bluuebunny/crossref_metadata_2025_split huggingface dataset:
Accurate prediction of somatic variants using deep learning model.
Authors: Zhang Peng , Wang Kai , Yao Ming , Wang Aodi , Chen Lijuan , Liu Angen , Shi Xiaoliang , Zhang Shiyue 
Published: May 2020

e13659 Background: Efficient and accurate identification of somatic variant is important for understanding the formation, progression, and treatment of cancer. It is necessary to conduct manual review by Integrative Genomic Viewer (IGV) in traditional variant calling process. However, the traditional manual is heavy workload when evaluating tumor with a high variant burden. In this study, a new convolutional neural network (CNN) method was created to train models for somatic mutation identification, which was suitable for Panel sequencing platform with different tumor purities. Methods: A total of 1000 tumor samples from next generation sequencing (NGS)-based genetic testing by a College of American Pathologists (CAP) accredited and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory. Through variant calling program, like GATK, the candidate mutation locations were identified and standardized by manual confirmation. For each candidate mutation location, reads of both tumor and control tissue were extracted. A 2-dimensional feature matrix M of size (2k+1) * 32 in each candidate base was created. The rows of 2k+1 represented the length of candidate region, and the 32 columns included the reads coverage frequency, mapping quality messages, and genome local scores of different tumor and control tissues. CNN model, which includes nine convolutional layers structured by Temporal Convolutional Networks (TCN) but with a different structure to adapt to the proposed input matrix, was used for training. The training data set including manually validated sequence data was used as benchmark test, and optimized by Stochastic Gradient Descent (SGD) optimizer with a learning rate of 0.01 was used for training. Results: The validation data set included 15 mixed samples which were composed of different proportions of known cell lines and real mixed blood samples. The pooled DNA contained 2,359 somatic variants, with expected variant allele frequencies ranged from 3% to 97% in each pool. The overall sensitivity and positive predictive value (PPV) of single nucleotide variants (SNVs) were 99.3% and 99.8%, respectively. Conclusions: A novel and sensitive computational tool for somatic variation detection in DNA Panel sequencing was developed. Our result showed that the deep learning CNN model could call variant in Panel sequencing data.
Association between PD-L1 variants and PD-L1 expression: A pan-cancer analysis.
Authors: Wang Xiang , Zhang Ding , Wang Guoqiang , Duan Anqi , Ruan Xiang , Zhao Teng 
Published: May 2020

e13661 Background: Programmed cell death-1 (PD-L1) expression has become a predictive biomarker of response to immune checkpoint inhibitors (ICIs) in several types of solid tumors. Patients with high expression of PD-L1 can benefit more from immunotherapy. However, whether PD-L1 variants would influence the PD-L1 expression has not been fully studied. Methods: Patients with both mutation and immunohistochemistry results for PD-L1 expression from our dataset was analyzed. Patients with both mutation and RNA expression data were obtained from The Cancer Genome Atlas (TCGA) and also analyzed. Results: In our dataset, 10002 patients were included in the analysis. 101 (1%) patients harbored PD-L1 variants, including 24 with single nucleotide variant (SNV), 1 with fusion, 3 with copy-number reduction, 59 with copy-number gain, and 16 germline SNV. The PD-L1 positive rate was 42% in patients with SNV, 100% in fusion, 0% in copy-number reduction, 78% in copy-number gain, 19% in germline SNV and 39% in patients without PD-L1 variants. 32 studies of 10071 patients from TCGA were included for analysis. 244 (2.22%) patients harboring PD-L1 variants, including 2 with frame shift mutations, 3 with nonsense mutations, 38 with missense mutations, 2 with splices, 3 with fusions, 83 with copy-number reduction and 118 with copy-number amplification. The PD-L1 expression in patients with PD-L1 variants was significantly higher than patients without PD-L1 variants (P < 0.001). Further analysis among PD-L1 variants groups showed that PD-L1 fusion and amplification were associated with higher PD-L1 expression. Conclusions: Our results suggested that the PD-L1 expression was associated with PD-L1 variants. Patients with PD-L1 fusion and copy-number amplification was associated with higher PD-L1 expression, while PD-L1 germline SNV and copy-number deletion was associated with lower PD-L1 expression.Our results suggested that the PD-L1 expression was associated with PD-L1 variants. Patients with PD-L1 fusion and copy-number amplification was associated with higher PD-L1 expression, while PD-L1 germline SNV and copy-number deletion was associated with lower PD-L1 expression.
Comprehensive next-generation profiling of clonal hematopoiesis in cancer patients using paired tumor-blood sequencing for guiding personalized therapies.
Authors: Li Ziyang , Huang Wensou , Yin Jiani , Na Chenglong , Wu Xue , Shao Yang , Ding Huaxin , Li Jinming 
Published: May 2020

e13662 Background: Clonal hematopoiesis (CH) is commonly observed during genomic profiling of cancer patients. However, the relevance of CH in Chinese patients has yet to be characterized. Methods: We analyzed next-generation sequencing (NGS) data from blood and matched solid tumors of 4,544 cancer patients. For delineating the impact of CH on panel-based estimation of tumor mutational burden (TMB), its correlation with whole-exome-based TMB calculation was analyzed in an independent cohort of 175 patients. Results: A total of 1,749 CH mutations in 237 genes were identified in the blood of 1,301 (28.6%) patients, among which 26% carried more than one CH mutations. DMNT3A (35.8%), TET2 (13.2%), NOTCH1 (4.8%), ASXL1 (3.8%) and TP53 (3.7%) were among the top altered CH genes, while the prevalence of several other known CH genes, including JAK2 and SF3B1, were below 1%. The predominant hot-spot mutation in DNMT3A at R882 showed varying frequencies of different amino acid changes. An age-associated accumulation of CH events was observed, with alterations in DNMT3A, TET2, ASXL1 and TP53 showing evidence of early changes. A large proportion (74.1%, 1296 mutations) of CH was detectable in the matched tumors. Of these, 453 (25.9%) were functionally annotated as oncogenic or likely oncogenic, including two EGFR kinase domain mutations (V742I and R776H), one KRAS mutation (F156L) and a loss-of-function BRCA2 mutation. With respect to immunotherapy, while CH was not associated with microsatellite instability, it had a negative impact on accurate TMB determination. Consequently, we developed a novel panel-based TMB estimation algorithm with CH filters that showed optimal concordance with exome sequencing in an independent cohort of 175 patients. Conclusions: Our findings highlight the clinical significance of CH in fulfilling the promise of precision medicine and emphasize the need for matched tumor-blood sequencing.
PALB2 mutations in Brazilian patients from North-Northeast regions.
Authors: Ferreira Thamara , Bomfim-Palma Thais Ferreira , Silva-Fernandes Isabelle Joyce de Lima , Felix Gabriela Espirito Santo , Caires Inacelli Queiroz De Souza , Silva Leandro Apolinário , Landeiro Luciana Garcia , Toralles Maria Betania , Azevedo Renata Gondim Meira Velame , Côrtes Juliana , Galvão Henrique de Campos Reis , Lima Marcos Venício Alves , Silva Paulo Goberlanio de Barros , Bezerra Maria Júlia Barbosa , Sant'Ana Rosane Oliveira , Bitencourt Flávio da Silveira , Oliveira Francisca Fernanda Barbosa , Picanço-Albuquerque Clarissa Gondim , Nascimento Ivana Lucia Oliveira , Machado-Lopes Taisa Manuela Bonfim ,   Oncogenetic Group from North/Northeast of Brazil
Published: May 2020

e13670 Background: Loss-of-function mutations in PALB2 gene are associated with increased risk for breast cancer and possibly pancreatic, ovarian, male breast, prostate, colorectal as others cancers. In Brazil it has been estimated that up to 1,516 new cases of hereditary breast cancer for 2020 in the North and Northeast regions. Analysis of susceptibility gene mutations helps identify precisely the high-risk patient and their families, whom need specific and personalized clinical management as high-risk individuals. Methods: Twenty-six patients with pathogenic mutations in PALB2 gene identify by next-generation sequencing from states of Bahia (11), Ceará (9), Pernambuco (5) and Rondônia (1) in the North and Northeast regions were analyzed. Results: Most of the patients analyzed had only breast cancer (80%), including two cases of male breast cancer (9,5%); the others were isolated cases of endometrial cancer (4%), breast and pancreas cancers (4%), breast and lung cancers (4%), only ovarian cancer (4%) and ovarian and breast cancers (4%). Most cancers were stage II or III (65%). Family history of cancer was observed in 22/26 (84%); the most common tumors were breast, prostate, pancreas and thyroid. The founder mutations were more frequent in exons: 4 (58%) and 12 (15%). Eleven variants were found as follow: c.1240C > T (19%); c.3256delC (15%); c.1671_1674delTATT (11.5%); c.355delC (11.5%); NC_000016.9:g.(?_23632673)_(23652488_?)del (11,5%). The greatest variety of mutations was found in the state of Bahia, probably due to the greater number of patients included (42%). Conclusions: These data suggest that changes in clinical management of PALB2 patients are needed since the phenotype observed exhibited pattern of hereditary tumors, including male breast cancer. Besides that, PALB2 gene should be included in painel gene analysis in patients from the North and Northeast of Brazil because its high frequency of pathogenic variants.
Super-MSI: CfDNA-based pan-cancer microsatellite instability detection.
Authors: Sun Xiaomeng , Xu Xiaohong , Lin Rongbo , Zhao Guodong 
Published: May 2020

e13672 Background: Microsatellite instability (MSI) is a molecular subtype found in many cancers, which is often associated with the benefits of immunotherapy. However, the application of traditional testing strategies (such as PCR or IHC) is largely limited due to their dependencies on sufficient tumor tissues. Here, we introduced Super-MSI, a cfDNA-based pan-cancer MSI detection method using next-generation sequencing (NGS). Methods: 5500 detectable microsatellite loci from 250 white blood cells (WBCs) and 29 PCR-validated MSI-H tissue samples were sequenced and characterized, while the former represented for MSS pattern, and the later, for MSI-H. 91 microsatellite loci with the most variable motif repeat numbers between patterns were filtered and the Super-MSI method was established. Plasma samples were collected from 608 patients with known MSI status assessed by PCR (593 MSS and 15 MSI-H) to validate the method. All samples were sequenced with a 642-gene panel, and initial microsatellite reads count distributions were profiled by MSIsensor. Results: We characterized each microsatellite locus by REF alleles (MSI-H:WBC ratio less than 1) and ALT alleles (MSI-H:WBC ratio more than 20), then defined the sum of ALT alleles frequency in WBC group as the baseline for each candidate locus. For plasma samples with unknown MSI status, hypergeometric distribution and FDR calibration were employed to assess the difference of ALT alleles frequency between the WBC baseline and plasma samples. Locus with FDR adjusted p-value less than 0.05 was defined as an unstable locus based on prior knowledge, and negative log-transformed FDR-p was defined as MSscore for the locus. The plasma sample with both unstable microsatellite proportion larger than 20% and total MSscore larger than 270 was defined as MSI-H, and contrariwise, MSS. For all evaluable samples in the validation cohort, Super-MSI showed high sensitivity and specificity of 60% (9/15) and 100% (593/593) for an overall accuracy of 99.0% (602/608), superior to its kind bMSISEA (83.5%, 106/127) and Guardant360 (98.4%, 934/949). Within LOD of 0.5% maxAF (approximately 1% ctDNA fraction), Super-MSI was able to detect 81.8% (9/11) of MSI-H samples, demonstrating high concordance with tissue-based PCR tests. Conclusions: Super-MSI can genotype pan-cancer patients with blood cfDNA samples and give highly accurate MSI evaluation with 81.8% sensitivity and 100% specificity above 1% ctDNA fraction.
Germline genetic mutational landscape and characteristics of men with prostate cancer (PCa): A single institution experience.
Authors: Adige Sunil , Bealin Lisa , Ventriglia Nicole , Geynisman Daniel M. , Anari Fern , Whitaker Kristen Danielle , Daly Mary Beryl , Plimack Elizabeth R. , Ghatalia Pooja , Hall Michael J. , Ruth Karen , Obeid Elias 
Published: May 2020

e13679 Background: The role of germline genetic testing (GGT) is rapidly changing for men with PCa. We describe the characteristics of men with PCa diagnosed with pathogenic (P) and likely pathogenic (LP) mutations on GGT. Methods: We conducted a retrospective single-institution study for all men with PCa who received single gene or multi-gene GGT from 1997-2019, unselected for disease stage, Gleason score, or age at diagnosis, and while most had a family history of cancer, some did not. All participants were from the Risk Assessment Program (RAP) database at FCCC and consented for research purposes at the time of GGT. Results: 160 men with PCa had GGT. 72/160 (45%) patients had no mutations. 41/160 (26%) patients had a variant of undetermined significance (VUS) (13 with 2 VUS, 1 with 3 VUS). 47/160 (29%) men were found to have a P or LP germline mutation. 26/47 (55%) with recurrent disease, and 1/47 (2%) unknown. 46 were Caucasian, and 1 was African American ( PALB2). 28/47 (60%) had Gleason Scores (GS) ≤7. 6/47 (13%) had a Prostate Specific Antigen (PSA) at diagnosis < 4.0 ng/mL. 23/47 (49%) were diagnosed < 60 years of age, and 8/47 (17%) at ≤ 50. 19/23 (83%) PCa cases with P/LP diagnosed below age 60 had DNA repair genes: BRCA2 (8), BRCA1 (4), CHEK2 (4), ATM (2), and PALB2 (1). 74/160 (46%) were tested after PCa NCCN genetics guidelines changed (October 2017), of which 19/74 (25%) had P/LP, and of those positive for P/LP, 6/19 (32%) had non-metastatic disease. Two patients had small cell neuroendocrine PCa ( CHEK2 and BRCA2), the remaining had adenocarcinoma PCa. Please see Table for full results. Conclusions: To our knowledge, this is the largest single-institution study reporting PCa characteristics and incidence of P/LP germline mutations. Rates of DNA-repair gene mutations were higher than previously reported, possibly reflecting our specialized cancer center’s population. While BRCA1/2 mutations were the most represented (55%), we describe PCa patients with mutations in ATM, CHEK2, NBN, PALB2, CFTR, and MUTYH, recognizing a few are not known to be linked to PCa. More than half of P/LP mutation carriers had GS ≤7. Additionally, 13% of the men with P/LP germline mutations had low PSA ( < 4.0 ng/mL) at diagnosis. Our findings highlight the importance of the new guidelines and GGT importance in some men with PCa, particularly if they could benefit from a different therapeutic approach, or be influenced into cascade GGT. [Table: see text]
Performance of cell-free tumor DNA testing for 101 clinical laboratories on College of American Pathologists proficiency tests.
Authors: Lockwood Christina M , Souers Rhona J , Vasalos Patricia , Kalicanin Tanja , Devereaux Kelly , Graham Rondell P. , Hameed M , Routbort Mark , Tsai Jonathan M , Merker Jason Derek , Lindeman Neal Ian , Moncur Joel T 
Published: May 2020

e13681 Background: Cell-free tumor DNA or circulating tumor DNA tests are increasingly used in clinical care to detect somatic mutations from solid tumors. However, data on laboratory performance characteristics using standardized samples is limited. Methods: Well-characterized reference materials were used for the College of American Pathologists (CAP) cell-free tumor DNA proficiency testing surveys, which consisted of stabilized DNA fragmented to simulate cell-free DNA in a synthetic plasma matrix. For the 2018A, 2018B, 2019A and 2019B surveys, laboratories tested for hotspot mutations (single and dinucleotide sequence changes) in EGFR, BRAF, KRAS, NRAS, and IDH1 at variant allele fractions ranging from 0.1% - 1.0%. As per CAP proficiency testing standards, results were scored according to the known mutation(s) engineered at designated variant allele fractions in each PT sample. Nine laboratories were excluded from analysis because they provided incomplete results. Statistical significance was calculated using a multivariate logistic regression model. Results: In 2018 and 2019, 101 laboratories submitted survey results for at least one proficiency testing mailing. There were 5088 total proficiency testing responses for EGFR, BRAF, KRAS, NRAS, and IDH1 mutations across 12 different samples. For the 3585 responses submitted for BRAF, KRAS, NRAS, and IDH1, sensitivity ranged from 94.6 – 100%, while specificity exceeded 99%. There were no significant differences in performance between analytical methodologies for BRAF, KRAS, NRAS, and IDH1 mutations. Performance characteristics for EGFR mutations among the 1503 responses showed a combined sensitivity of 87.1% and specificity of 98.7%. For laboratories detecting mutations in EGFR, next-generation sequencing methods exhibited a sensitivity (true positivity) of 95.7% while the sensitivity of non-NGS methods was lower at 81.7% ( P= 0.02). Conclusions: These findings demonstrate high sensitivity and specificity for clinical laboratories performing cell-free tumor DNA tests. For EGFR mutations, NGS outperformed non-NGS methods. These data suggest excellent overall agreement among laboratories performing clinical cell-free tumor DNA tests. Further investigation across variant allele fractions and additional variant types is warranted.
The prevalence of BRCA1/2 germline mutation in Chinese pan-cancer.
Authors: Ma Fei , Li Lixi , Yi Zongbi , Shi Jianming , Jiang Hua , Chen Chen , Dai Pingping , Zhu Weipei , Jin Chunhui , Tan Qin , Xia Xuefeng , Guan Yan-Fang , Yang Ling , Yi Xin 
Published: May 2020

e13684 Background: Pathogenic variants in cancer predisposition genes BRCA1/2 confer susceptibility to breast and ovarian cancer and well-studied. But the characteristics of BRCA in other cancers is unknown, we identified and characterized BRCA germline variants in a large pan-cancer in China. Methods: NGS was performed on genomic DNA from 29,676 pan-cancer patients. Large fragment deletions were all verified by QPCR. We integrated guidelines of ACMG/AMP, ENIGMA and China expert consensus. Based on the in-house system, variants were interpreted one-by-one and classified into 5 grades: Benign (B), Likely Benign(LB), Variant of Uncertain significance(VUS), Likely pathogenic (LP), Pathogenic (P). Results: Among 29,676 patients, 300 BRCA1 mutations and 440 BRCA2 mutations were detected in our study. The proportion among P/LP/VUS/LB/B were 36.1%, 11.6%, 36.6%, 11.1% and 4.6%. Consistent with previous reports, the mutations spread around the whole genes. Missense and frameshift were most common types in BRCA1 (40%, 25.3%) and BRCA2 (42.3%, 29.3%). 192(25.9%) mutations were not reported in any of the databases. Among these newly reported mutations, 32 (16.7%) were classified as P, 62 (32.3%) LP and 98 (51%) VUS. Totally, 522 (1.8%) patients were identified with P/LP BRCA1/2 mutations. No founder mutations in Chinese population were defined, but BRCA1 5470_5477delATTGGGCA (I1824Dfs*3) and BRCA2 3109C > T (Q1037*) had the highest prevalence indicating the common P/LP mutations in Chinese. On the whole, BRCA-associated hereditary cancer harbored higher P/LP percent than other cancer types (11.1% vs 0.7%). Different distribution and percent were observed in BRCA1 and BRCA2, the P/LP mutations were found in double primary cancers of breast and ovary (76.9% vs 38.5%), followed by ovarian cancer (15.5% vs 6.3%), breast cancer(3.8% vs 4.0%), endometrial cancer(1.6% vs 2.4%), prostatic cancer(1.3% vs 1.9%), pancreatic cancer (0.3% vs 1.8%), biliary tract tumor (0% vs 1%), thyroid cancer (0% vs 0.9%), NSCLC(0.2% vs 0.5%) and colorectal cancer(0.08% vs 0.4%). Except for SNV/Indels, large range heterozygous deletions were found in 9 patients, including 4 (0.6%) OC, 4 (0.2%) BC and 1 NSCLC, almost all interfering with BRCA1. Conclusions: This analysis depicted a comprehensive landscape of germline BRCA1/2 variants in Chinese pan-cancer. Besides breast and ovarian cancer, lots of other cancers also harbor BRCA germline mutation, retrospective family history and hereditary cancer risk assessment needs further study.
Rural challenges in a decade of crowdfunding for cancer care.
Authors: Khalil Ahmed , Higbee Sheetal L. , Khasawinah Khalid 
Published: May 2020

e14013 Background: Improving access and affordability to oncology care for patients in rural America is a national imperative given growing health disparities in cancer morbidity and mortality. Crowdfunding has emerged as a rescue tool for cancer patients facing difficulties paying for treatment costs. While such platforms present opportunities to increase access, patients who live in rural areas face increased challenges compared to those in urban areas. Methods: We crawled the pages of GoFundMe fundraising campaigns from 2010 – 2020 using a custom Python script. We then indexed these pages for campaigns focused on cancer treatment in the US and identified variables of interest using text analysis, including cancer type, demographics, clinical characteristics, and social network features, resulting in 151,051 campaigns. Rural status was identified by analyzing zip codes against the database provided by the US Census. Descriptive statistics, χ2, and t-tests were used to compare variables by rural status using R 3.6.3 software. Results: The 10 most prevalent types of cancer in our data were metastatic (26.8%), breast (17.0%), lung (12.4%), colorectal (6.6%), brain (6.3%), liver (4.2%), leukemia (3.2%), stomach (2.7%), pancreas (2.6%), and bone (2.1%). We found a statically significant difference between urban and rural areas in key variables including unemployment rate, insurance status, metastatic cancer rate, treatment type, social network reach, and fundraising totals. Conclusions: Since the 2011 launch of (ASCO) task force for improving cancer care of rural patients, a tremendous effort has been directed towards that. In our study of 151,051 patients over a 10-year period, we found that disparities between rural and urban America in cancer are not just limited to clinical management, but also in an era of crowdfunding, rural patients are still struggling to get the attention they need. We must increase efforts to raise awareness and find solutions to improve access to cancer care. [Table: see text]