bluuebunny/crossref_metadata_2025 huggingface dataset:
Genomic characterization of preclinical models derived from primary and metastatic sites from rapid autopsy patients in PDMR.
Authors: Chen Li , Patidar Rajesh , Das Biswajit , Evrard Yvonne A , Karlovich Chris Alan , Vilimas Tomas , Nair Nikitha , Peach Amanda , Lee Fong Anna , Romero Luis , Jiwani Shahanawaz , Dutko Lindsay , Benauer Kelly , Radzyminski Marianne , Dougherty Kelly , Eugeni Michelle , Newton Dianne , Hollingshead Melinda G. , Williams Paul M. , Doroshow James H.
Published: May 2020

e13506

Background: The National Cancer Institute has developed a repository of preclinical models [Patient-Derived Models Repository (NCI PDMR, https://pdmr.cancer.gov )] including patient derived xenografts (PDXs), organoids (PDOrgs) and in vitro tumor cultures (PDCs) from patients with solid tumor cancer histologies. A subset of these preclinical models is derived from post-mortem collections from rapid autopsies representing the end point in disease progression. Clinical annotations and genomic datasets associated with these models provide a unique opportunity to study tumor evolution, mechanistic insights into the metastatic process, and treatment resistance. Methods: To date, 43 PDXs, 21 PDCs, and 23 PDOrgs using rapid autopsy specimens from 8 primary and 35 metastatic sites of 18 patients have been developed by the Biological Testing Branch (DTP, DCTD, NCI Frederick, MD) for the PDMR. Whole exome (WES) and total transcriptome (RNASeq) data were processed to generate mutation, copy number alteration (CNA) and gene expression data. Multi-model lineage trees were reconstructed based on putative somatic variants for all the models derived from all patients. The fraction of the genome affected by CNA was compared both within and across PDX models. Results: Most of the rapid autopsy PDX models (32/43) are derived from pancreatic adenocarcinoma (PAAD) patients (13/18), with metastatic specimens originating from sites including liver, colon, omentum, and lung. Driver mutations are present in all preclinical model specimens derived from the same patient. For instance, KRAS p.G12D is present in all patient-derived model specimens derived from PAAD patient 521955. The fraction of the genome affected by CNA remains stable within a PDX model across passages (n = 24, mean = 6.39%, sd = 5.90%). However, we found that this increased when comparing PDX models derived from metastatic sites versus the primary site (n = 19, mean = 16.92%, sd = 10.46%). This indicates presence of tumor heterogeneity between metastatic and primary sites. The lineage tree for models from patient 521955 indicates that one liver metastasis has a unique seeding event compared to the other 4 metastatic sites. Unsupervised clustering analysis on gene expression data also confirms the observed tumor site relationships. Conclusions: Our data demonstrate the potential use of these preclinical models available from the NCI PDMR. These models provide a unique resource for preclinical studies in tumor evolution, metastatic spread mediators, and drug resistance.
NGS-based molecular profiling (a multi-center collaborative, observation study in Japan) highlights pathogenic variants of DNA-repair genes in advanced or recurrent endometrial cancer.
Authors: Fujiwara Hiroyuki , Oda Katsutoshi , Takahashi Nobutaka , Sakata Jun , Taneichi Akiyo , Ikeda Masae , Tanikawa Michihiro , Kusakabe Misako , Mitsuhashi Akira , Kobayashi Yoichi , Yamashita Hiroshi , Suzuki Nao , Akiyama Azusa , Tokunaga Hideki , Tanaka Naotake , Mikami Mikio
Published: May 2020

e13510

Background: Although tumor molecular profiling has now become prevalent, next-generation sequencing (NGS)-based molecular profiling with adequate annotation is limited in recurrent endometrial cancers. We investigated the frequency of alterations in cancer-related genes in a Japanese cohort of incurable endometrial cancer patients. Methods: We enrolled 102 endometrial cancer patients, who had discontinued standard therapy, and extracted tumor DNA from their formalin-fixed paraffin-embedded specimens. Oncomine Comprehensive Assay v3 (ThermoFisher), which covers 161 cancer genes, was used as a comprehensive NGS assay. We only defined variants with the annotations “pathogenic” or “likely pathogenic.” Oncogenicity and actionability were defined with the Oncomine Knowledgebase and “Chrovis database” ( https://chrov.is/ ). The protocol was approved by the institutional ethics committee at each institute, and written informed consent was obtained from all patients before enrollment. Results: The ratios of pathogenic mutations in the PI3K-AKT pathway were 34.3%, 15.7%, and 3.9% for PIK3CA, PTEN, and AKT1, while those in the receptor tyrosine kinase-RAS-MAPK pathway were 3.9%, 2.0%, 3.9%, and 1.0% for FGFR2, KRAS, NF1, and BRAF, respectively. The pathogenic mutation ratios of TP53, ATM, CTNNB1, and FBXW7 were 21.6%, 3.9%, 10.8%, and 9.8%, respectively. In addition to 5.9% of MSH2 variants (five patients with 5-20% and one patient with 56% variant allele frequency (VAF)), pathogenic variants of BRCA1 and/or BRCA2 were identified in 7.8% (seven patients with 5-20% and one with 40% VAFs). Three fusion genes were identified in three patients ( TPR- NTRK1, ESR1- CCDC170, and TBL1XR1- PIK3CA). “Actionable” gene variants (applicable for clinical trials or approved drug available in Japan) were identified in 49.0% of patients. Candidate drugs for patients with actionable variants included ROS1/TRK, AKT, immune checkpoint, and PARP inhibitors. Conclusions: Molecular profiling in poor-prognostic endometrial cancer highlighted the significance of DNA-repair related genes ( TP53, ATM, BRCA1, and BRCA2) and Wnt-beta catenin signaling pathway, and the infrequent alterations in PTEN and KRAS genes, although PIK3CA was frequently mutated. Our data suggest that targeting DNA repair pathway (including PARP inhibitors), may be a treatment option in certain endometrial cancer patients. Clinical trial information: UMIN000027294.
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.
Prevalence of BRCA1 and BRCA 2 and other mutations in Chilean population.
Authors: Selman Carolina , Hurtado Mabel , Chahuan Badir , Mella Fabiola , Marsiglia Hugo
Published: May 2020

e13553

Background: Arturo López Pérez Foundation (FALP) is a Chilean Institution aimed to treatment of cancer patients. Since 2016 it has an Unit for Oncological Genetic Counseling (AGO) for patients with warning flags of potential cases of cancer of genetic origin AGO Unit is aimed to capture patients with warning flags and deliver information through pre-test counseling, offer possibility of a genetic test and post-test counseling. The purpose of this review is to provide relevant results of four years of this Unit. Methods: A descriptive study was carried out from patient care in the Oncological Genetic Counseling Unit of FALP between 2016 and 2019. It was considered those cases in which the process of pretest/post-test counseling was performed. Six "warningflags" were established: cancer in patients under 50 years of age, triple negative breast cancer, breast cancer in men, ovarian cancer, history of 2 or more primary cancers and a family history of cancer The number of test performed was analyzed. The results were expressed in positive pathogenic variants, uncertain variants and negative results. Results: 365 genetic counseling processes were carried out during the period. The average consultation age was 43.2 years (20.8 and 75.5) and 90.1% (329 attentions ) were female. Of the patients, 79.7% (294) perform the genetic test. 18.5% tested positive for a pathogenic variant, 6.5% for a pathogenic variant plus an uncertain variable, and 2.8% for two pathogenic variants. The mutations found were BRCA2 32.6% BRCA1 29.1%, ATM 10.1% RAD51C 6.7% CDKN2 A 5.6%, MUTYH 3.4% TP53 3.4%, MSH2 3.4% RAD51D 2.4%), NF1 1.1%, NTHL1 1.1%, RET 1.1% A 64.9% (237 patients) had cancer diagnosed at the time of the consultation, versus 33.1% of healthy care. 2% had no information. The type of cancer present was 79.7% breast cancer (189), 8.0% ovarian cancer, 2.1% thyroid cancer, 1.7% breast and ovarian cancer, 0.9% colon and/or endometrial cancer and 7.6% other cancers. The warning flags present were 41.2% age below 50 years, 26.2% family history, 15.4% relatives of people with positive results, 8.5% patients with triple-negative breast cancer, 5.3% patients with ovarian cancer, 2.8% patients with 2 or more primary cancers, and 0.6% male breast cancer patients. Conclusions: The highest percentage of patient care was for women with breast cancer, under 50 years of age. The overall test positivity rate is a cumulative 29%. Mutations in BRCA 1 and BRCA 2 were the most detected mutations, as reported in the literature. The slight predominance of BRCA 2 may be due to a familiar component. This is the largest report made in the Chilean population.
MLsurvival: an automated machine learning tool for survival analysis of cancer patients.
Authors: Zhou Wei , He Ji
Published: May 2020

e13555

Background: Survival analysis is used to establish a connection between covariates and the time of event with censored data. Compared with traditional statistical methods, machine learning approaches based on sophisticated and effective computational algorithms are more capable for handling complex multi-dimensional medical data. Methods: We developed an automated machine learning tool MLsurvival to analyze survival data of cancer patients, algorithms of which include the statistical cox regression and machine learning based on linear model (elastic net), ensemble model (gradient boosting with least squares or regression trees and random forest) and support vector kernel (linear and non-linear). The workflow of MLsurvival is comprised with four modules: preprocessing (missing data remove or imputation and feature standardization), feature selection (unsupervised multi-statistics and supervised machine recursive feature elimination with cross-validation), modeling (hyperparameter and performance evaluation) and prediction. To evaluate the performance of this tool, we analyzed medical data for 222 hepatocellular carcinoma (HCC) patients at stage II-III who underwent surgical resection and developed five machine learning approach based estimation models for overall survival (OS). Models were trained on 155 patients with 300 features, including clinical information, somatic mutation and copy number variation, and independently validated on the rest 67 patients. Results: The ensemble model of gradient boosting fitted by MLsurvival using 48 selected features for the data of 155 HCC patients possessed the highest mean AUC and C-Index value. For 67 patients in validation set, this model predicted half year mortality of patients with an AUC of 0.9 (95% CI, 0.771-1.029) and one year mortality with an AUC of 0.897 (95% CI, 0.816-0.978). In addition to that, this model was also predictive for the time of recurrence (pvalue < 0.0001). Furthermore, we also utilized this tool in survival analysis for extensive real data from patients with breast, lung, and esophagus cancers, while most of results showed superior accuracy and stable performance. Conclusions: MLsurvial is an automate tool for survival analysis of cancer patients with well performance. The risk scoring system implemented in this tool offers a novel strategy for incorporating multi-dimensional risk factors to predict clinical outcome, contributes to the better understanding of disease background and helps to optimize the clinical follow-up and therapeutic treatment for cancer patients.
“Smoke and screens”: How streaming spreads the habit of smoking.
Authors: Brandon Maximiliano , Ramirez Ilene , Abal Mariana , Garcia Gerardi Carlos , Tognelli Flavio , Niewiadomski Dario , Marin Ordoñez Alba , Gil Deza Ernesto , Gil Deza Lourdes , Gercovich Natasha , Rivarola Edgardo G. J. , Morgenfeld Eduardo L. , Gercovich Felipe G.
Published: May 2020

e13563

Background: In Argentina, half of the media content reaches viewers through streaming platforms. This papers studies the frequency of smoking in fifty of the most watched programs on Netflix Argentina, and the average exposure to this habit in one hour of viewing. Methods: Between October 1, 2019, and January 10, 2020, we observed fifty of the most watched series on Netflix Argentina, set in the twentieth century or afterwards. The programs were grouped by Netflix Maturity Rating to analyze the frequency of smoking in shows available to different age groups. We established if smoking was present in the show and randomly selected one episode of each to time the amount of smoking. All times were standardized to 60 minutes to compare episodes of different duration. Results: Table shows the frequency of smoking in each of the Netflix Maturity Rating categories. The average exposure time to smoking is 2.5 minutes (r = 0-8 min) every 60 minutes. Conclusions: 1) Viewers are exposed to smoking in 64% of the most watched series on Netflix Argentina, for an equivalent of time to at least three tobacco advertisements per hour. 2) Smoking takes place in 50% to 73% of the series available to teenage viewers (rated 13+ or 16+). 3) Netflix has publicly committed to eradicate smoking from its series. We must ensure this commitment is fulfilled and extended to other streaming platforms and production companies. [Table: see text]
Importance of public awareness of the association of tobacco products to bladder cancer.
Authors: Mullai N , Ruby K. Eric , Weiss Ryan
Published: May 2020

e13564

Background: Many cancers have well-known association with the use of tobacco products. Cancers of lung, esophagus, head and neck, urinary tract including bladder, kidney, pancreas, cervix, etc. have proven causation to tobacco use. This study highlights the close association of the use of tobacco products to bladder cancer and emphasizes the need for increased public awareness in this regard. Methods: Data were collected from the medical records of patients treated during a five-year period (2012-2017). Three hundred sixty-two (362) biopsy proven bladder cancers were analyzed retrospectively. The association of bladder cancer to tobacco use was established and presented. Results: Three hundred sixty-two pathology proven bladder cancers were studied. Eighty percent (80%) of the occurrences were in men and twenty percent (20%) were in women. Twenty-five percent (25%) of the events were multiple occurrences in same patients. The most common histology was urothelial (transitional cell) cancer. A majority, eighty-one percent (81%) had a history of using tobacco products. Only thirteen percent (13%) were non-smokers. However, several of the non-smokers had exposure to secondary smoking or to chemicals of uncertain nature. About six percent (6%) of the cases had no definitive documentation of their risk factors. Conclusions: Bladder cancer is the ninth most common malignancy in the United States. Urothelial carcinoma is the most common histology. The most important risk factors are the use of tobacco products and exposure to certain environmental factors. More than sixty known carcinogens in tobacco smoke are attributed as the casual factors. Field cancerization is one of the hypotheses that account for multiple occurrences of urothelial cancer. The risk due to tobacco use is associated in 50%-65% in men and 20%-30% in women, which triples the incidences of malignancies as compared to non-smokers. Although, the public are well aware of the association of the use of tobacco products with cancers, such as lung, esophagus, and head and neck, there is less awareness that it is also a casual factor for bladder cancer. This study stresses the importance of this conclusion and the need to create a wide spread awareness among the public on the use of tobacco products as a cause for bladder cancer in both men and women.
Breast cancer in younger patients in Southeast of Brazil: 10-year analysis.
Authors: Aleixo Sabina B. , Pulido Jose Zago , Parmanhane Narelle
Published: May 2020

e13567

Background: Breast cancer in Brazil is the most common cancer among women and is also responsible for the highest number of cancer deaths in this group. For Brazil, 66,280 new cases of breast cancer are estimated for the year 2020. This corresponds to an estimated risk of 61.61 new cases per 100 thousand women. For Espírito Santo, the estimate is 790 new cases.. Affection in women under the age of 40 is still infrequent, but it has been growing in the country with more aggressive and advanced cancer at diagnoses. It happens that in Brazil, with the publication of Ordinance 61/2015 by the Ministry of Health, the procedure became exclusive to women aged 50 to 69 years, contrary to what Federal Law 11.664 / 2008 requires, which determines the right mammography exam for all women over 40 years of age. In other words, asymptomatic women who are under 50 or over 70 years of age cannot take the exam on the public network. Methods: The data presented in this study correspond to patients diagnosed with breast cancer from 2007 to 2017 and were extracted from the database of the Hospital Cancer Registry of the Evangelical Hospital of Cachoeiro de Itapemirim (RHC / HECI) through SisRHC, a tool of management of the computerized database for Hospital Cancer Records. Results: Over the 10 years analyzed, in the south Espírito Santo region, 1,546 women started treatment for breast cancer and of these 528 were aged 49 years or less, stratified by age group: 15-24 years 9 cases (1.71%), 25-34 years 64 cases (12.13%)., 35-39 years 96 cases (18.18%), 40-44 years 156 cases (29.54%), 45-49 years. 203 cases (38.44%). A very important factor when making the diagnosis is the clinical staging (EC) of the disease, a fact that directly influences the type of treatment and the woman's survival. Of the cases analyzed, 464 had complete staging data, of these 27 (5.82%) of the cases were EC 0, EC I were 89 (19.18%), 193 (41.60%) with EC II, 122 ( 26.30%) with EC III and, finally, 33 (7.10%) in EC IV. Conclusions: In Brazil, there is a divergence between the guidance of the INCA (National Cancer Institute), an organ linked to the Ministry of Health, which recommends routine mammography after the age of 50, and the Brazilian Mastology Societies and the Brazilian College of Radiology, which indicate the exam for women over 40 years of age. In this scenario, the reduction in the supply of mammograms puts the country against the recommendations of specialists and medical societies. Mammography is a right for all Brazilian women over 40 years of age. This is the law and we need to enforce it, since the incidence of cancer cases in this age group represented one third of the cases.
The study on the effect of depression on breast cancer incidence through IDO/kynurenine pathway.
Authors: Zhang Yanmei , Zhu Ling , Chen Dandan , Xu Rui , Ren Liping , Wei Xiaoqing , Tang Fan , Zhang Yuzhu , Chen Qianjun
Published: May 2020

e13569

Background: Psychosocial factors have been considered as the most common causes for women with breast cancer. However, it remains unclear whether mental stress can influence cancer incidence and progression. This study aims to investigate the relationship between them and the potential molecular mechanism. Methods: Depression model was established by restricting MMTV-PyMT mice in a 50ml-fixator for 4 h per day for 21 consecutive days. Behavioral tests including light-dark box test, open-field test and force swimming test were performed. Then blood, brain and mammary samples were collected at the indicated time points. ELISA was used to detect the concentration of neurotransmitters serotonin, epinephrine and norepinephrine and inflammatory factors IL-6, TNF-a and IL-1β in brain tissue and serum. Real-time quantitative qPCR and western blot were used to detect indoleamine 2, 3-dioxygenase (IDO) expression. The level of tryptophan was measured by high performance liquid chromatography(HPLC). Flow cytometry was used to evaluate the exhaustion of CD8+ T cells. Besides, the correlation between IDO expression detected by immunohistochemistry and the severity of mammary tumors was analyzed in the tumor specimens. Results: We observed that chronic stress caused depression-like behaviors, abnormal secretion of neurotransmitters serotonin, epinephrine and norepinephrine and promoted the development of breast cancer in MMTV-PyMT mice. Depression elevated the secretion of inflammatory factors IL-6, TNF-a and IL-1β in brain tissue and serum, which upregulated the expression of IDO and decreased the level of tryptophan in mice. Furthermore, T cells are sensitive to low tryptophan concentration, so elevated IDO expression suppressed and exhausted CD8+ T cells, ultimately promoting cancer incidence. Administration of xiaoyao pill (a well-known Chinese herbal formula for treating depression) or IDO inhibitor reversed the depression-like behaviors in mice and slowed the development of breast cancer. At the same time, the analysis of clinical samples showed that depression identified by Hamilton Depression Scale(HAMD) and IDO expression in mammary tumor tissues were positively correlated with the severity of mammary tumors. Conclusions: Altogether, our results suggest that depression can promote tumor immune privilege and cancer occurrence through inducing upregulated IDO expression.
Assessing risk-based LDCT screening strategies versus the current USPSTF lung cancer screening recommendations at an institutional setting.
Authors: Velez Martinez Carol , Thurlapati Aswani , Hirani Samina , Cole Constance Larea , Abad Jade , Beedupalli Kavitha , Mansour Richard P.
Published: May 2020

e13572

Background: Lung cancer is the leading cause of cancer related deaths in men and women with 1.76 million deaths worldwide in 2018 [1]. Given its high prevalence and mortality, trials were developed to improve screening strategies. National-Lung-Screening-Trial showed a 20% relative-risk-reduction in mortality in people screened with annual low-dose-CT-scan [2] leading to the implementation of current USPSTF guidelines. We used USPSTF screening criteria to estimate the proportion of non-small cell lung cancer (NSCLC) patients that would have been screening-eligible at our institution.Upon chart review 33% of overall lung cancer patients at our institution did not meet the screening guidelines. We decided to investigate the need to modify the current screening guidelines of our institution based on individual risk assessment. Methods: We conducted a retrospective observational cohort study of the new diagnoses at Louisiana-State-University-Shreveport from 2011-2015. Patients were categorized into high-risk (groups 1 and 2), moderate risk, and low risk according to 2018 NCCN Lung Cancer Screening Guidelines Version 1.2020 [3]. To differentiate between high-risk group 2 and moderate risk, the Tammemagi lung cancer risk calculator was employed, considering 1.3% threshold of lung cancer risk over 6-year time frame [4]. According to NCCN, high-risk group 1 and 2 are eligible for annual low-dose-CT-scan. Results: 33% of overall lung cancer patients at our institution did not meet the screening guidelines criteria, among the 33% ineligible for screening, only 12.5% fell under the high-risk category based on the Tammemagi calculator. Conclusions: Despite using individual risk assessment based on Tammemagi calculator, 87.5% of lung cancer patients ineligible to current USPSTF guidelines are still missing the eligibility for screening at our institution. We believe more efficient risk prediction models have to be developed to improve selection of individuals for lung cancer screening.
Breast cancer incidence and behavior in younger patients: A study from the surveillance, epidemiology, and end results (SEER) database.
Authors: Nasim Zuha , Girtain Christine , Patel Ishan , Gupta Varsha , Hossain Mohammad
Published: May 2020

e13581

Background: Breast cancer screening for women less than 40 years old is practically nonexistent. Since screening can detect cancer at an early stage, not having a surveillance guideline for breast cancer in younger women can result in detection of the cancer at advanced stage. The purpose of this study was to investigate the incidence and behavior of breast cancer in younger women. Methods: The Surveillance Epidemiology, and End Results (SEER) registry data from 2004-2014 was accessed for the study. All women diagnosed with breast cancer and with complete information were included in the study. The data was further divided into two groups based on the age of the patient at the time of diagnosis. The younger group consisted of women < 40 years old (group 1) and the older group consisted of women ≥40 years old (group 2). Both groups were compared on demography and characteristics of the cancer. The continuous variables were tested using student t-tests and categorical variables were compared using Chi-squared or Fisher exact tests. Multivariate analysis was done to find the association of high-grade cancer using a logistic regression model. All p-values are two sided and values < 0.05 were considered statistically significant. Results: Of 599,782 patients who satisfied the inclusion criteria, 28, 243 (4.71%) diagnosed with breast cancer were younger women age < 40 years old. A higher proportion of these younger women presented with larger tumor sizes (between 5.1-10.0 cm), poorly differentiated cancer cells (55.88% vs. 32.85%, P < 0.001) and triple negative receptors (6.83% vs. 3.81%, P < 0.001) than older women respectively. Younger age was significantly associated with high-grade tumor at presentation when controlling for race and marital status. There was roughly 3% increased risk of a high-grade tumor with each decrease of 1 year (odds ratio 0.97, 95% confidence interval [CI] [0.96, 0.99], P = 0.001). Conclusions: This study found that the incidence of breast cancer in younger women was just below 5%, however, when the cancer was diagnosed, these group presented in advanced stages and more aggressive cancer types.