Version 26.0. Results: Across 105 countries, the median PM2.5 level was 18 ug/m3 (range; 6-94 ug/m3). The WHO has set 10 ug/m3 as the upper limit for PM2.5 levels; 91 (86.7%) of countries had rates higher than this. The ASLCIR was surprisingly higher in countries with PM2.5 ≤ 10 ug/m3 (median 28.7 vs. 13.9 per 100,000 population, Pearson correlation coefficient -0.386, p < 0.001). Countries with PM2.5 levels ≤ 10 ug/m3 tended to have a higher GDP (median $55,709 vs. $5,931, p < 0.001), and an older population (median 41.5 vs. 30.4, p < 0.001); however, the proportion of population who smoked was no different in countries with low vs. high PM2.5 levels (20.3% vs. 22.5%, p = 0.847). Controlling for age, GDP, and proportion of the population who smoke in a multiple linear regression model, ASLCIR were not influenced by median PM2.5 (see linear regression table below, p = 0.888). Removing PM2.5 levels from the model did not significantly affect the model fit (R2= 0.749 in both models). Conclusions: These results demonstrate that air pollution levels do not significantly impact lung cancer incidence rates, which are more related to age, tobacco use, and GDP. [Table: see text]