bluuebunny/crossref_metadata_2025_split huggingface dataset:
Precision medicine, genetics and genomics in a community cancer clinic.
Authors: Darabi Sourat , Braxton David R. , Homer Jeanne , Weatherill Chelsey , Brodie Taylor , Buchanan Luanna , Demeure Michael J. 
Published: May 2020

e13511 Background: With advances in technology and the decreasing cost of next generation sequencing (NGS) to identify both germline and somatic pathogenic variants, there is a critical need for curation and interpretation of these results. Clinicians often order the tests simultaneously. Our objective was to analyze results of NGS testing in a community cancer care clinic setting with a coordinated precision medicine program. Methods: In a retrospective review, we analyzed the germline NGS results from patients who were seen by the Hereditary Cancer Program (HCP) at Hoag Family Cancer Institute since 2001. Additionally, we compared those who had both positive genetic testing results and had tumor molecular profiling. Results: A total of 8,239 patients were seen by HCP, 6,100 had germline testing done, approximately 50% had multi gene panel testing (MGPT). 15% of the patients with germline testing had a pathogenic or likely pathogenic mutation. Of those with the positive results, 71% were breast and ovarian cancer and 29% were other cancer types. We also analyzed NGS results for 713 tumors tested through a commercial laboratory in one year. All cases were subjected to our secondary annotation, resulting in additional recommendations in 40% of cases, beyond what was in the commercial report and additional clinical trial options in 30%. Based on a new initiative in the past year, we examined tumor profiling results for indications of possible germline mutations. By analyzing those results, we made recommendations for genetic counseling in 91 (12.8%) cases. Conclusions: The data show the importance of genetic counseling and MGPT in a community setting in patients with personal and/or family history of cancer. Adoption of somatic and germline testing is increasing at our cancer center due to demonstrated benefit to patients and increased physician understanding of the clinical utility of molecular testing.
Genomic alterations and clinical correlations of Chinese patients with hepatoid adenocarcinoma of the stomach/alpha-fetoprotein gastric cancer.
Authors: Liu Tianshu , Chen Erbao , Xu Chen , Li Wei , Li Qian , Cui Yuehong , Yu Yiyi , Shi Weiwei , Lian Baofeng , Qu Yue-Ting 
Published: May 2020

e13514 Background: Hepatoid adenocarcinoma of stomach (HAS) is a rare subtype of gastric cancer (GC) with poor prognosis due to frequent liver metastasis. HAS, recognized as an extrahepatic cancer that resembles hepatocellular carcinoma (HCC), is characterized by solid sheet-like growth structures with hepatoid differentiation and excessive production of alpha-fetoprotein (AFP). This HAS subtype of GC (AFPGC) is genetically distinct compared to other common GC but requires more evidences for better characterization. Methods: Formalin-fixed, paraffin-embedded (FFPE) tumor tissues were collected from 25 HAS and 9 AFPGC patients at Zhongshan Hospital from July 2013 to August 2017 for whole exome sequencing (WES) test. The testing was carried out by a College of American Pathologists (CAP) accredited and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory. Results: Our cohort included 25 males and 9 females who had undergone surgical treatment. The 25 HAS patients had a median age of 66.5 years (range 48-82) and the 9 AFPGC patients had a median age of 64 years (range 52-76). Patients with AFP>20 had a significantly better overall survival (OS) compared with patients with AFP≤20. The most frequently mutated genes were TP53 (44%), TTN (44%), and MUC19 (30%) in HAS tumor samples and CDC27 (44%), NKX2-3 (44%), and TTN (44%) in AFPGC samples. Patients with URI1 or POP4 alterations had a significantly poorer OS than patients without those genes mutations (7.6 months vs. 19.8 months, p = 0.016, and 10.9 months vs. 19.7 months, p = 0.038, respectively). However, patients with SPTA1 alterations had a significantly better OS compared to patients without SPTA1 alterations (27.6 months vs. 15.8 months, p = 0.042). Patients with higher tumor mutational burden (TMB) (≥3.9 muts/Mb) had a significantly better OS compared with patients with lower TMB (<3.9 muts/Mb), which indicated TMB may be an independent prognostic factor (HR: 0.032, 95%CI: 0.003-0.33, p = 0.004). Conclusions: Our study revealed the genomic profile of HAS/AFPGC patients. The most frequently mutated genes in HAS and AFPGC were different, which helps to better characterize these tumors. AFP and TMB may be potential biomarkers for predicting patients’ prognosis.
Novel mutations of SYK gene in solid tumors.
Authors: Shi Jian , Shan Baoen , Luo Ningning , Li Lihua , Zhang Xing , Liu Rongfeng , Song Chao , Shan Yujie , Lu Yi 
Published: May 2020

e13519 Background: Spleen tyrosine kinase ( SYK) is a non-receptor tyrosine kinase (NRTK) in cytoplasmic and plays a crucial role in multiple signaling pathways. The deletion of SYK gene expression will lead to the formation and metastasis of multiple solid tumors. Previous studies focus on the methylation of the SYK gene promoter and the protein isomers, including SYK (L) and SYK (S) which are differed by 23 amino acids in functional domains. Nevertheless, the knowledge of mutations in SYK remains poorly understood. Herein, next generation sequencing were performed to explore SYK mutations for further clinical research. Methods: We retrospectively analyzed the somatic mutations from a comprehensive genomic profiling in tumor tissue or blood ctDNA of 4,093 patients with pan-cancer, of which 2,213 patients using 528 genes panel and 1,880 patients using 539 genes panel, both of the panels contained all exon regions of SYK gene. SYK mutations analyzed by TCGA database was used as validation to our results. Results: In 4093 patients with pan-carcinoma, 36 patients were found mutations in SYK gene and the mutation frequency was 0.880%, of which 4 intron mutations and 32 cases of exon mutations were found in patients, respectively. A number of 9 mutations might affect protein function, which were stop-gained mutations and frameshift mutations and their proportion was 0.220%. The mutation frequency of SYK was consistent with TCGA. Among 9 mutations, 3 mutations were also found in TCGA, which were R574*, M34fs, E376*, respectively. And the rest 6 mutations were newly found, which were V395fs, N615fs, Y74*, G185*, Y74fs, Q145*, respectively. Colorectal cancer was the most common cancer type harboring SYK mutations, and TP53 was the most frequently co-mutated gene of SYK which was counted 5 both in our detected results and in TCGA database. Conclusions: Firstly report of 6 novel stop-gained and frame-shift mutations in SYK gene expanded the understanding of SYK in solid tumors. As a retrospective study in pan-cancer with a relatively small population and the mechanism is unclear, the conclusions of this study needed to be verified with a larger sample.
Characteristics of EGFR uncommon mutations in Chinese cancer patients.
Authors: Wang Minghui , Li Shuben , Wang Hongbiao , Xie Jianjiang , Zhang Junhang , Li Yun , Li Kunsong , Huang Jian , Cheng Chunyan , Wang Kai 
Published: May 2020

e13527 Background: Exon 19 deletions and exon 21 L858R substitutions are the most common mutations of epidermal growth factor receptor (EGFR) in cancers, and the remaining other mutations are called uncommon mutations. Recent studies have shown the clinical relevance of EGFR uncommon mutations with tyrosine kinase inhibitors (TKI) therapies and immunotherapies. Therefore, understanding the distribution and characteristics of EGFR uncommon mutations in cancers would provide evidence for future design of trials and drug development. Methods: Next-generation sequencing data were obtained from 3,026 Chinese tumor samples which have been identified with EGFR mutations. Single nucleotide variations (SNV), short and long insertions/deletions (indel), copy number variations and gene rearrangements were assessed. All tests were carried out in a College of American Pathologists (CAP) accredited and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory in Shanghai, China. Results: EGFR mutations including 32% L858R substitutions, 28% exon 19 deletions, and 40% uncommon mutations were detected in this cohort. EGFR uncommon mutations were most frequently detected in lung cancers, followed by esophageal and gastric cancers. The uncommon mutations of EGFR including 54% SNVs, 30% amplifications, and 9% rare types of mutations such as rearrangement, long indels and complex mutations were detected. The SNVs in exon 18 to 21 which encode the tyrosine kinase domain of EGFR consisted of 16% EGFR mutations. Among them, the mostly frequently SNV was G719X in exon 18 and had 3% EGFR mutations. Mutations in other function domain of EGFR, including extracellular EGF binding domain (0.8%), transmembrane domain (0.03%) and intracellular autophosphorylation domain (0.7%) were also detected. Conclusions: Our data indicated that EGFR uncommon mutations were widely distributed in a variety of cancer types in Chinese patients, mostly in lung cancers. SNVs in the tyrosine kinase domain were the most frequent uncommon mutations. These data will provide clues for future clinical studies.
Association of tumor mutations with arterial thromboembolism risk in patients with solid cancer.
Authors: Ho Ka-wai , Gupta Dipti , Bolton Kelly L , Dunbar Andrew Jeffrey , Willeit Peter , Soff Gerald A. , Jee Justin , Zehir Ahmet , Bryce Yolanda , Sidlow Robert , Devlin Sean M. , Nahhas Omar , Navi Babak B. , Mantha Simon 
Published: May 2020

e13537 Background: Patients with cancer have an increased risk of arterial thromboembolic events (ATE). Clinical characteristics such as medical comorbidities, cancer type, cancer stage and a history of smoking are established risk factors for ATE, but scant data exist about the effect of cancer-specific genomic alterations. We aimed to determine whether individual tumor mutations influence ATE risk. Methods: We performed a retrospective cohort study using tumor mutational data from adults with solid cancers who had MSK-IMPACT testing at Memorial Sloan Kettering Cancer Center between 2014 and 2016. MSK-IMPACT is an FDA-authorized DNA sequencing panel targeting 341+ oncogenes and tumor suppressor genes identifying mutations, copy number alterations, and gene fusions in solid malignancies. The primary ATE outcome was defined as ischemic stroke, myocardial infarction or coronary revascularization and detected by systematic electronic health record assessments. Patients were followed up to one year from the date of tissue-matched blood control sampling to the first ATE or death. We used Cox proportional hazards regression adjusting for age, cancer type, cytotoxic chemotherapy treatment (time-dependent) and tobacco use to determine hazard ratios (HR) of individual genes for ATE risk. We adjusted for multiple comparisons using the Benjamini-Hochberg method. Results: Among 11,317 patients, mean age was 59 years (SD = 14 years) and 55% were women. The most frequent cancers were lung (16%), breast (15%), and colorectal (10%), and 73% were metastatic. During a median follow-up of 253 days, 151 patients had an ATE (1.3%). In multivariable analysis, genomic alterations in KRAS (HR, 2.11; CI, 1.41-3.16), STK11 (HR, 2.62; 95% CI, 1.49-4.59), and ROS1 (HR, 5.3; 95% CI, 1.93-14.58) were independently associated with an increased risk of ATE. Presence of clonal hematopoiesis was not found to be associated with an increased risk of ATE in this cohort (HR, 0.96; 95% CI, 0.63-1.47). Conclusions: In a large genomic tumor-profiling registry of patients with solid cancers, alterations in KRAS, STK11, and ROS1 were associated with an increased risk of ATE independent of cancer type. [Table: see text]
Communication of genetic testing results and cascade testing among Mexican carriers of cancer-associated variants and their families.
Authors: Chavarri Guerra Yanin , Rodríguez-Faure Andrés , Bolano Guerra Laura Margarita , Rodriguez Olivares Jose Luis , Arteaga Jazmin , Castillo Danielle , Mejia Rosa , Herzog Josef , Blazer Kathleen Reilly , Weitzel Jeffrey N. 
Published: May 2020

e13541 Background: Most hereditary cancer syndromes exhibit autosomal dominant inheritance. Therefore, communicating results to family members and performing cascade testing is crucial in order to identify individuals at risk and offer them appropriate risk-reducing strategies. The process of communicating medical information within families is highly variable and might be affected by several factors (including culture, education, understanding of results, and family conflicts) which remain understudied among individuals living in developing countries. We sought to investigate communication of results and cascade testing reach within the families of Mexican individuals carrying cancer-associated pathogenic variants (PVs). Methods: Individuals seen at a single center in Mexico City carrying a cancer-associated PV and enrolled in the Clinical Cancer Genomics Community Research Network (CCGCRN) were included. Carriers received genetic counseling at the time of results disclosure, a family letter was provided to facilitate the communication of results, and cascade testing was offered. After >3 months from results disclosure, participants were surveyed regarding genetic testing results communication patterns, performance of cascade testing, and surveillance behaviors. Data was analyzed using descriptive statistics. Results: Among 354 probands, 53 (15%) were identified as carriers of a cancer-associated PV. Mean age was 48.3 (range 21-82) years. Cascade testing (≥1 family member) was initiated in 74% of families (n = 39), with a median of 3 (range 0-16) family members tested per proband. 53 carriers responded the survey (29 probands and 24 relatives). 98% (n = 43) had shared results with their family, and 53% (24/45) had shared them with their treating physicians. Most respondents were receiving active surveillance (n = 36, 80%); with 43% (n = 15) reporting having at least one barrier for complying with surveillance (financial: n = 8; distance to the hospital: n = 3). Around half of the carriers perceived their cancer risk to be of ≥50%. Conclusions: Our results show that both the communication of genetic testing results and the proportion of cascade testing within Mexican families are high. Family involvement in health care decision-making is common in Mexico, as in other Latin American countries, which might lead to improved family communication. However, strategies to improve communication with providers are needed in order to tackle barriers and improve surveillance of individuals carrying cancer associated PVs.
Characters of germline mutations in Chinese non-small cell lung cancer patients.
Authors: Qiu Yuan , Liu Liping , Deng Qiuhua , Yang Haihong , Chen Hanzhang , Xiao Dakai , Li Weiwei , Jiang Wenxi , Zhu Changbin , Lin Yongping , He Jianxing 
Published: May 2020

e13542 Background: Environment factors are associated with lung cancer occurrence. Genetic susceptibility to lung cancer remains unclear. This study assessed germline mutations in Chinese non-small-cell lung cancer (NSCLC) patients. Methods: 506 FFPE samples were collected from 469 patients pathologically confirmed as lung adenocarcinoma. A 508-gene panel including 63 hereditary cancer genes was applied to detect mutations on MGI-seq 2000. Raw data was processed and analyzed. Variation pathogenicity was categorized following ACMG 2015 guideline. Results: 21 patients (4%) carried (likely) pathogenic (P or LP) mutations in 15 cancer predisposition genes. 11 germline variations included MUTYH (1/21), BLM (1/21), BRIP1(2/21), RAD50(1/21), PMS1(1/21), TP53(1/21), BRCA2(1/2), PALB2(1/21), NF1(1/21), CDH1(1/21) and MRE11A (1/21) genes. Nine likely pathogenic mutations were identified in MRE11A, RAD51C, RAD50, ATR, BRCA2, BLM, PMS1 and VHL genes. These mutations are involved in homologous recombination repair, mismatch repair, Fanconi anemia, and Li-Fraumeni syndrome. Germline mutations were commonly occurred in females (female vs Male: 13 vs 7) without statistical significance. No significant correlations of age of onset and TMB were observed between NSCLC patients with germline wild type and mutation. Other clinical characters like histology and clinical stage presented similar results. Somatic mutations with high frequency like EGFR, KRAS were distributed equally in patients with both germline mutation positive and negative. Conclusions: In this study, there is no significant correlation of germline susceptibility gene mutations with clinical and genetic characters of NSCLC patients. Further investigation on germline genetic aberrations of NSCLC is definitely needed to clarify germline impact on the etiology of NSCLC. [Table: see text]
SLC3A2 mutation as a genetic biomarker for dMMR in colorectal cancer.
Authors: Xiao Jian , Yang Bo , Liu Ming , Huang Tanxiao , Zhang Xiaoni , Liu Yuanyuan , Duan Jingxian , Li Shanshan , Chen Shifu 
Published: May 2020

e13545 Background: SLC3A2 (solute carrier family member 2) 3 is a member of the SLC3 family Ⅱ transmembrane glycoprotein, which is a key component of heteromeric amino acid transporters (HATs). The association between SLC3A2 and cancer was established, given that the amino acid supply by SLC3A2 is required for the resistance of oxidative stress and the maintenance of cell proliferation. However, whether SLC3A2 mutation plays a role in carcinogenesis remains unclear. Methods: This study enrolled 1000 colorectal cancer patients. Tumor tissues and paired peripheral blood mononuclear cells (PBMC) were collected for the sequencing of cancer-related genes by target capture and next-generation sequencing. Results: p.Lys301Argfs*31 mutation in SLC3A2 were detected in 40(40/1000, 4.0%) patients. low TMB and MSS were reported in 2 cases while the remaining 38 cases exhibited high TMB and MSI-H. 41(41/1000, 4.1%) DNA mismatch repair (dMMR) were identified in 41(41/1000, 4.1%) tumor samples, 27(27/41, 65.9%) of which had p.Lys301Argfs*31 mutation. Moreover, this frameshift mutation (COSM253097) was observed in 28 cases of large intestine cancer, 1 case of peritoneum cancer, 1 case of Stomach cancer, 1 case of biliary tract cancer and 1 case of ovary cancer in the COSMIC database. Conclusions: p.Lys301Argfs*31 mutation of SLC3A2 was identified in the majority of colorectal cancer cases with dMMR events, suggesting that this mutation may be a biomarker of dMMR.
The prognostic value of HRD mutations in liver cancer.
Authors: Chen Jinzhang , Huang Tanxiao , Liu Ming , Liao Wenting , Fu Mimi , Yang Bo , Duan Jingxian , Chen Shifu , Guo Yabing 
Published: May 2020

e13546 Background: Liver cancer is the sixth most common cancer in the world and the fourth most common cause of cancer mortality. Genomic alterations including homologous recombination deficiency (HRD) mutations often lead to aberrant regulations of signaling pathways, which play an important role in tumorigenesis. The prognostic value of HRD mutation and its correlation with overall survival in liver cancer is unclear. Methods: We used cBioPortal platform to analyze a cohort of 978 liver cancer samples. Mutations in 13 genes (BRCA1, BRCA2, ATM, BARD1, BRIP1, CHEK1, CHEK2, ABRAXAS1, MRE11, NBN, PALB2, RAD51C, RAD51D) were screened due to the fact that they are the most common indication of deficiency in the homologous recombination (HR) DNA repair pathway. We define overall survival (OS) as the time between the sample collection (surgical) date and the date of death or the last follow-up visit. We conducted Kaplan-Meier survival analysis, and the statistical differences were compared by log-rank tests. Results: 228 of the cases harbored at least one mutation of the HRD-indicator genes. Based on the result, patients were divided into the HRD and non-HRD group. The median OS of the HRD group was 45.47, which is significantly shorter than the OS of the non-HRD group (log-rank test p = 1.6196e-4, Table). Conclusions: HRD mutations are significantly associated with a shorter OS in liver cancer patients. HRD mutation was a negative prognostic factor for overall survival in liver cancer, but the underlying mechanisms remain to be explored. [Table: see text]
Next generation sequencing analysis of key genes in breast cancer patients from Kazakh population.
Authors: Abdrakhmanova Aliya , Omarbayeva Nazgul , Kaidarova Dilyara , Zhunussova Gulnur , Abdikerim Saltanat , Yessenkulova Saule , Jakipbayeva Aizhan , Chingissova Zhanna , Djansugurova Leila 
Published: May 2020

e13548 Background: Breast cancer (BC) shows a high incidence both in Kazakhstan and worldwide. Approximately 20-30% of cases of hereditary breast cancer are caused by presence of BRCA1/2 genes defects. Also, there are additional genes, which can increase the risk of BC and they are still under study. In our study we identify new, detectable and objective markers of key cancer genes by next-generation sequencing (NGS) of young BC patients in Kazakh population. Methods: The study enrolled 235 unrelated patients from Kazakh population(the average age 34.25 ± 4.56) with BC. Genomic DNA was obtained from peripheral blood and sequencing was performed using TruSight Cancer Kit on the MiSeq platform. Studio Variant was used to annotate and interpret genetic variants. 26(11.1%) patients had a maternal family history of BC, 21 (80.8%) of them had first- degree relatives diagnosed with BC at different age. Results: Bioinformatics analysis of NGS data identified 23,915 variants in 83 genes. 64 pathogenic variants in the heterozygous state were found in 62 (26.4%) patients, 8 (12.5%) variants were not previously described in databases (LOVD, ClinVar, 1000 Genomes, ESP6500 and ExAC). The most frequent pathogenic mutations were in the genes BRCA1 (24 variants (37.5%) and BRCA2 (18 (28.1%)). Additional pathogenic variants were identified in the non-BRCA genes (APC, ATM, BLM, CHEK2, PALB2, TP53, ERCC2, FANCA, FANCM, NBN, PMS1, PMS2, SDHB and XPA). A hereditary history was recorded in 29.1% and 27.8% of representatives of the group with pathogenic mutations in the BRCA1 and BRCA2, respectively, higher compared to the group of patients without pathogenic mutations and to the group of patients with non-BRCA genes. Conclusions: The frequent and novel germline mutations in BRCA1/2 and non-BRCA genes were identified by NGS. Diagnostic and prevention tools for key genes are considered to be developed and included in the National guidelines of Republic of Kazakhstan after final statistic data processing.