bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genomic characterizations of KIT and PDGFRA in Chinese pan-cancer patients.
Authors: Xiong Xianze , Zhou Feng , Luo Ming , Li Jingdong , Zheng Haiping , Liu Changjun , Chen Xiong , Wang Wenjing , Wang Weifeng , Wang Kai 
Published: May 2020

e13654 Background: KIT and PDGFRA gene mutations have been identified as biomarkers for targeted therapy in gastrointestinal stromal tumor. Mutations and amplification of KIT and PDGFRA are also considered as potential targets in solid tumors in clinical trials. We assessed the characteristics of KIT and PDGFRA alterations in a variety of cancers and tried to provide genomic landscape of these genes. Methods: Formalin-fixed, paraffin-embedded (FFPE) tumors and their matched blood samples were collected from 10,010 patients for 450 cancer genes targeted next-generation sequencing (NGS) panel.The testing was carried out in a College of American Pathologists (CAP) accredited and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory. Genomic alterations including single nucleotide variations, short and long insertions/deletions, copy number variations, and gene rearrangements were assessed. Results: Alterations of KIT and PDGFRA were detected 2.1% and 1.6% respectively in Chinese pan-cancer patients. KIT alterations was detected most frequently in gastrointestinal stromal tumor (68.8%), soft tissue sarcoma (10.8%), melanoma (10.3 %), thymic tumors (7.7%) and small cell lung cancer (5.1%), and PDGFRA alterations was detected in gastrointestinal stromal tumor (18.7%), melanoma (5.2 %), primary hepatic carcinoma (4.3%), bone sarcoma (4.2%) and soft tissue sarcoma (3.4%). Particularly, KIT and PDGFRA amplifications accounted for 0.68% and 0.58% respectively in pan-cancer patients and were highly co-existed. Conversely, KIT and PDGFRA mutations were mutually exclusive which indicated an independent role of driver genes. Furthermore, tumor with microsatellite instability high (MSI-H) status had a significantly higher rate of KIT or PDGFRA mutations compared to microsatellite stable (MSS) tumors (p < 0.001). Conclusions: KIT and PDGFRA alterations occurred in 2.1% and 1.6% respectively in Chinese pan-cancer patients and mutually exclusive with known driver genes. KIT and PDGFRA alterations may act as driving oncogenic factors across cancers and warrant drug development strategy.
The prevalence of CDK12 alterations in Chinese cancer patients and the association with tumor mutation burden(TMB) and survival.
Authors: Li Ke , Guo Xi , Mao Yunhua , Yang Mengmei , Huang Mengli , Xie Wenzhuan , Liu Xinyi , Wang Dejuan , Qiu Jianguang , Zu Xiongbing 
Published: May 2020

e13663 Background: Cyclin-dependent kinase 12 (CDK12) is a cyclin-dependent kinase that regulates transcription and RNA splicing, thereby modulating multiple cellular processes. It has been suggested that CDK12 loss-of-function mutations lead to a higher neoantigen burden and favorable responses to PD-1 inhibitors in advanced prostate cancer. Given this potentially actionable molecular subtype, we sought to determine the prevalence of CDK12 alterations in Chinese cancer patients and the association with TMB and overall survival(OS). Methods: The prevalence of CDK12 alterations were queried in 3D Medicines database with 15,745 Chinese cancer patients involved. Whole-exome sequencing data of 464 patients with prostate adenocarcinoma(PRAD) from the Cancer Genome Altas (TCGA) were downloaded to explore the association between CDK12 gene alteration and OS. And the association with TMB were analyzed in a cohort of 731 patients with various cancer types published by Memorial Sloan Kettering (MSKCC) (Samstein et al., Nature Genetics, 2019). Results: Any CDK12 and known or likely deleterious CDK12 mutations were identified in 598(3.8%) and 98(0.62%) patients, respectively. Across all cancer types, prostate adenocarcinoma(PRAD) was found to have the highest frequency of deleterious mutations(8.75%, 23/263), followed by breast cancer (4.97%, 25/503). Mutations were also detected in multiple cancer types including bladder cancer, ovarian cancer, lung cancer, colorectal cancer and so on with a frequency of less than 1%. CDK12 mutations were associated with shorter OS (HR = 15.25; 95% CI, 2.88-80.73; p < 0.001) in TCGA PRAD and cholangiocarcinoma datasets, which was not seen in other cancer types. Patients harboring CDK12 mutation had a significant higher TMB(p < 0.001) in the pan-cancer study of publicly-available cohort from MSKCC. Conclusions: CDK12 alterations existed across tumor types in Chinese patients with relatively high frequencies detected in PRAD and breast cancer and represent extremely rare events in multiple cancers. CDK12 mutation was a poor prognostic factor in PRAD and cholangiocarcinoma. In a pan cancer analysis patients with CDK12 mutation tended to have a significant higher TMB and may benefit from PD-1/L1 blockade immunotherapy.
Clinical significance of serial tumor next generation sequencing (NGS) in 155 pediatric cancer patients.
Authors: Zhao Xiaonan , Li Marilyn M. , Schubert Jeff , Wu Jinhua , Lin Fumin , Wertheim Gerald B , Surrey Lea , Luo Minjie , Zhong Yiming , Wu Chao , Cao Kajia , Aplenc Richard , Bagatell Rochelle , Mosse Yael P. , Olson Timothy S. , Santi Mariarita , Tasian Sarah K. , Storm Phillip , Maris John M. , Hunger Stephen 
Published: May 2020

e13666 Background: Molecular profiling using NGS technology is critical for tumor diagnosis, risk stratification, and treatment selection. There are limited data in childhood cancers regarding evolution of genomic changes under the selective pressure of chemoradiotherapy. Here we report on serial testing of hematologic and solid pediatric tumor specimens across the spectrum of diagnosis, during treatment and disease relapse. Methods: Since 2016, 2,144 somatic NGS assays from 1,727 unique cancer patients were performed using the Comprehensive Hematological Malignancy Panel (CHMP) or the Comprehensive Solid Tumor Panel (CSTP). Serial tumor analysis was performed on 155 patients. All tumors were profiled for SNVs/indels, copy number alterations (CNAs), and fusions. The clinical impact on diagnosis, prognosis, and therapy was assessed. Results: 85 and 70 patients were tested with CHMP and CSTP, respectively. 86.5% (134/155) of patients underwent 1 subsequent genetic testing, while 13.5% (21/155) were serially tested for 3 - 6 times. Relapsed or therapy-refractory tumor was the most common indication for repeat CHMP and CSTP analysis of tumor genomics (64.5%, 100/155), primarily to survey for new targetable cancer driver mutations. The second most common reason for serial testing with CHMP was to monitor clonal evolution for patients with bone marrow failure syndromes and/or myelodysplastic syndromes, which resulted in a new cancer diagnosis in 14.6% (6/41) patients. For CSTP, the second most common reason for serial testing was to test a different part of the same tumor for tumors with histologic and/or radiographic heterogeneity (27.1%, 19/70). Of all patients with serial testing, 70 had at least one clinically significant new SNV/indel, 44 had distinct CNAs, and 4 had new clinically actionable fusions. Overall, clinically significant new results were detected in 81 (52.3%) patients, including 53 patients with new clonal changes indicating disease evolution, 31 of diagnostic significance, 9 of prognostic significance, and 8 suggesting new treatment options. Conclusions: Taken together, these data highlight the clinical importance of serial testing of pediatric tumors for potential biomarkers that may impact patients’ care at various time points across the spectrum of their diseases.
Biomarker testing patterns and trends among patients with metastatic lung cancer.
Authors: Wang Suwei , Huang Hu , Arriaga Yull Edwin , Tkacz Joseph , Preininger Anita M , Solomon Metasebya , Jackson Gretchen Purcell , Dankwa-Mullan Irene 
Published: May 2020

e13667 Background: Guidelines for biomarker testing of metastatic lung cancer patients aid oncologists in making targeted treatment decisions. Despite evidence demonstrating the benefits of genomic and immune biomarker identification in these patients, variations in testing exist. This population-based, retrospective, observational study examined trends in testing rates and timing, assessing associations between testing and patient characteristics, sociodemographic factors, and regional patterns using insurance claims data. Methods: We evaluated patterns of biomarker testing in the IBM MarketScan database between 1/1/2013-12/31/2018. Inclusion criteria consisted of lung cancer patients with an initial diagnosis of metastasis within the study period, continuous insurance coverage from 12 months before to 4 months post-diagnosis, and biomarker testing (EGFR, ALK, ROS1, BRAF V600E, NTRK, PD-L1) within 4 months of diagnosis. Temporal trends were evaluated by the Cochran-Armitage method. Multivariate logistic regression evaluated associations between testing rates and patient-specific factors (i.e., age, gender, comorbid conditions), insurance type, and region (i.e., Northeastern, North central, Southern, and Western) in the United States (US). Results: Of the 8977 patients with metastatic lung cancer, 1040 (12%) had claims for biomarker testing. During the study period, testing rates increased significantly, from 8.4% in 2013 to 20.6% in 2018 (P <.0001); the likelihood of testing increased by year (2014, OR 1.20, 95% CI 0.97 - 1.48 vs. 2018, OR 2.83, 95% CI 2.26 - 3.54). Of patients tested, 25.8% (N = 268) were tested on the day of diagnosis, 70.7 % (N = 735) within 30 days, and 85.6% (N = 890) within 60 days. A lower likelihood of testing was associated with increasing age (OR = 0.97, 95% CI 0.96 - 0.98), enrollment in preferred provider health plans (OR 0.69, 95% CI 0.53 – 0.93), or pre-existing comorbidities of congestive heart failure (OR 0.76, 95% CI 0.59 – 0.98) or diabetes (OR 0.82, 95% CI 0.68 – 0.99). Testing was more likely to occur in females (OR 1.24, 95% CI 1.09 – 1.42), age < 55 years (OR 1.67, 95% CI 1.32 – 2.12) or residence in Northeastern US (OR 1.26, 95% CI 1.05 -1.51). Conclusions: Biomarker testing rates for an insured cohort of metastatic lung cancer patients increased significantly over time, but the likelihood of testing varied based on age, sex, insurance type, comorbidities, and region. Results of this study may inform policy or outreach strategies by highlighting population-based factors influencing biomarker testing rates.
Application of next generation sequencing (NGS) in gastrointestinal stromal tumor (GIST).
Authors: Li Bin , Bai Jun , Zhu Lingjun , Zhang Sen , Wang Guihua , Dai Pingping , Huan Jiaojiao , Gao Wei , Xia Xuefeng , Guan Yan-Fang , Yi Xin , Yang Ling 
Published: May 2020

e13675 Background: The majority of GISTs harbor activating mutations in KIT or PDGFRA. However, the clinical relevance of other genomic alterations, tumor mutation burden(TMB), microsatellite instability(MSI) as well as ctDNA-based clinical utility were poorly examined. Methods: A total of 106 samples obtained from 92 patients (Table) were sequenced by NGS with 1021 cancer-associated gene panel. Results: In 62 treatment naïve patients, the most common primary localization was stomach (29), followed by small intestine (22). KIT mutations were found in 52 (89.0%) cases. The most frequent alterations occurred in exon 11(48/55), followed by exon 9(6/55) and then exon 17(1/55). The primary foci of GIST patients harboring KIT exon 9 mutations was small intestine mainly. There was one patient presented with PDGFRA mutation in exon 18 (1.9%,1/62). All these cases were absent of BRAF, RAS, PIK3CA mutations, while actionable mutations detected from other genes, including CDKN2A(6/62), NF1(4/62) TSC1(2/62), PTEN(2/62) and BRCA2(2/62). Six (6/62, 10.0%) patients were KIT/ PDGFRA wild type and two of them (33.3%) detected pathogenic mutation in NF1 gene, with diagnosed age at 36 and 38 years old respectively. TMB and MSI status were analysed in 30 GIST using NGS method and no TMB-H or MSI-H sample found. Thirty-six patients who resistance to imatinib or sunitinib were screened. Nine (47.4%) and four patients (16.0%) harbored resistant mutations in KIT gene detected from tumor and blood sample cohort, concurrent sensitive and resistance mutations remain the major subtype (Table). The low percent of ctDNA detection were consistent with previous studies that clinical characteristics (tumor size, Ki67, etc.) could influence the results. Conclusions: Panel-based NGS could comprehensively elucidated the landscape of GIST and identified more tumor-specific genetic alterations which can be managed by targeted therapy. But immunotherapy and liquid biopsies remains challenging and needs further investigation from our results. [Table: see text]
Prevalence of BRCA1/2 pathogenic variants in triple negative breast cancer patients stratified according to age at diagnosis.
Authors: Blatnik Ana , Banjac Marta , Strojnik Ksenija , Hotujec Simona , Stegel Vida , Škerl Petra , Šetrajčič Dragoš Vita , Klančar Gašper , Novakovic Srdjan , Borstnar Simona , Besic Nikola , Žgajnar Janez , Perhavec Andraž , Krajc Mateja 
Published: May 2020

e13677 Background: Triple negative breast cancer (TNBC) is strongly associated with germline BRCA1 pathogenic/likely pathogenic variants (PV/LPVs), with up to 28% TNBC patients being BRCA1 PV/LPV carriers. More recently, PALB2 variants have also been shown to be associated with TNBC. Genetic testing in Slovenian hereditary breast and ovarian cancer (HBOC) patients yields consistently high BRCA1/2 detection rates. Four BRCA1 PVs are particularly common, suggesting possible founder effects. Our aim was to analyze the results of panel based genetic testing in Slovenian TNBC patients, with an emphasis on BRCA1/BRCA2 mutational spectrum and detection rates depending on age at diagnosis. Methods: We evaluated the results of genetic testing, performed using a multi-gene panel in 1000 consecutive breast cancer cases. Only 210 patients with TNBC were included in further analysis. We analyzed the mutational spectrum and BRCA1/2 detection rates in TNBC patients stratified according to age at diagnosis. Results: In 80/210 (38.1%) TNBC patients PV/LPVs in BRCA1/2 were identified. Of these, the majority (74/80) were BRCA1-positive. The following variants: c.181T > G, c.5266dupC, c.1687C > T, and c.844_850dupTCATTAC were identified in 64.4% of BRCA1 carriers. BRCA1/2 detection rate decreased with age at diagnosis but was still 18.2% after age 60 (for BRCA1/2 detection rates stratified according to age at diagnosis see table). In 12/210 (5.7%) TNBC patients PV/LPVs in three other genes were identified (3.3% PALB2, 1.4% CHEK2, and 1% ATM). Conclusions: Prevalence of PVs in BRCA1 appears very high in Slovenian TNBC patients and warrants further population-based allele frequency studies with implications for future population screening. High rates of BRCA1/BRCA2 PVs in patients older than 60 years at diagnosis justify testing all TNBC patients, especially in view of treatment options which now include PARP inhibitors. PALB2 was the second most commonly mutated gene in our patients. [Table: see text]
Tumor sequencing aids to identify individuals with hereditary cancer.
Authors: Imizcoz-Fabra Teresa , Cañada-Higueras Eva , García de Vicuña-Bilbao Nerea , Ramírez-Horcada Beatriz , Bielsa-Colás Arancha , Mora Maria Isabel , Ursúa-Noain Javier , Prat-Barásoain Olga , Abengozar Marta , Alkorta-Aranburu Gorka , Herraiz Maite 
Published: May 2020

e13678 Background: Early identification of individuals with hereditary cancer significantly improves survival in patients and relatives. New genomic tools can identify germline pathogenic variants via tumor-only genomic sequencing in addition to treatment guiding biomarkers. Methods: Our tumor sequencing protocol in medical practice since 2018 via Oncomine Comprehensive Assay (OCA) interrogates several hereditary cancer associated genes; therefore, we aimed to evaluate OCA’s capacity to point out individuals’ with hereditary cancer. But first, OCA’s technical validity was evaluated by testing up to 20 year old FFPE block isolated tumor genomes of individuals known to carry 19 pathogenic variants. Results: All variants were present in the OCA raw dataset but 26% were not called by the commercial software due to specificity of the variant calling algorithm and bias caused by amplicon-based enrichment and limited coverage. Even with this limitation, OCA’s clinical utility was evaluated next. A pathogenic variant candidate to be germline was identified in 5% (26/510) of tumor genomes routinely tested looking for treatment guiding biomarkers, but up to 8% (26/317) when excluding lung cancer patients. Importantly, 73% (14/19) of the ones that were followed-up by peripheral blood testing were confirmed to be germline, so inherited nature of the cancer was confirmed in 9% of ovarian, 8% of endometrium, 5% of biliary tract, 4% of breast, 1% of colorectal and 1% of lung cancer patients whose tumor genome was tested for routine treatment guiding biomarker identification. Conclusions: OCA is a useful genomic tool for identifying individuals with hereditary cancer that opens a new era in clinical practice in oncology. An increased awareness among physicians about this new genomic tool includes understanding the importance of peripheral blood confirmation to define the germline nature of the OCA-identified candidate variant; and proper genetic counseling and germline testing when OCA does not find a candidate variant in a patient with strong family history due to the lack of comprehensive identification of every type of pathogenic variants in all known genes associated with inherited cancer via tumor sequencing tools like OCA.
A DNA-mutational panel for liquid biopsy-based pan-cancer early detection.
Authors: Yi Zhao , Chen Weizhi , He Ji 
Published: May 2020

e13687 Background: Early detection through liquid biopsy can significantly increase the successful chances of treatment. The sensitivity and specificity of early detection are limited by lower signal-to-noise ratio. Thus, well design of liquid biopsy panel is important. Methods: We adopted comprehensive data sources for designing the liquid biopsy panel, including databases of TCGA, ICGC, COSMIC, MSK Cancer Hotspots, while the panel of HCCscreen and CancerSeek. We also considered the database of somatic mutations in Chinese cancer patients generated by us (Genecast (Beijing) Biotechnology Co., Ltd.). We first calculated pan-cancer carrier ratio of somatic mutations in each database and constructed the distribution of mutation counts on step-wise increased carrier ratio. Then, we selected the set of somatic mutations with “elbow point” carrier ratio from each database as part of the panel. Finally, we integrated collected hotspots with the panel of HCCscreen and CancerSeek. Results: We selected 408, 521, 214, 146 and 330 hotspots from databases of TCGA, ICGC, COSMIC, MSK Cancer Hotspots and somatic mutations in Chinese cancer patients, respectively. After integration with the panel of HCCscreen and CancerSeek, this designed panel contains 3,334 bases distributed on 23 chromosomes and 915 gene models. Comparison of hotspots collected from different databases showed that few of them shared the same genomic location except for ones from the database of MSK Cancer Hotspots, indicating the well complementarity between them. Especially, there are 186 unique hotspots collected from the database of somatic mutations in Chinese cancer patients, which can improve the sensitivity of early detection for Chinese and Asian population. Next, we evaluated detected sensitivity of the designed panel based on sequencing data of plasma samples from more than 12,000 Chinese cancer patients collected in Genecast. The result showed that the maximum sensitivity is 66.67% for small cell lung cancer and the overall sensitivity is 45.71% for 26 cancer types, in which hotspots uniquely collected from the database of somatic mutations in Chinese cancer patients accounted for 5.11%. Conclusions: We designed a liquid biopsy panel for pan-cancer early detection and evaluated its sensitivity based on sequencing data of plasma samples from more than 12,000 Chinese cancer patients. Satisfactory performance of our designed panel shows its potential application in cancer screening for healthy and highly risky individuals.
Characteristics and survival of secondary male breast cancer: SEER database analysis.
Authors: Khoury John , Yadav Siddhartha , Rangarajan Tara , Zakalik Dana 
Published: May 2020

e13690 Background: Male breast cancer (MBC) is rare accounting for less than 0.5% of all cancer diagnoses in men. We used the term secondary male breast cancer (sMBC) to refer to ipsilateral and contralateral recurrences in addition to new primary MBC. Given its low incidence, data regarding the risk of developing sMBC and its characteristics are scarce. Methods: Multiple Primary Standardized Incidence Ratios (MP-SIR) session was conducted from the SEER*Stat software. We included all patients diagnosed with stage I,II and III MBC between 1990 to 2015 from the Surveillance Epidemiology and End Results (SEER) 18 registry. The standardized incidence ratio (SIR) was calculated as an estimate of the risk of a second primary malignancy based on the incidence in the general population. Descriptive statistics and Kaplan-Meier analysis were performed using SPSS software. Results: Among all 2321 men diagnosed with a first primary MBC during the study period, 28 patients had a subsequent diagnosis of MBC. The risk of sMBC was significantly elevated with SIR of 33.12 (95% CI, 22.18 – 47.56). The median latency period between the initial and subsequent diagnoses was 5.9 years. 82.1% of the patients were White, 14.3% Black and 3.6% Asian/Pacific Islander. Majority of the cases constituting 85.7% of sMBC were diagnosed in the contralateral breast. 67.8% of the sMBC remained hormone receptors status positive similar to the initial status of the primary diagnosis. 42.9% of the sMBC patients were diagnosed with stage I, 17.9% with stage II, 3.6% with stage III, 17.9% with stage IV and 17.9% of unknown stage. The median overall survival for sMBC was 96 months (95% CI, 11.3-180.6). We also found an increased risk of developing liver cancer (SIR: 2.16), prostate cancer (SIR: 1.29), thyroid cancer (SIR: 3.08) and acute myeloid leukemia (SIR: 2.4) in individuals after a diagnosis of MBC. Conclusions: Men diagnosed with breast cancer are at increased risk of sMBC in addition to other malignancies which require careful monitoring after completing initial treatment. Contralateral mammogram screening or prophylactic contralateral mastectomy can be considered based on patient’s preferences and values.