bluuebunny/crossref_metadata_2025 huggingface dataset:
Serum phospholipids fatty acids and breast cancer risk by pathological subtype: EpiGEICAM study.
Authors: Pollan Marina , Lope Virginia , Guerrero-Zotano Angel , Casas Ana , Baena-Cañada José Manuel , Bermejo Begoña , Perez-Gomez Beatriz , Sanchez-Rovira Pedro , Ramos Vazquez Manuel , Anton Antonio , Garcia-Saenz Jose Angel , Munoz Montserrat , de Juan Ana , Andres Raquel , Llombart Cussac Antonio , Hernando Blanca , Franquesa Rosa María , Caballero Rosalia , Martin Miguel , Priego Feliciano
Published: May 2020

e13604

Background: The role of fatty acids (FA) in breast cancer (BC) etiology is unclear. Most studies are based on self-reported dietary intake, without considering their internal transformation. This analysis tries to assess whether serum levels of 26 phospholipid FA (PL-FAs) and markers of their endogenous metabolism are associated with BC risk, both globally and by pathological BC subtype. Methods: EpiGEICAM-01 is a Spanish multicenter matched case-control study. BC cases and healthy women completed a lifestyle and a food frequency questionnaire, and serum samples were collected. Serum PL-FAs percentages were measured by gas chromatography-mass spectrometry (GC–MS). Conditional and multinomial logistic regression models were used to quantify the association of PL-FAs tertiles with BC risk, overall and by pathologic BC subtypes [luminal, HER2+ and triple negative]. Models were adjusted for age and region (multinomial models), education level, body mass index (BMI), menopausal status, age at menarche and at first birth, hormone replacement therapy, alcohol consumption, last year physical activity, history of benign breast disease, family history of BC and caloric intake, and were corrected for multiple testing. Stratified analyses by BMI and menopausal status were also performed. Results: Questionnaires and serum samples were collected from 795 case-control pairs. Women with high serum levels of stearic acid [odds ratio (OR)T3vsT1= 0.44; 95% confidence interval (CI) = 0.30-0.66], linoleic acid (ORT3vsT1= 0.66; 95% CI = 0.49-0.90) and arachidonic to dihomo-γ-linolenic acids ratio (OR T3vsT1= 0.64 95%; CI = 0.48-0.84; differences were remarkable in overweight/obese women) presented lower BC risk. Participants with high concentrations of palmitoleic acid (ORT3vsT1= 1.65; 95% CI = 1.20-2.26), trans-ruminant palmitelaidic acid (ORT3vsT1= 1.51; 95% CI = 1.12-2.02; differences observed were noticeable both in postmenopausal and in overweight/obese women), trans-industrial elaidic acid (ORT3vsT1= 1.52; 95% CI = 1.14-2.03; markedly both in premenopausal and in non-obese women), and high oleic to stearic acids ratio (ORT3vsT1= 2.04; 95% CI = 1.45-2.87) showed higher risk. These associations were similar in all BC pathological subtypes. Conclusions: Our results, which should be confirmed in future studies, emphasize the importance of analyzing fatty acids individually, as well as the desaturase activity indices. A decrease in the dietary intake of trans-monounsaturated fatty acids could be a good strategy for BC prevention.
Meta-analysis and single-center experience on the comprehensive genomic characterization and landscape of BRCA1 and BRCA2 in Turkey.
Authors: Bisgin Atil , Boga Ibrahim , Sonmezler Ozge , Mujde Cem , Hanta Abdullah , Tug Bozdogan Sevcan
Published: May 2020

e13611

Background: The detection of BRCA1 and BRCA2 mutations both somatic and germ-line became essential for the clinical management strategies of different cancers. Aiming at the identification of common and recurrent mutations that answer the questions about the association between a variant and phenotype, we collected the data of 1126 probands with pathogenic, likely pathogenic variants and variants of uncertain significance (VUS) distributed across 22 Turkish cities. Methods: Peripheral blood samples from 1126 individuals were collected and sequenced via the GeneReader (Qiagen, Hilden, Germany) and MiSeq (Illumina, San Diego, USA) NGS systems for BRCA1/ BRCA2 genes. QCI-Analyze and QCI-Interpret bioinformatics tools were used for bioinformatics analyses. Results: Total of 68 and 108 distinct variants were identified in BRCA1 and BRCA2 genes, respectively. Twenty novel variants were identified in both genes, while BRCA2 had higher heterogeneity. However, there had been no any recurrent mutations identified in any certain geographic region. Among all distinct mutations identified 11.9% were novel, corresponding to 12.8% of all carriers and 28.4% were VUS, corresponding to 32.1% of all carriers. Conclusions: This study presented with three important outcomes. First, a significant molecular heterogeneity in BRCAs among Turkish carriers were confirmed with 15.63% positivity rate. Most notably as the second, this is the first study showing the profiles of recurrent and common mutations that might be unique to Turkish landscape. In conclusion, it is critical to identify all the genetic variants, to aid in diagnosis, prevention, prognosis and treatment. Third and the last, the identification of novel mutations in BRCAs is a vital information that should be shared with mutation databases, in order to use for further clinical interpretation of Turkish population. Key words: Landscape of BRCA1/2, genetic testing, BRCA profiling, population data.
Male breast cancer: Epidemiological evaluation and clinical outcomes.
Authors: Cavalcante Edla Renata , Marchetti Katia Regina , Silva Jamile Almeida , Testa Laura
Published: May 2020

e13619

Background: Male breast cancer (BC) is a rare neoplasia, with a risk of 1:1.000 in USA. Data from Sao Paulo Cancer Registry has shown that BC adjusted incidence rates is about 1.21 per 100,000 at the period from 2001 to 2005, but there is no incidence data for the whole country. Methods: We conducted a unicentric retrospective cohort, with histologically proven male BC patients whose first appointment was between 2008 and 2018 at Instituto do Câncer do Estado de São Paulo in Brazil. The primary endpoint was OS according to metastatic status and initial staging. OS and RFS were analyzed by Kaplan–Meier method and the difference calculated by log-rank test; reported hazard ratios by univariate Cox Models and P-values by score test. Multivariate analysis was calculated through COX regression. Results: 89 male BC patients were accessed, average age at diagnosis was 63.3 yeas-old. 84.2% had carcinoma of no special type (88,7% estrogen positive receptor, 84,2% progesterone positive receptor). When Charlson Comorbidity Index (CCI) was calculated, most (23.5%) were ≥ 7 (10-year survival: 0%), being 17.9% stage IV. Mastectomy was performed at 73% patients, 38.2% received adjuvant chemotherapy; 44.9% received adjuvant radiotherapy and 64% received adjuvant endocrine therapy (94.7% tamoxifen). For metastatic disease, endocrine therapy was the first option in 52%. Median OS was 75 months (95% CI, 39.2-110.7) in M0 and 39 months (95% CI, 25,2–52,8) in M1 ( p = 0.001). CCI showed be an independent death factor (HR 0.37, 95% CI, 0.17-0.8, p = 0.011). Median RFS was 97 months [95% CI, 47.3–146.7]. When BMI was evaluated for patients with obesity (> 30) there was no difference in disease relapse ( p = 0.29). Conclusions: Our results are consistent with those from previous literature, regarding histology, biomarkers and later stage at diagnosis. A quarter of our patients had high CCI and this could had impacted on best treatment option choices. Treatment approaches use to be similar from those of female population. However, as disease biology and hormonal physiology are different between gender, there is a lack of specific protocols and trials in male population.
Breast cancer, cardiac events, and survival: Do outcomes differ in urban and rural populations? A retrospective analysis of a midwest population.
Authors: Tandan Nitin , Cheema Asad , Mirihagalle Noupama , Maini Ruby , Parajuli Priyanka , Regmi Manjari Rani , Lara Garcia Odalys Estefania , Koester Cameron , Abedrabo Sabree , Sahib Hamsa , Niaz Zurain , Ibrahim Abdisamad M. , Johnson Alexander , Bhandari Bishal , Delfino Kristin , Robinson Kathy , Desai Meghna R. , Kulkarni Abhishek
Published: May 2020

e13620

Background: Breast cancer is the most common female malignancy diagnosed in the US. According to the CDC and WWAMI Rural Health Research Center, rural areas have a lower incidence of cancer than urban areas, yet have higher breast cancer related death rates (1,2). Adverse cardiac outcomes may contribute to decreased survival in rural populations. In this abstract, we discuss how environment impacts survival and cardiac outcomes in patients with breast cancer. Methods: An IRB-approved retrospective study was performed utilizing ICD codes to analyze patients diagnosed with biopsy-confirmed breast cancer between January 1, 2014 and December 31, 2017. 478 of 1618 de-identified patients qualified for this study. Statistical analysis was performed with SAS v9.4. Descriptive statistics were computed for all study variables. Continuous variables were described with measures of central tendency (mean, median) and dispersion (range, standard deviation). Categorical variables were summarized as frequencies and percentages. Comparisons between categorical variables were compared with the Chi-Square test (or Fisher’s Exact) where appropriate. Survival curves were estimated using Kaplan-Meier methodology and analyzed with a log rank test. Predictors of survival were assessed with Cox proportional hazards regression analyses. All significance is assumed at the p < 0.05 level. Results: Of 478 eligible patients, the calculated HR was 0.323 with 95% CI between 0.074 and 1.397 (p = 0.130), suggesting greater likelihood of survival in the urban population as compared to the rural population. Cardiac events like heart failure and ACS resulted in Fisher’s Exact p-value of 1, suggesting no significant difference in cardiac outcomes between the two populations. While results were not statistically significant, the trend of decreased survival in the rural population is noteworthy. Conclusions: Per our study, urban populations may have higher propensity for survival as compared to rural populations. There was no statistically significant difference in cardiac events among the two different population. Socioeconomic factors may play a large role in improved survival outcomes in the urban population, which may include but are not limited to travel to/from appointments and cost of medical care. Further large-scale, prospective studies should be performed to confirm the aforementioned trends with respect to survival outcomes in urban and rural populations.
Epidemiology, prevalence, and prognosis of multiple malignancies of a subpopulation of a large German cancer center.
Authors: Rüter Gina , Schmidt Robin , Abdelatif Yassen , Keilholz Ulrich , Burock Susen
Published: May 2020

e13634

Background: Cancer patients have an increased risk of developing secondary primary neoplasia (SPN) compared to the general population. These multiple primary malignancies (MMs) represent an increasing challenge for patients and physicians. So far, little is known about risk factors, patient characteristics, and survival. The study’s purpose was to obtain an overview of the occurrence and distribution of MMs and the outcome and prognosis of affected patients reporting to a large cancer center in Germany. Methods: The cancer registry data base of the Charité Comprehensive Cancer Center was queried for patients, which had their first cancer diagnosis between 01.01.2009 - 31.01.2010 and consecutively developed at least one more primary cancer within the follow-up period till 31.03.2019. For defining MM the rules from the Surveillance, Epidemiology, and End Results (SEER) Program were used. General tumor and patient characteristics as well as outcome were analyzed. Results: In total, 231 patients (155 male; 76 female) were included in the final analysis. Out of the 231 patients, 203 (87.9 %) presented with 2 primary tumors, 27 patients (11.7 %) with 3 and 1 patient (0.4%) with more than three. MMs occurred mostly in patients > 65 years (59.3%) and between 50-64 years (30.3%). According to the SEER definition 75.3% of the patients had metachronous and 24.7% had synchronous MMs. Most male patients presented initially with cancer of the bladder and the urinary tract (20.6%) and developed SPN in the prostate and the testicles (53.1%). The second most common initial cancer in this cohort was cancer of the prostate and testicles (18.1%) and the subsequent developed SPN was cancer of the bladder and the urinary tract (28.6%). For female patients the most common initial diagnosis was breast cancer (32.9%) followed by breast cancer as SPN in 60%. Overall, most frequent SPN were cancer of the prostate and testicles (13.4%), cancers of the lung and trachea (12.6%), and breast cancer (10.4%). Most patients (37.7%) developed the SPN within the 1st year and 28.6% after 5 years or later. Patients with synchronous MMs had a more than 40 months shorter OS than patients with the metachronous MM (79.00 ± 14.58 months vs. 122.00 ± 9.66 months). Conclusions: We could show that most MMs develop within the first year but that there is another peak after 5 years. However, it is still unclear how often SPN are misinterpreted as progressive disease. Therefore, further analyses and close follow-up are necessary.
Survival and cardiac outcomes in elderly individuals with breast cancer: A retrospective study from an academic center.
Authors: Maini Ruby , Tandan Nitin , Regmi Manjari Rani , Parajuli Priyanka , Lara Garcia Odalys Estefania , Koester Cameron , Cheema Asad , Sahib Hamsa , Mirihagalle Noupama , Abedrabo Sabree , Niaz Zurain , Ibrahim Abdisamad M. , Bhandari Bishal , Johnson Alexander , Delfino Kristin , Robinson Kathy , Desai Meghna R. , Kulkarni Abhishek
Published: May 2020

e13635

Background: Approximately 40% of females over the age of 65 are newly diagnosed with breast cancer. When considering elderly patients with breast cancer ( > 65 years old), complex decision making is required as patients have multiple cardiac comorbidities that may confound treatment goals. In this abstract, we aim to identify survival and cardiac outcomes in elderly individuals. Methods: This study was conducted using a retrospective cohort design with use electronic patient records. ICD diagnoses codes were used to identify breast cancer patients. Our initial search criteria revealed 1618 patients. Our eligibility criteria included adult patients 18 years and older with newly diagnosed breast cancer from January 1st, 2014 – January 31st, 2017 which yielded 478 patients. All data was collected through retrospective chart review. Analysis was performed with SAS v9.4 software. Qualitative variables were analyzed using Chi-Square Test. Survival curves are estimated using Kaplan-Meier methodology and analyzed with a log rank test. Predictors of survival are assessed with Cox proportional hazards regression analyses. All significance was assumed at the p < 0.05 level and reported as hazard ratios (HR). Results: Of our 478 breast cancer patients, 260 (59.5%) patients were less than age 65 and 177 (40.5%) patients were older than age 65. Of these two age groups, cardiac events including new diagnosis of heart failure (HF), heart failure (HF) hospitalization, and acute coronary syndrome were studied. For patients with age less than 65: n = 11 for new diagnoses of HF, n = 4 for HF hospitalizations, and n = 3 for ACS. For patients with age greater than 65: n = 5 for new diagnoses of HF, n = 3 for HF hospitalizations, and n = 2 for ACS. Comparing these two groups, there was no statistically significant cardiac event (p = > 0.05). Comparing survival among these two age groups also did not yield statistically significant results (p > 0.05). Conclusions: Per our data, it appears that there is no statistically significant difference in cardiac outcomes in different age groups for patients with breast cancer. Additionally, there was no difference in mortality among different age groups with breast cancer patients. Further prospective studies should be performed to confirm trends of mortality.
Promoting genetic counseling among African American women with hereditary risk for breast cancer.
Authors: Parekh Pooja , Henderson Vida , Hoskins Kent , Kendall LeChaun , Madrigal Jessica , Newsome Jennifer , Coffey Vickii , Grumbach Giesela , Comer-Hagans DeLawnia , Rogers Carolyn
Published: May 2020

e13639

Background: Breast cancer (BC) mortality is substantially higher for African American (AA) women compared to their white counterparts. Genetic counseling (GC) is a key step in management of women with hereditary BC risk, but medically underserved women of color are less likely to receive these services. We report preliminary data from a pilot study examining the impact of a culturally sensitive, multimedia educational video created to motivate AA women with hereditary BC risk to attend GC. Development of the intervention was guided by the Integrative Model of Behavioral Prediction and qualitative research with the target audience. Methods: AA women eligible for GC for hereditary BC according to national criteria were identified through cancer genetic risk assessment (CGRA) performed at the time of a screening mammogram at the University of Illinois Health System in Chicago, IL, and were invited to participate in the study. Participants completed a baseline survey, viewed the educational intervention, and completed a post-intervention survey. The surveys included five-item Likert scales on intentions to act on the information presented, normative beliefs about GC, knowledge, and acceptability of the intervention. Responses were summarized as frequencies and proportions, and changes pre/post-intervention were evaluated using McNemar’s test. Results: The proportion of participants (n = 30) who rated they were “Extremely Likely” to make an appointment with a genetic counselor increased from 50% at baseline to 70% following the intervention (p = 0.04). After viewing the video, the proportion who rated they were “Extremely Likely” to speak with their doctor about genetic counseling increased from 60% to 77% (p = 0.10). There was a 16.6% increase (p = 0.05) in the proportion of women who indicated their family would be interested in learning more about GC, and 96.6% and 90% of participants agreed that the intervention video was enjoyable to watch and that they could relate to what the actors were saying, respectively. Changes in intentions to act on the information presented were not accompanied by changes in knowledge. Conclusions: A culturally sensitive multimedia intervention based on a theoretical model of health behavior increased intentions to attend GC among high risk AA women. The intervention was enjoyable for minority women to watch and increased intentions to discuss GC with family members. These findings indicate that culturally tailored motivational interventions have the potential to increase uptake of GC in underserved communities.
Analysis of gene copy number in esophageal patient-derived tumor xenografts.
Authors: Lukbanova Ekaterina A. , Timoshkina Natalya N. , Kolesnikov Evgeniy N. , Kozhushko Mikhail A , Kit Sergei , Sanamyants Sergey V. , Anisimov Aleksandr E. , Goncharova Anna S. , Protasova Tatiana P. , Kutilin Denis S. , Volkova A. V. , Mindar M. V. , Tkachev Sergey Yu. , Zaikina Ekaterina V. , Khodakova D. V. , Maksimov Aleksey Yu. , Vladimirova Liubov Yu
Published: May 2020

e13648

Background: Patient-derived tumor xenograft (PDX) models are a valuable resource for studying cancer biology and antitumor drug evaluation. The suitability of tumor models in vivo depends on how accurately they mimic a human disease and reproduce the histotype and molecular genetic features of a human tumor. The purpose of the study was to create a PDX model of human cancer and analyze its characteristics. Methods: PDX models of esophageal cancer were obtained by transplanting a tumor fragment from a patient with esophageal squamous cell carcinoma to the BALB/c Nude athymic mice (n = 10 for one PDX generation). Preservation of the tumor histotype was confirmed histologically (hematoxylin and eosin staining). 5 PDX were generated. An analysis of the relative copy number of the YAP1 and KDM6A genes (Real-Time qPCR) in xenograft and donor tumor tissues was performed in each generation. Results: A decrease in the copy numbers of the YAP1 and KDM6A genes by 3.8 and 2.2 times, respectively, was observed in PDX tumor samples (F3 generation) compared to normal donor tissues (p < 0.05). This trend maintained in F4 and F5 generation PDX samples. No changes in the copy numbers of the YAP1 and KDM6A genes were detected in PDX tumor samples in F1 and F2 generations. A cluster analysis (Hierarchical Clustering, Euclidean distance) demonstrated that samples of the first and second generations of esophageal cancer PDX models were closest to the patient tumor tissues in gene copy numbers. Conclusions: Later generations of esophageal cancer PDX models are characterized by changes in the genes copy numbers due to changes in the tumor and clonal selection. Early PDX generations better reproduce genetic, molecular and morphological features of tumors.
Estimating molecular variability of patient-derived xenografts of esophageal cancer.
Authors: Protasova Tatiana P. , Timoshkina Natalya N. , Kolesnikov Evgeniy N. , Averkin Mikhail A. , Gaziev Umar Muhmadovich , Kit Sergei , Anisimov Aleksandr E. , Goncharova Anna S. , Kutilin Denis S. , Volkova A. V. , Mindar M. V. , Tkachev Sergey Yu. , Zaikina Ekaterina V. , Khodakova D. V. , Lukbanova Ekaterina A. , Maksimov Aleksey Yu. , Vladimirova Liubov Yu , Kit Oleg I.
Published: May 2020

e13649

Background: The survival of patients with esophageal squamous cell carcinoma depends not only on clinical signs (TNM, tumor site), but also on the molecular genetic subtype of the tumor. Identification of the molecular genetic subtype and the presence/absence of clinically significant mutations is an important step towards finding new effective drugs and choosing the most appropriate therapeutic strategies. A patient-derived xenograft (PDX) model is a valuable resource to solving the problem, provided that the model accurately reproduces the basic clinical and molecular genetic characteristics of a human tumor. Our purpose was to create a PDX model of a human tumor and to study 7 polymorphisms of the xenograft tissue and tissues of a donor tumor. Methods: PDX models of esophageal cancer were produced by transplanting a tumor fragment from a patient with esophageal squamous cell carcinoma to the BALB/c Nude athymic mice (n = 10 for one PDX generation). 5 PDX were generated. 7 polymorphisms (NFE2L2 (c.85G > A), NOTCH1 (c.1379C > T), NOTCH1 (c.1451G > T), ZNF750 (c.414C > A), ZNF750 (c.1621G > A), SMARCA4 (c.2272C > T), KMT2D (c.15508C > T)) were determined by the HRM analysis in tissues of each PDX generation and in the donor tumor. Results: All examined samples demonstrated the absence of ZNF750 (c.1621G > A) and NOTCH1 (c.1379C > T) polymorphisms and the presence of ZNF750 (c.414C > A), SMARCA4 (c.2272C > T) and KMT2D (c.15508C > T) polymorphisms. Polymorphisms in the NFE2L2 (c.85G > A) gene and in the NOTCH1 (c.1451G > T) gene were found in the F3, F4 and F5 PDX generations, but were absent in the donor tumor and the F1 and F2 generations. Conclusions: Molecular and genetic characteristics of the donor tumor change through several PDX generations. Early PDX generations are recommended for the studies as they better reproduce molecular and genetic characteristics of the original tumors.
Accurate prediction of somatic variants using deep learning model.
Authors: Zhang Peng , Wang Kai , Yao Ming , Wang Aodi , Chen Lijuan , Liu Angen , Shi Xiaoliang , Zhang Shiyue
Published: May 2020

e13659

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

e13661

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

e13662

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

e13670

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

e13672

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

e13679

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

e13681

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

e13684

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

e14013

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