bluuebunny/crossref_metadata_2025 huggingface dataset:
Genome-wide chromosomal instability by cell-free DNA sequencing to predict patient survival in metastatic breast cancer.
Authors: Mo Hongnan , Wang Xiaobing , Ma Fei , Qian Ziliang , Sun Xiaoying , Yi Zongbi , Guan Xiuwen , Li Lixi , Liu Binliang , Xu Binghe
Published: May 2019

e12591

Background: Cell-free DNA (cfDNA) could well recapitulate the genomic features of tumor with minimal invasion. For metastatic breast cancer (MBC), prior applications of cfDNA have focused on tracking specific gene locus. We aimed to evaluate the prognostic value of genome-wide chromosomal instability derived from cfDNA in patients with MBC. Methods: We retrospectively identified 65 patients with MBC who were intended to change line of therapy and had blood draw for cfDNA. We performed low-coverage whole-genome sequencing of cfDNA from plasma, and chromosomal instability was analyzed and represented by chromosomal instability (CIN) score. Results: 32 (53.3%) samples resulted to have high CIN score, with similar clinicopathologic characteristics relative to patients with low CIN. None of patient’s age (P = 0.073), receptor status (P = 0.136), disease stage at primary diagnosis (P = 0.353), or previous lines of therapy (P = 0.067) was correlated with genome-wide chromosomal instability. Different subtypes of MBC exhibit remarkably diverse copy number profiles. High CIN score was associated with significantly shorter overall survival after blood draw, median 21.2 months (95% CI 14.1-28.3) versus not reached (P = 0.006). Besides, patients with high CIN had worse progression free survival compared with the low CIN group (median 7.3 vs 11.0 months, P = 0.034). CIN score remained an independent prognostic factor in multivariate analysis (hazard ratio, 3.563; 95%CI, 1.481 to 8.572; P = 0.005). Conclusions: Here we present a framework for minimally invasive genomic characterization of different subtypes of MBC, and subsequent integration with clinicopathologic data and patient outcomes. Genome-wide chromosomal instability tracking by cfDNA is reliable and predicts survival in patients with MBC.
Fixed dose, dose-dense capecitabine in metastatic breast cancer.
Authors: O'Dea Anne , Khan Meshaal , Haines Haley Isabela , Kimler Bruce F. , Nye Lauren Elizabeth , Sharma Priyanka , Khan Qamar J.
Published: May 2019

e12593

Background: Capecitabine (C) is the only oral chemotherapy agent for metastatic breast cancer (MBC), and compared to IV agents, can be continued indefinitely if toxicities can be managed. The optimal dose and schedule of C are not known. FDA approved dose of 2500 mg/m2 daily is associated with median PFS (progression free survival) of 4-5 months and dose reduction and discontinuation rates from toxicity of 35% and 16% respectively. According to Norton-Simon mathematical model of tumor growth in which dosing schedules are determined based on efficacy, a 7 day on and 7 days off (7-7) schedule of C was predicted as optimal. We report efficacy and toxicity of fixed dose C (1500 mg BID) on a 7-7 schedule in MBC. Methods: Retrospective chart review of patients with MBC treated at our institution between June 2013 and December 2018 and received fixed dose C (1500 mg BID) on a 7-7 dosing schedule were included. Results: 39 patients with MBC were identified; 14 (35%) had de novo MBC and 25 (62.5%) had recurrent disease. 31 (77.5%) had ER+ disease, 6 (15%) were HER2+, and8 (20.5%) had triple negative breast cancer (TNBC). 10 (25%) had received no prior chemotherapy, 15 (37.5%) had received 1 line of chemotherapy, and 14 (35%) had received ≥2 lines of chemotherapy. Median PFS was 13 months. PFS was 17 months in ER+ patients and 8 months in patients with TNBC. Palmar plantar erythrodysesthesia (PPE) was the most frequent toxicity with 11 (27.5%) having mild PPE, 2 (5%) with moderate PPE, and 5 (12.5%) with severe PPE. Mild diarrhea was experienced by 14 (35%) and one patient experienced severe diarrhea. One patient experienced grade 3 neutropenia. No patients discontinued C due to toxicity. 11 (27.5%) required a dose reduction. Conclusions: Fixed dose capecitabine (1500 mg oral BID) on a 7 day on and 7 day off schedule is associated with encouraging PFS and has limited toxicity and a low rate of dose reduction and therapy discontinuation. Randomized trial comparing this dose and schedule of capecitabine to standard dose and schedule of capecitabine is ongoing.
Prognostic significance of tartrate-resistant acid phosphatase expression in breast cancer.
Authors: Dai Ming-Shen , Lo Hao-Chan , Chen Li-Jia , Tseng Shun-Fu
Published: May 2019

e12594

Background: Tartrate-resistant acid phosphatase (TRAP) is a metalloproteinase-like protein that is expressed in several primary and metastatic tumors, and its expression is positively correlated with the oncogenic process. Tartrate-resistant acid phosphatase is also a novel product of activated macrophage. We have previously demonstrated the clinical significance of TRAP expression in tumor-infiltrating macrophages and serum TRAP in patients with metastatic breast cancer (BC). Therefore, TRAP protein can potentially be a predictive and prognostic marker to evaluate disease progression and therapeutic response in breast cancer patients with bone metastasis. We aim to investigate the role of TRAP expression in breast cancer metastasis and survival. Methods: RNA-seq expression data were obtained from The Cancer Genome Atlas (TCGA) database. Estrogen receptor (ER)-positive, human epidermal growth factor receptor-2 (HER2)-negative, and TNBC subtypes were included in the analyses. The TRAP-overexpressed and -silenced breast cancer cells (MCF7, 4T1, MDA-MB-231) were used for validation. Survival data was also retrieved from the TCGA database to verify the prognostic biomarker. Results: Through TCGA database analysis, we found that TRAP expression correlated to the Ki-67 expression indicating the cancer cell proliferating activity. Additionally, TRAP expression positively correlated with mesenchymal markers (SNAIL, CDH1, MMP9, Fibronectin), and negatively correlated with epithelial markers (SMAD2, SOX10), implying that the TRAP expression is related to the breast cancer Epithelial-Mesenchymal-Transition process. This phenomenon was validated in TRAP-altered cell and confirmed inferior survival with TRAP-expressed breast cancer patients in TCGA database. Conclusions: Combining clinical TCGA data and cell-based analyses showed that TRAP expression was significantly associated with breast cancer proliferating activity, metastatic potential, and inferior survival. TRAP serves as a breast cancer prognostic biomarker and can be considered as a therapeutic target. Further investigation is warranted.
A comparison of platinum-based chemotherapy versus capecitabine-based chemotherapy in the treatment of breast cancer metastasis to the liver.
Authors: Chen Yimeng , Mo Hongnan , Wang Jiayu , Li Yiqun , Guan Xiuwen , Wang Zijing , Lin Shaoyan , Yi Zongbi , Xu Binghe
Published: May 2019

e12595

Background: Liver metastasis have long been known to indicate an unfavourable disease course in breast cancer (BC). A variety of drugs have been used in first choice for anthracycline-resistant and/or taxane-resistant breast cancer. This study aimed to systematically investigate the impact of different treatments. Methods: Between January 2003 and December 2013, we examined the clinical outcome of breast cancer patients with liver metastases from database in China National Cancer Center. 284 patients who received platinum or capecitabine based chemotherapy as first-line treatment were analyzed and followed up until December 2018. Results: Overall, 284 patients (female:280/284 (98.6%); male:4/284 (1.4%)) breast cancer with liver metastasis were available for this analysis. 205/ 284 patients (72.2%) received capecitabine-based chemotherapy including docetaxel/capecitabine (TX) and vinorelbine/capecitabine(NX), while 79/284 patients (27.8%) received platinum-based chemotherapy including docetaxel/ platinum (TP) and vinorelbine/platinum(NP).The median PFS (10.1 vs 8.3 months; P = .329; 95%), and the median overall survival (OS) (35.3 vs 19.8 months; P = .012) in the TX/NX group appeared to be longer compared with those in the NP/TP group, among which NP group seemed to be the poorest. Patients aged ≥50 years who were postmenopausal were more likely to benefit from the TX/NX regimens in terms of OS, however hormone receptor and human epidermal growth factor receptor 2 status did not affect differences in PFS and OS between the TX/NX and TP/NP groups. Conclusions: Capecitabine-based chemotherapy for advanced breast cancer with liver metastasis led to longer OS than platinum-based chemotherapy. These findings should be validated in more prospective cohorts.
Real-world evidence evaluating the use of an NK-1 antiemetic in the systemic chemotherapy treatment of metastatic breast cancer.
Authors: Lord Kevin , Feinberg Bruce A. , Kish Jonathan , Laney Jalyna R. , Chopra Dhruv , Liassou Djibril
Published: May 2019

e12599

Background: Severe and persistent nausea and vomiting (n/v) impacts quality of life and may lead to treatment discontinuation. While antiemetics assist with minimizing these effects, newer drugs can be expensive and carry their own side effect profile. Prior research has suggested that neurokinin 1 receptor inhibitor(NK-1) antiemetics are overly prescribed. Using the package insert recommendations for aprepitant, an NK-1, we evaluated the frequency of its prophylactic use to prevent emesis in patients receiving systemic chemotherapy(chemo) with moderate to high emetogenic risk. Methods: Patients were identified from a third-party, administrative claims database. Using medical and pharmacy claims, any female with ICD-9/10 codes for both breast cancer and metastases diagnosed between Jan-2013 and Dec-2017, who initiated systemic chemo and received aprepitant prophylactically were selected. Chemo regimen emetogenic potential was scored using the Hesketh scale and aggregated into two cohorts: low risk (grade 1-2 = none- < 30%), and moderate-high risk (grade 3-5: > 30- > 60%). If patients received combination chemo, the assigned risk level was the highest risk of any individual agent. The frequency of NK-1 use for each risk cohort was calculated per line of therapy independent of the previous treatment. Results: 10,342 patients met the selection criteria with 2,868 patients administered moderate-high emetogenic risk chemotherapy regimens. Mean age at initiation of treatment was 61.7 years (SD = 12.12). By line, the aprepitant utilization rate was: 1 line(L) 43% ,2L 27%, 3L 18%, 4L 16%, 5L 11% and 6L 12%. Across all lines of therapy, aprepitant was used prophylactically in 23% of patients treated with high risk chemo regimens and in 2% of patients who had received low risk regimens. Conclusions: Prophylactic use of the NK-1 inhibitor aprepitant was less than 50% in 1L moderate-high emetogenic risk chemotherapy and declined with consecutive lines of treatment. NK-1 use with low risk regimens was minimal. Further research is needed to understand the pattern of use and clinical outcomes between moderate-high emetogenic risk patients who do and don't receive NK-1 antiemetic supportive care.
Alteration of TGF-β signaling pathway predicts worse prognosis in pancreatic ductal adenocarcinoma.
Authors: Tian Bole , Li Mao , Cao Dan , Li Ang , Zhao Xiaochen , Hou Shengzhong , Lu Shan , Mou Yu , Liu Xubao , Cai Shangli
Published: May 2019

e13006

Background: Transforming growth factor beta (TGF-β) signaling pathway is one of the core pathways involved in tumor initiation and progression. The prognostic value of TGF-β pathway genes as a functionally related group in pancreatic ductal adenocarcinoma (PDAC) is rarely studied. Methods: 72 PDAC patients who underwent surgery between November 30, 2015 and September 13, 2017 in West China Hospital, Sichuan University were identified and included in this study. Whole-exome sequencing (WES) or targeted next-generation sequencing was performed with tumor tissue from all the participants. Clinical data was retrospectively collected. Clinicopathologic characteristics and overall survival (OS) were analyzed. Results: Genetic alterations were detected in 71 patients (98.6%). While 1 patient (1.4%) had only one genetic alteration, 33 patients (45.8%) had 2-4 genetic alterations and 37 patients (51.4%) had ≥5 genetic alterations. Overall, 25 patients (34.7%) with alteration of TGF-β pathway and 47 patients (65.3%) with wild type of TGF-β pathway were identified as TGF-βm+ group and TGF-βm- group respectively. Mutation of TGF-β pathway was independently associated with inferior OS in present cohort (HR, 2.22; 95% CI, 1.05-4.70; P = 0.04), adjusted for tumor stage, metastasis, surgery method and comorbidity. Subgroup analysis showed that patients with mutation of TGF-β pathway had shorter OS after radical surgery (HR, 3.25, 95% CI: 1.01–10.49; P = 0.04). While in the subgroup of patients who underwent palliative surgery, OS was not statistically different (HR, 0.93, 95% CI: 0.41–2.09; P = 0.86). Conclusions: Inferior prognosis was observed in PDACs with mutations of TGF-β pathway. Genomic information could help screen out patients at risk after surgery and adjuvant therapy might benefit this subgroup of PDACs.
BRCA1/2 germline mutations and response to PARP inhibitor treatment in lung cancer.
Authors: Fang Wenfeng , Cai Xiuyu , Zhou Huaqiang , Wang Yinguang , Zhang Yaxiong , Hong Shaodong , Shao Yang , Zhang Li
Published: May 2019

e13007

Background: Germline mutations in BRCA1/2 (BReast CAncer genes 1 and 2), which are targets for PARP inhibitors in breast and ovarian cancer, have been previously identified in patients with non-small cell lung cancer (NSCLC). However, its prevalence and clinical outcomes to targeted therapy in NSCLC still remains unknown. Methods: We conducted a retrospective review of 9,324 Chinese NSCLC patients who underwent targeted next-generation sequencing (NGS) during 2015/11/01 and 2018/10/31. Patients with BRCA1/2 somatic and germline mutations were identified. We summarized their prevalence and explored their co-existing driver mutations. Then we initially reviewed the response to PARP-inhibitor targeted therapy in patient with BRCA2 germline mutation. Results: 459 (4.9%) patients are BRCA1/2 positive (germline/somatic mutation). Most patients are diagnosed with LUAD (372, 81.1%), with a median age of 63 years (range: 2-101). Slightly more male patients were carrying BRCA1/2 mutations (59.9%, 275 out of 459). The prevalence of BRCA1 and BRCA2 somatic mutations was similar (145, 1.56% vs. 169, 1.81%, p = 0.19). BRCA2 germline mutation was more common in lung cancer than BRCA1 germline mutation (148, 1.59% vs. 20, 0.21%, p < 0.0001). When specified to the common driver gene mutation subgroups, the prevalence of BRCA2 germline mutation is similar to the entire population (EGFR 1.79%; ALK 1.74%; KRAS 2.05%; BRAF 2.86%; ERBB2 0.93%; p > 0.05). K2729N is the most common BRCA2 germline mutation (41, 27.7%), followed by C315S (26, 17.6%), V2109I (12, 8.1%), R2108C (11, 7.4%), I2490T (10, 6.8%), T582P (5, 3.4%). About 20% patients with BRCA2 germline mutation carried at least one concomitant mutations of DNA repair genes, including MLH1, MLH3, MSH6, CHEK2, BARD1, BLM, BRCA1, MUTYH, RAD50, RECQL4 and XRCC1. One 56-year-old male LUAS patient, with germline BRCA2 rs80359490 frameshift deletion mutation (p.S1722Yfs*4), received the targeted therapy with PARP inhibitor Olaparib after multi lines therapies. This patient showed a great PR response to Olaparib, with a PFS of at least 6 months. Conclusions: BRCA1/2 germline mutations were rare in Chinese NSCLC patients. Patients with BRCA2 germline mutations might benefit from PARP-inhibitor treatment.
Comprehensive germline panel testing across cancer types: Diagnostic yield and clinical utility in 100,000 patient dataset.
Authors: Yang Shan , Michalski Scott T. , Pineda Alvarez Daniel Esteban , Lincoln Stephen E , Whitworth Pat W. , Nussbaum Robert L. , Esplin Edward D. , Esplin Edward D.
Published: May 2019

e13013

Background: Over 608,000 patients with ovarian, breast, pancreatic, prostate and colorectal cancer are diagnosed each year. NCCN guidelines recommend offering germline genetic testing to all patients with ovarian and pancreatic cancer, and patients with prostate and breast cancer who meet specific criteria. We present data from ~113,000 patients who were tested on a comprehensive multigene panel and compare the diagnostic yield and clinical actionability with that of a limited gene panel strategy. Methods: We analyzed de-identified sequence data for 83 cancer-risk genes in patients with breast, ovarian, prostate and pancreatic cancer referred for germline genetic testing. Positive rates for a minimal gene panel for the respective indication were computed and compared to the positive rates when the comprehensive 83 gene panel was analyzed. Results: Four percent of 103,428 patients with breast, ovarian, pancreatic and prostate cancer harbored a BRCA1 or BRCA2 germline mutation including: breast 3.7%, ovarian 8.2%, prostate 5.2% and pancreatic 4.2%. When the comprehensive panel is applied, the overall diagnostic yield for all 113,107 patients increased to 16%. Excluding mono-allelic P/LP variants in recessive cancer-risk genes (e.g. MUTYH) reduces the diagnostic yield to 13%. Stratified by cancer type, and removing mono-allelic recessives, positive yield was: breast 11.8%, ovarian 18%, prostate 15%, and pancreatic 16%. Conclusions: These data show that comprehensive panel testing in patients with a broad range of cancers more than doubles the diagnostic yield, providing actionable results for an additional 9,737 per 113,107 patients tested. Potential germline-based clinical actionability for these patients includes: 1) pan-cancer eligibility for PARP inhibitor clinical trials, 2) FDA approved PD1 blockade for advanced cancer of ANY type and a molecular diagnosis of Lynch syndrome, 3) cascade family variant testing.This study suggests that genetic testing guidelines should be expanded to include recommendations supporting multigene panel testing in patients with cancer to improve the care of patients and their family members.
Germline EGFR mutation and cancer predisposition in adolescent and young adult (AYA) females with adrenocortical carcinoma.
Authors: Akhavanfard Sara , Yehia Lamis , Padmanabhan Roshan , Romigh Todd , Ni Ying , Eng Charis
Published: May 2019

e13014

Background: Adrenocortical Carcinoma (ACC) is a rare endocrine tumor with poor overall prognosis and slight overrepresentation in females. In children, ACC is associated with inherited cancers, predominantly Li-Fraumeni syndrome, with 50-80% of childhood ACC harboring TP53 germline mutations. ACC in AYA are rarely due to germline TP53 mutations; IGF2, PRKAR1A and MEN1 are other less common germline mutated genes in this age group. Methods: We analyzed exome sequencing data from 21 children (C, < 15y), 32 AYA (15-39y), and 60 adult patients ( > 39y) with ACC, originating from the Cleveland Clinic, and TCGA and St. Jude’s datasets. We utilized the Integrative Variant Analysis platform to classify variants based on the American College of Medical Genetics guidelines. We retained all pathogenic, likely pathogenic, and highly-prioritized Variants of Uncertain Significance. Results: Pathway analysis on prioritized variants showed EGFR and p53 pathways as the two top pathways among our C-AYA patients. We found that 4.8% of children and 6.2% of AYA, all female patients, harbored a non-kinase-domain germline EGFR mutation, compared to only 1.7% of adult patients with ACC. As proof-of-principle functional validation, we engineered a lentiviral-mutant stable ACC-cell line, harboring an EGFR variant from a 21 y/o female with aggressive bilateral ACC (p.Asp1080Asn), without germline TP53 mutation. We showed that mutant cells grow slower, yet migrate faster and are characterized by a stem-like phenotype compared to wildtype cells. Osimertinib, among all tested EGFR inhibitors, resulted in the highest growth inhibition of mutant cells. While EGFR inhibitors had no effect on the stemness of mutant cells, Sunitinib, a multi-receptor tyrosine kinase inhibitor, significantly reduced the stem-like behavior. Conclusions: Our data suggest that EGFR is a novel underlying germline predisposition factor for ACC, especially in the female C-AYA population. Although our pre-clinical observations need to be further validated, identifying a targetable gene for ACC has the potential to improve precision oncology management of this disease, which is known to have limited therapeutic options.
Landscape of multilocus inherited neoplasia alleles syndrome in China.
Authors: Ouyang Quchang , Gao Jie , Huang Jun , Dai Pingping , Zhang Mingming , Chen Chen , Guan Yan-Fang , Yang Ling , Yi Xin , Xia Xuefeng
Published: May 2019

e13027

Background: Comprehensive gene panels are able to identify patients with more than one pathogenic germline mutations. This phenomenon is known as multilocus inherited neoplasia alleles syndrome (MINAS). The frequency and phenotype of double heterozygous carriers in China are still unknown. Methods: A cohort of 12514 unrelated patients with solid tumor were screened using a validated panel. DNA damage repair-associated genes ( BRCA1, BRCA2, PALB2, ATM) and DNA mismatch repair genes ( MLH1, MSH2, MSH6, PMS2, MLH3, MSH3, PMS1) are taken focused on this study. Results: 10 (2.16%) cases harboring two pathogenic/likely pathogenic mutations were identified in 464 patients with germline variant. All patients had at least one high-risk gene mutation except for G10(LC, 73y), which carried 2 ATM variants in the same allele. All patients developed tumors associated with only one of the mutation identified until now. Among 3 patients had PMS2/MSH6 mutation, G6 & G7 did not translated into recognized Lynch Syndrome due to abnormal BRCA1/2(H-risk for BC), while G8 harboring ATM (M-risk for BC) mutation developed to CRC. All of the five patients developed to breast cancer were TNBC molecular subtype. The median ages of diagnosis for BC were similar to single variation patients (44.3 vs 42, p=0.6190). Conclusions: Two double heterozygotes did not appear to have severe or different manifestations than single heterozygote. With the growing implementation of NGS based panel testing, relevant variants in two (or more) genes will be found more frequently. [Table: see text]
Discovering HPV16 and HPV18 infection status and cancer gene variations in cervical cancer patient specimens by using Next-generation sequencing.
Authors: Meng Bo , Quan Lili , Yang Wenjuan , Lang Jidong , Chen Lanyou , Dong Ruyi , Zhao Juanyu , Tian Geng
Published: May 2019

e13040

Background: Human papillomavirus (HPV) infection has been reported as an important cause of cervical cancer for many years. HPV16 and HPV18 are the two most prevalent types in cervical cancer5. Integration of HPV DNA is a crucial genetic event in cervical carcinogenesis. Therefore, it is important to know the HPV integration hot spots in human genome to predict the cervical cancer development status of patients. Although many studies have addressed the HPV integration sites in human genome, it is still a technique barrier to precisely determine the HPV integration sites of each patient, especially at early disease development stage with limited integration sites existing. Methods: To solve this problem, we first designed HPV probes to capture HPV integrated sequences of genome using next generation sequencing (NGS). And then we analyzed the integration sites by two methods with the NGS results, HPV Detector. We applied the study on 17 patient samples, 15 of them were found HPV16 positive and 2 of them were found HPV18 positive. Among them 16 were detected with HPV integration sites. Results: The results indicated that different samples showed different numbers of integration sites with limited overlapped positions in genome. The integrated positions of HPV16/18 located in all the genes of the virus, but mostly distributed in gene E1, L1 and L2. We identified integration sites HPV16 E6/GATC， E6/WWTR1， L2/DGKB, E1/EHHADH, ect. Some of the integrated sites in human genome are belong to intergenic region. We also used cancer gene panel, which cover 143 cancer related genes exon regions, to identify the mutation sites of each samples. We summed up a highly occurred mutated cancer gene list, which include ALK, NF1, PIK3R1, ROS1, TSC1, TSC2, ect. Most of them are either cancer driver genes or have been found highly related to cervical cancer. Further study is still carrying on. Conclusions: In conclusion, our HPV probe could successfully detect HPV16 and HPV18 in patient samples and enrich HPV integration sites in human genome of cervical samples significantly. It could provide detailed information for cervical cancer discovery and early detection.
Meta-analysis utilizing public data suggests role of innate immunity in the pathogenesis of hurthle cell carcinoma (HCC).
Authors: Allen David , Wanner Ross , McDermott Sean , Aljabban Jihad , Syed Saad , Elmaraghy Charles , Hadley Dexter
Published: May 2019

e13048

Background: Hurthle Cell Carcinoma (HCC), a variant of follicular thyroid carcinoma, is a rare form of thyroid cancer. Though it accounts for 3-10% of thyroid cancer cases, very little is known about its pathogenesis. While HCC holds good survival rates, it is still vital to understand the pathogenesis of HCC in order to further optimize treatment protocols. Methods: We tagged 46 HCC samples and 90 healthy thyroid samples as a control. Gene signatures were analyzed in Ingenuity Pathway Analysis, using statistical significance p < 0.05 and absolute log ratio > 0.5 between disease and controls. Methods: Search Tag Analyze Resource was employed to conduct meta-analysis using the National Center for Biotechnologys Gene Expression Omnibus to define HCC pathogenesis. Results: Hepatic fibrosis, hepatic stellate cell activation and retinoic acid receptor (RAR) activation were the top canonical activators associated with HCC. Of the molecules involved, Defensin Beta 1 (DEFB1), Lipocalin-2 (LCN2), Aldehyde Dehydrogenase 1 Family Member A3 (ALDH1A3), and CDC28 Protein Kinase Regulatory Subunit 2 (CKS2) had the highest associations with HCC. The most down-regulated molecules were Hemoglobin Subunit Beta (HBB), Hemoglobin Subunit Alpha 1 and 2 (HBA1/HBA2), Cellular Retinoic Acid Binding Protein 1 (CRABP1), and BH3-Interacting Domain-Containing Protein 3 (HRK). Conclusions: These results suggest that there are a variety of factors at play regarding the development of HCC. Defensins are peptides made by neutrophils, however DEFB1 is specifically known for its ability to resist bacterial growth on epithelial surfaces, playing a major role in innate immunity. LCN2 is also known for resisting growth on surfaces and does so by sequestering iron-containing siderophores, thus effectively stopping growth of microorganisms. Additionally, ALDH1A3 and CRABP1 are associated with RAR activation. While the exact pathogenesis of HCC is not well known yet, we demonstrate that the two most up-regulated factors in HCC are strongly involved in innate immunity. This suggests that the dysfunction of innate immunity may play a vital role in the neoplastic pathogenesis of HCC.
The landscape of POLE/POLD1 mutations in Chinese solid tumor patients.
Authors: Pang Linrong , Xu Tao , Tao Hua , Chen Gang , Ni Bin , Zeng Daobing , Wang Aodi , Shi Weiwei , Wang Kai , Yao Ming
Published: May 2019

e13050

Background: DNA polymerase epsilon and polymerase delta encoded by the POLE and POLD1 gene are the major components participating in DNA replication, which both carry a proofreading (exonuclease) domain allowing error correction during replication. In case of POLE/POLD1 mutation, a deficient DNA repair activity results in a hypermutated phenotype of cancer, which would be a promising biomarker for immune checkpoint inhibitors (ICPIs). However, the prevalence of POLE and POLD1 in Chinese patients (pts) with solid tumors remained unknown. Methods: Targeted panel sequencing of 450 cancer genes were performed on FFPE tissues and matched blood samples obtained from 6313 Chinese pts with 23 different types of solid tumors. In our cohort, 41% were female pts with a median age of 56-year-old (range: 1-91), while 59% were male with a median age of 59-year-old (range: 1-96). The major cancer types were NSCLC (29%), HCC (11%), CRC (11%), gastric cancer (GC, 7%), soft tissure sarcoma (6%), pancreatic cancer (5%), intrahepatic cholangiocarcinoma (5%), and others. Somatic genomic alterations (sGAs) including single base substitutions, short and long insertions/deletions (indels), copy number alterations (CNA), rearrangements, TMB and MSI status were assessed by NGS. Results: Clinical relevant genomic alterations (CRGAs) were defined as known loss-of-function mutations, truncations, mutations on splicing sites and confirmed somatic mutations in COSMIC. CRGAs of POLE and POLD1 accounted for 2.1% and 1.3% of Chinese solid tumors respectively. Tumors with highest frequency of POLE CRGAs in Chinese cohort were endometrial cancer (8.3%), urothelial cancer (4.8%), CRC (4.3%), GC (3.2%), breast cancer (2.9%), cancer of unknown primary (CUP, 2.5%), ovarian cancer (2.1%) and NSCLC (2.0%), which tumors with highest frequency of POLD1 CRGAs were endometrial cancer (8.3%), urothelial cancer (4.8%), GC (3.0%), CRC (2.8%), SCLC (2.1%), HCC (1.9%), cervical cancer (1.6%), CUP (1.2%) and pancreatic cancer (1.2%). In addition, 1.6% and 1.2% of Chinese solid tumors harbored variants of unknown significance of POLE and POLD1, respectively. Conclusions: For the first time, our study reported prevalence of somatic mutations of POLE and POLD1 in large samples of Chinese population. Comparing with large cohort study of western population (ESMO 2017, 1170P), more CRGAs of POLE were identified in Chinese solid tumors (2.1% vs. 0.6%, p < 0.0001) indicating ethnic differences of ICPIs potential candidates between Chinese and western populations.
Detect and visualize tumor microsatellite instability status from next-generation sequencing data by simulating PCR techniques.
Authors: Chen Shifu , Qu Hongyue , Yang Bo , Huang Tanxiao , Zhang Xiaoni , Liu Yuanyuan , Zhou Yanqing , You Qin , Ivanov Kamen , Gu Jia
Published: May 2019

e13052

Background: Although multiplex PCR is still the golden standard technology for detecting microsatellite instability (MSI), it has some disadvantages. Firstly, its results are not quantized, and the interpretation of results can be varying for different operators. Secondly, PCR requires extra sample amount and may affect the sample amount for next-generation sequencing (NGS). So we developed a method to detect MSI status from NGS data. Methods: We developed a tool called VisualMSI, which simulates the PCR behaviors to detect the instability level of microsatellite loci. For each microsatellite locus, a pair of PCR primers are simulated by extracting the sequence from reference genome. The read pairs covering this microsatellite locus will be merged first, and then the simulated PCR primers will be mapped to the merged sequences to evaluate the inserted length. For paired tumor/normal samples, VisualMSI evaluates the earth mover's distance (EMD) between the inserted length distributions of tumor and normal. MSI status is determined by the EMD value, and is also visualized on a HTML page for manual validation. As a comparison, the MSI was also evaluated using a multiplex PCR comprising 5 loci (NR27, NR21, NR24, BAT25, and BAT26). Results: To evaluate the concordance of VisualMSI results and PCR-based results, we enrolled a group of 92 patients (39 lung cancers, 33 colorectal cancers and 20 others). For each patient, a tumor tissue sample and a blood sample were collected. White blood cells from the blood samples were also sequenced as normal control. For each patient, the 5 major MSI loci, including BAT-25, BAT-26, NR-21, NR-24 and NR-27 were evaluated by VisualMSI from NGS data, and by PCR. MSI status was categorized as MSI-H or MSI-L for each MSI locus. Finally, for the total 460 MSI loci, the VisualMSI and PCR results were concordant for 425 of them (92.39%), and were not concordant for the rest 35 (7.61%). The sensitivity is 89% (95% CI) and the specificity is 95% (95% CI), indicating that they were highly consistent. Conclusions: We developed a tool for detecting and visualizing MSI status from NGS data. The data shows that results of VisualMSI and PCR are highly concordant. This tool is now open-sourced at: https://github.com/OpenGene/VisualMSI.
A new method towards calculating the cancer cell fraction in cell-free DNA.
Authors: Han Tiancheng , Yu Jianing , Lin Xiaojing , Xie Hongyu , Song Xue , He Ji , Chen Weizhi
Published: May 2019

e13053

Background: Circulating tumor DNA (ctDNA) has been applied and showed potential in cancer early/late-stage detection, tumor genotyping and post-operation recurrence monitoring. The fraction of ctDNA in cell-free DNA (noted as ccf hereby), in addition to standard SNV/INDEL/CNV analysis, has also been showed to associate with the tumor progression and prognosis. In theory, accurate ccf can further be useful in correcting and improving given SNV/INDEL/CNV results. Existing tools capable for calculating ccf (PureCN, FACETS, Sequenza, etc.) use coverage data in targeted regions and SNP allele frequency to calculate the tumor fraction, which fail to give accurate estimation at relatively low ctDNA concentrations. Methods: A Maximum Likelihood model was built to estimate ccf. We first select informative SNPs with significantly different VAF in the case and paired-control samples. The mutation type of an informative SNP is determined by the variant allele frequency (VAF) in the paired samples and the copy number of the case sample. Likelihood of each SNP given a specific ccf was then calculated. After clustering SNPs into clones, the ccf of each clone was estimated using a global likelihood. Results: Performance of the method was validated by ctDNA dilution series analysis. 6 cfDNA from cancer patient was diluted (concentrations: 1/3 - 1/81). Detection limit of the method is ~2%, and correlation between estimated and expected ccf ranged from 0.93 to 0.98. Conclusions: We have developed a novel method to better estimate cancer cell fractions in cell-free DNA. Results showed our method is able to calculate ccf at lower ctDNA concentrations with higher accuracy and stability than benchmarked tools. We describe here a method for target-sequencing data that is more sensible, accurate and stable than currently available tools.
Diagnosis of lung cancer by canine olfactory detection in urine and breath samples.
Authors: Feil Charlotte , Stein Thorsten , Forster Andreas , Schmidtmann Irene , Riemann-Seibert Thomas , Berger Martin , Owen Robert , Schimanski Carl Christoph
Published: May 2019

e13067

Background: Lung cancer is the leading oncological cause of death in western countries. The WHO estimated 2.09 million newly diagnosed lung cancer patients in 2018 worldwide. Although early detection is crucial for patients outcome, no surveillance tools exist. Dogs have a highly sensitive olfactory system which is already used in several ways, such as drug and ketone detection. The aim of the study was to evaluate the capability of a classically conditioned domestic dog to accurately distinguish samples of lung cancer patients of all tumor stages in urine and breath from healthy controls. Methods: This monocentric clinical trial was an original study and approved by the local ethics committee. After conditioning a domestic dog with samples of 186 patients (36 cancer patients and 150 control patients), further 246 patients aged between 45 and 80 entered into the study: 41 patients with a histologically proven lung cancer comprising all different stages and 205 control samples of healthy individuals with no cancer history. Two urine and two breath samples were collected of each patient and immediately shock frozen at -80°C. Urine and breath samples were separately exposed to the dog in a randomized, double-blinded manner, resulting in a specific conditioned reaction indicating the cancer sample. Results: The dog correctly predicted cancer in 36 of 41 urine samples, corresponding to a sensitivity of 87.8% and a specificity of 97.6%. Concerning the breath samples, the dog correctly predicted cancer in 32 of 41 samples, corresponding to a sensitivity of 78% and a specificity of 95.6%. Combining both techniques, the dog correctly identified 40 of 41 cancer samples, leading to an overall sensitivity of 97.6%. The specificity is not evaluable. Conclusions: Urine and breath carry volatile organic compounds indicating cancer growth, as previously reported. Canine olfactory detection of lung cancer is a simple tool to detect lung cancer non-invasively. Further identification of target compounds for technical translation of this approach is under way, with the potential for the development of a bionic electronic nose.
Design and implementation of an Internet-based cancer risk assessment tool: Use over 10 years.
Authors: Lariviere Michael Joseph , Chao Hann-Hsiang , Amaniera Isabella , Vachani Carolyn , Hampshire Margaret K. , Bach Christina , Arnold-Korzeniowski Karen , Metz James M. , Hill-Kayser Christine E.
Published: May 2019

e13075

Background: Prevention and early intervention can improve survival and quality of life across all cancers. Patient understanding of risk factors, and associated actionable lifestyle changes and screening programs, is not well understood by clinicians. Methods: The Internet-based OncoLink “Reduce My Risk” tool was created in 2009 to provide information about cancer risk after individuals responded to a comprehensive survey regarding demographics and cancer risk factors. Research related to these data has been IRB-approved. Results: 28,001 surveys were submitted. Median age among respondents ≥18y was 26y (18-101). 60% were female, 87% lived in North America, and 76% were White/Non-Hispanic. 37% had at least a bachelor’s degree, and 22% had household income > $100,000/y; most lived in a city/suburb (81%). 13% were current smokers, 23% previous smokers, 10% used cigars or pipe tobacco (10%), 6% used oral snuff/chew/quid, and 29% reported secondhand smoke exposure. Other substance use included marijuana (22% former users, 10% current users), alcohol (52% current users, 8% of those ≥14 drinks/w), and areca nut, betel leaf, or exotic smoking (1%). BMI was ≥30 in 19%. 74% reported dietary risks and 36% infrequent exercise. Early intercourse and > 10 sexual partners were reported by 43% and 10%, respectively. Excess UV exposure was reported by 19%, and exposure to known carcinogens 14%; 1% were exposed to DES in utero, and < 1% took DES while pregnant. Nonmodifiable risk factors included family cancer history (64%) or genetic syndrome (3%), and cancer-predisposing health condition (26%). 31% of women began menstruating < 12y and 33% gave birth to a first child > 30y. Conclusions: This free, publicly accessible cancer risk assessment tool has a large user population with higher educational status, higher income, and smaller household than the general population. 97% of users report behaviors associated with cancer risk. Another 72% report non-modifiable risks. By understanding detailed characteristics of a large number of respondents, these data have the potential to answer many hypothesis-generating questions, with the ultimate goal of improving educational interventions to reduce cancer risk across the general public.
An analysis of the sociodemographic factors contributing to patient nonadherence to recommendations for screening mammograms.
Authors: Ansari Ahmer Mohammad , Pericot-Valverde Irene Mohammad , Merchant Krupa Mohammad
Published: May 2019

e13077

Background: There were 2 million newly diagnosed cases of breast cancer in the United States during 2018 with 40,920 associated deaths1. The number of deaths has been decreasing over time due to effective breast cancer screening by mammogram. Routine mammograms lead to early recognition and treatment of breast cancer leading to an overall improvement in breast cancer outcomes. However, not all patients are adherent to screening mammogram schedules. The main aim of this study is to explore the current prevalence of breast cancer screening among women in the US. A secondary aim is to determine whether cancer screening is associated with identifiable sociodemographic determinants and cigarette smoking. Methods: Data were drawn from the Health Information National Trends Survey- (HINTS), a cross-sectional, nationally representative survey (N = 3,527) conducted in 2018. Responses from women aged 18-74 were used in this study. Descriptive analyses and chi-squared tests were conducted to estimate the prevalence of breast cancer screening by mammogram, as well as its association with certain sociodemographic characteristics and smoking status. Results: The survey sample included 1,722 women. The majority of the respondents were aged 45 years or older. A total of 5% of women had previously been diagnosed with breast cancer, most of them being between 65 and 74 years old. Overall, 22.1% of respondents reported that they had never had a mammogram. Breast cancer screening was significantly lower among young women aged 18 to 34 (76.0%), Hispanic (28.2%) and Asian (39.7%), and current smokers (24.6%). Conclusions: This study shows that there is a significant percentage of women in the US that do not adhere to screening recommendations for breast cancer. This study provides new and continuing evidence, regarding the profiles of women with poor adherence to these screening mammogram schedules. Overall, the findings from this study emphasize the importance of addressing racial and sociodemographic factors in an effort to improve screening mammogram adherence. References: 1. Cancer stat facts: Female breast cancer. Surveillance, Epidemiology, and End Results (SEER) Web site. https://seer.cancer.gov/statfacts/html/breast.html . Updated 2019. Accessed 02/10, 2019.
Renal cell carcinoma epidemiology in the era of widespread imaging.
Authors: Orlin Ido , Silverman Barbara G , Dekel Yoram , Stein Avi , Friedman Boris , Ben-Lasson Maya
Published: May 2019

e13083

Background: Cancers of the kidney and renal pelvis are the third most commonly diagnosed urological cancers. Renal Cell Carcinoma (RCC) is the most common histological type. The age-standardized rate (ASR) of RCC world-wide is 4.4/100,000 with higher rates in higher income countries. One third of diagnosed RCC patients have metastatic disease at presentation, although recent reports indicate smaller proportions. It has been suggested that the widespread use of imaging performed for various reasons has led to a rise of incidentally diagnosed RCC. We conducted a retrospective analysis of trends in cancers of the kidney and renal pelvis in Israel. Methods: We selected all cases of renal cell carcinoma of the kidney and renal pelvis neoplasms reported to the Israel National Cancer Registry (INCR) for the years 2000-2015. Demographic and clinical variables extracted from the registry included gender, population group, dates of birth/death, tumor size, stage at presentation (according to the Surveillance, Epidemiology and End Results (SEER) summary staging manual 2000). We calculated the overall and population group age-standardized incidence, using the direct method and the Segi World Standard population. Results: A total of 9,595 cases of RCC were identified. The average ASR was 7.7/100,000. RCC incidence was highest in the seventh decade of life with a male/female ratio of 1.7:1. Incidence was higher in the Jewish population than in the Arab population. The proportion of cases with metastatic disease at time of diagnosis was 10%; this figure was unchanged during the study period. Masses smaller than 4 cm. comprised almost two thirds of localized tumors with a significant increase in trend during the period of the study (p < 0.001). Five-year overall survival for localized and metastatic disease was 86% and 12%, respectively. Survival was similar in the Arab and Jewish populations (p = 0.06). Conclusions: RCC incidence and survival in Israel mirror those of other western countries. The proportion of cases with distant spread at diagnosis is smaller than elsewhere reported. Small incidental renal masses (less than 4 cm) are increasingly diagnosed in the localized stages, possibly due to increased using of imaging.
Epidemiological profile of lung cancer in a Nepalese population: A single-institution review.
Authors: Piya Madan Kumar
Published: May 2019

e13087

Background: Lung cancer is one of the common cancers worldwide, and is the commonest cancer in Nepal, with an incidence of 16%. There is a high incidence of smoking in Nepal, being highest in the mountain region in the north and lowest in the tarai region in the south. Smoking kills around 15,000 people per year. The prevalence of smoking in the urban population of Kathmandu over the age of 15 has been estimated at 64.6% in men and 14.2% in women. Nepal has diverse population with various ethnicities and different cultures. The aim of this study was to determine the relation of smoking, epidemiology of lung cancer and distribution of lung cancer in various ethnicities of Nepal. Methods: All patients attending National Hospital and Cancer Research Center in Kathmandu who were diagnosed with lung cancer between January 2012 and December 2018 were enrolled in the study. Informed consent was taken before enrollment and data was collected by the nursing staffs prospectively using a preset questionnaire for interviewing patients. Results: Data was collected from 250 patients over the seven years with histologically proven lung cancer. About 85.6 % of patients were male and 80% of them were smokers. 50% of men and 30 % of the women were smokers. Most common age to start smoking was in 11-20 years group (60%). 58% of patients were from Kathmandu valley, and 42% of patients from outside the valley. 38% of male were literate and 16% were illiterate where as 13.6% of female were literate and 32.4% were illiterate. Among the various ethnic groups, 44% were Newars, 20% Mongols, 18% in Chhetris and 18% Brahmins. The incidence of lung cancer was highest (57.6%) in the age 61-80 years age group. 14.4% of the patients had family history of cancer M = 8.6% and F = 6.0%). Squamous cell carcinoma was the highest (51.2%) followed by small cell carcinoma (22%) and adenocarcinoma (26.8%). Carcinoma of right lung was frequent (62%) compared to the left lung (38%). Local cigarette were used by 82.5% of the smokers and 54.5% of them used filtered cigarettes. 40% practiced relighting the butt ends. Conclusions: The study shows that smoking is a single major contributing factor observed in lung cancer in Nepal across various age groups as well as diverse ethnic groups. Given the high incidence of smoking starting before the age of 20, there is an urgent need for organized mass anti-smoking campaigns, especially in schools targeting the younger age group. Need of awareness against the smoking and the cause of lung cancer needs to emphasized to reduce the burden of the lung cancer.