bluuebunny/crossref_metadata_2025_split huggingface dataset:
The impact of tumor NGS testing on hereditary cancer risk assessment and population management in an integrated community health care system.
Authors: Thomas Sachdev P. , Suga Jennifer Marie , Truong Thach-Giao , Sundaresan Tilak Kumar , Pan Minggui , Kim Won , Jiang Chen , Hoodfar Elizabeth , Chung Elaine , Tse Pamela , Achacoso Ninah , Cheng Lirong , Habel Laurel A. 
Published: May 2020

1517 Background: Next-generation sequencing (NGS) for tumor molecular profiling is used in Oncology to identify ‘actionable alterations’ for clinical trials or on/ off-label therapy. Tumor NGS can also reveal potentially heritable germline mutations. The frequency of such incidental germline mutations has been estimated to be 4-15%. The 2015 ASCO Statement supports communication of medically relevant incidental germline findings from somatic mutation profiling to patients (PTS). The impact of tumor NGS testing on hereditary cancer risk assessment programs in the context of a wider population management strategy is unknown. We sought to evaluate this within our Kaiser Permanente Northern California (KPNC) population with ready access to tumor NGS and an ongoing hereditary cancer risk assessment program. Methods: Kaiser Permanente Northern California (KPNC) is part of a large, integrated health care system. NGS at KPNC is performed in collaboration with STRATA Oncology, a precision oncology partnership. All NGS results are reviewed by a multidisciplinary KPNC Genomic Oncology Committee (GOC)which also includes genetic counselors and pathologists. We examined all NGS reports between November 2017 through December 2019 to determine the types of cancers tested, number with a possible germline mutation and number referred for genetic counseling and testing (GCT). Results: 4,825 PTS with advanced cancer underwent STRATA NGS testing. A total of 207 PTS (4.3%) were identified as potential germline mutation carriers, all 207 were recommended for GCT referral. Of these, 92 (45.0%) separately met 2020 NCCN Criteria for Genetic/Familial High-Risk Assessment (2020NG/FA), prior to tumor NGS; 115 (53.6%) did not and 3 (1.4%) had insufficient information. The cancers most frequently meeting NCCN criteria were pancreatic, breast and colon. Of the 92 PTS who met 2020NG/FA, 60 (65%) underwent GCT and 34 (57%) were confirmed to have a germline mutation. Of the 115 PTS that did not meet 2020NG/FA, 47 (41%) underwent GCT and 19 (40%) were confirmed to have a germline mutation. Overall germline mutations were confirmed in 16.5% of patients who did not meet 2020NG/FA and 37% who did. Conclusions: In our community-based integrated healthcare system, systematic review of next-generation sequencing results by an expert GOC led to more robust identification of germline mutation carriers and navigated them to appropriate GCT. Ongoing work will clarify data on cascade testing. We are currently developing automated workflows for GCT.
Characterization of clonal hematopoiesis of indeterminate potential mutations from germline whole exome sequencing data.
Authors: Wu Hsin-Ta , Kalashnikova Ekaterina , Mehta Samay , Salari Raheleh , Sethi Himanshu , Zimmermann Bernhard , Billings Paul R. , Aleshin Alexey 
Published: May 2020

1525 Background: Clonal hematopoiesis of Indeterminate Potential (CHIP) is an age-related phenomenon where somatic mutations accumulate in cells of the blood or bone marrow. It is a source of biological noise that causes false-positives in ctDNA analysis and is present in up to 20% of individuals over the age of 70. The presence of CHIP has been linked to an increased risk of hematologic cancers and cardiovascular disease. The Signatera assay filters CHIP mutations through tumor tissue and germline sequencing thereby reducing false-positive results and focuses on tumor-specific mutations for each patient. Methods: Whole exome sequencing data (average depth ~250x) analyzed from patients’ buffy coat (n = 159) was used to characterize CHIP mutations. Variant calling was performed using Freebayes variant caller with allele frequency threshold between 1% and 10%. Following which variant annotation and selection was performed based on the top 54 genes that are most implicated in myeloid disorders. The selected variants were further screened based on the reported variants in the literature and/or the Catalog of Somatic Mutations in Cancer (COSMIC). Results: The analysis revealed an average of 0.14 (0-2) CHIP mutations per patient with an average variant allele frequency of 3.49% (1%-8.5%). The most common CHIP mutations were observed in DNMT3A, (n = 17), TET2 (n = 7) and TP53 (n = 7) genes. The percentage of patients with at least 1 mutation found in DNMT3A, TET2, and TP53 were 4.2%, 1.94%, and 1.38%, respectively. Other genes containing CHIP mutation included CEBPA, ETV6, HRAS, PDGFRA, NRAS, KMT2A, EZH2, GATA2, GNAS at a frequency below 1%. CHIP mutations were not observed in patients younger than 40 years, but they increased in frequency with every decade of life thereafter. The incidence of CHIP increased from 0.04 for the 40-50 yrs age group to 0.18 for individuals older than 60. Further analysis of associations between incidence of CHIP and cancer type, prior exposure to chemotherapy as well as longitudinal evolution of CHIP mutations during cytotoxic treatment are underway and will be presented. Conclusions: CHIP, a common finding in the elderly population is an important factor to consider in ctDNA analysis and most frequently involves DNMT3A, TET2, and TP53 genes. The frequency of CHIP can be impacted by a number of other factors such as cytotoxic chemo- or radiotherapy.
Evaluating the association between clonal hematopoiesis and germline pathogenic and likely pathogenic variants in cancer predisposition genes.
Authors: Comen Elizabeth Anne , Razavi Pedram , Patel Parth Bhargav , Martin Axel , Seshan Venkatraman E. , Mandelker Diana , Ptashkin Ryan , Kemel Yelena , Stadler Zsofia Kinga , Ladanyi Marc , Berger Michael F. , Zehir Ahmet , Robson Mark E. , Reis-Filho Jorge S. , Norton Larry , Levine Ross L. 
Published: May 2020

1535 Background: Clonal hematopoiesis (CH) is most commonly associated with mutations in genes with a known or putative role in leukemia and with an increased risk for hematologic malignancies. Nearly 50% of primary breast cancers contain leukocytes with CH mutations and CH mutations can be found in breast cancer (BC) tumor infiltrating leukocytes years prior to the development of secondary leukemia. It is currently not known whether CH is more prevalent among BC patients with both germline pathogenic variants and likely pathogenic variants (collectively referred to as PV) in cancer predisposition genes. Here we evaluated the relationship of CH to PV in 546 BC patients (pts). Methods: 546 BC pts underwent targeted capture sequencing of tumor and peripheral blood (PB) samples using MSK-IMPACT. Sequencing results from PB were used for identifying PV affecting up to 89 cancer predisposition genes and somatic mutations in 15 genes commonly associated with CH using previously validated methods. All pts consented via an IRB-approved protocol. Results: The majority (82.3%) of pts had non-metastatic disease. 59.7% of the 546 pts received chemotherapy and 42.7% received radiation. Of the 546 pts, 90 patients had germline PV in a cancer predisposition gene for a total of 98 germline PV identified (8 patients had 2 germline PV). Mutations in DNMT3A followed by TET2 were the most common CH mutations identified. CHEK2 PV were statistically significantly associated with CH in a multivariate analysis after controlling for age, prior chemotherapy and radiation therapy (OR: 3.94, CI: 1.51-10.26, p-value ≤0.005). Age by decade was significantly associated with the presence of CH in that model (OR: 1.93, CI: 1.53-2.42, p value ≤0.001). Of the 8 patients with CHEK2 germline PV and CH, the most common mutated CH genes were DNMT3A (4 pts), followed by TET2 (2 pts), although our sample size is too small to test for significant enrichment for any specific CH gene, type of CH mutation, or trinucleotide context. Further, CH was not associated with germline PV in other cancer predisposition genes. Conclusions: Our findings provide evidence of an association between CHEK2 germline PV with CH in BC pts, which will be further tested in an expanded cohort. If this association is confirmed, it might have theoretical and practical implications, including cancer prevention strategies.
Test of an online tool to facilitate NCCN guideline-compliant access to cancer genetics care.
Authors: Milliron Kara J. , Cook Amanda , Keren David , McCain Lynn A. , Schroeder Lee , Hulswit Bailey , Arthurs James , Harper Diane M , Ernst Susan , Zazove Philip , Parvaz Jasmine , Merajver Sofia 
Published: May 2020

1542 Background: Minority populations experience inequities of access to cancer genetics. We developed and tested an online family history collection and interpretation tool, InheRET, to determine acceptability, validity and utility.Patients are mostly unable to recall accurate family history in clinic and providers have little time to collect the 3-generation pedigree. Thus, ~90% of high risk patients remain unidentified. We evaluated the impact InheRET has on facilitating National Comprehensive Cancer Network (NCCN) Guideline-compliant referrals for cancer genetic counseling. Methods: Patients from 3 clinics were consented online to participate. A user experience survey for patients and providers followed the health history questionnaire. Results: 628 patients were consented over a year, 555 (>88%) completed the tool. 439 (79%) completed the post-questionnaire user experience. Review of Inheret's recommendations by a genetic counselor found 100% accuracy. Ease of Use: 84-87% of patients reported tool was easy to use. Understandability: 92-97% of patients reported tool was easy to understand. No significant differences were reported between those with high school (n=28, avg age 50.1 yrs) compared to those with advanced degrees (n=139, avg age 45.4 yrs); patients age 70+ experienced increased difficulties. Among primary care patients (n=135), 43 established patients were newly identified as meeting NCCN referral criteria. Healthcare providers found InheRET useful, did not require extra clinical time, and all wish to continue to use it. The patient provided data were more complete and encompassed more family members than with paper forms. Turn-around-times to receive the patient’s information were decreased from 4-6 weeks to ~ 72 hours. A patient scheduling backlog of 400 patients was cleared using InheRET. Previously, 40% of cancer genetics patients were lost to follow up, due to not completing their intake forms. This number was reduced to 6.5%. Conclusions: Patients find InheRET to be easy to use and understand and they complete this health history tool more frequently and in greater detail than by paper forms. InheRET provides accurate results, verified by in person interviews, in a timely fashion, saving clinical time, possibly enabling increase in earned clinical revenues (under analysis), and improving patient care overall. Importantly, the 43 primary care patients identified to be at increased risk were already established patients, who had not been previously identified as such by their healthcare providers as being at increased risk.
Potential germline findings identified during somatic tumor testing: Room for improvement.
Authors: Khan Sundas , Wright Heather , Cuke Melissa , Folefac Edmund , Verschraegen Claire F. , Wood Marie 
Published: May 2020

1543 Background: Genomic testing, useful for treatment planning and identification of patients for clinical trials, may indicate the presence of a germline mutation. We sought to evaluate the incidence of potentially actionable germline mutations detected via genomic testing and determined rates of germline testing among patients with potential germline mutations. Methods: This was a retrospective review of patients undergoing genomic testing at The University of Vermont Cancer Center (UVMCC) between 03/02-11/19. Testing was reviewed for mutations in 60 genes associated with hereditary cancer and recognized as clinically actionable by the American College of Medical Genetics. Records were reviewed for clinical follow-up. Positive (pathogenic or likely pathogenic) genomic test results were evaluated with descriptive analyses. Proportions with 95% confidence intervals are presented and comparisons made using a χ2 test. Results: 342 patients underwent genomic testing at UVMCC over the study period, with a median age of 61. Common tumor types include: CNS (19%), NSCLCA (17%), ovarian (8%), and sarcoma (7%). 59% (203/342) had a mutation in ≥ 1 gene associated with hereditary cancer. Most common tumor types with potential germline mutations include: NSCLCA (25%), CNS (18%), ovarian (8%), sarcoma (8%), and endometrial (7%). Potential germline mutations were most commonly identified in TP53, CDKN2A, PTEN, and RB1 (each with mutations in >6% of patients). 58 patients in the cohort have undergone germline testing, of which 19% were positive for germline mutations. Of patients with mutations in the highly penetrant BRCA, PALB2, and Lynch genes, 71% were positive for germline mutations. Young age ( < 50) did not enrich for germline mutations (p > 0.05). Only 18% (36/203) of patients with potential germline results were referred for genetic counseling. Conclusions: Genomic testing can reveal hereditary cancer syndromes. While the majority of patients with tumor mutations in genes associated with hereditary cancer will not have germline mutations, genetic testing is the only way to confirm this. 19% of patients who underwent genetic testing in this cohort had a pathogenic germline mutation. This was enriched to 71% when considering genes rarely mutated in tumors (BRCA, PALB2, and Lynch genes). Only 17% of this cohort underwent genetic testing, representing a significant missed opportunity given the implications of these findings for both patients and families. Patients and their providers should be aware of the potential for germline findings when genomic testing is performed.
Outcome of patients with breast cancer and a germline BRCA mutation in a prospective cohort.
Authors: Arun Banu , Gutierrez Barrera Angelica , Layman Rachel M. , Gruschkus Stephen K. , Bedrosian Isabelle , Albarracin Constance T. , Barcenas Carlos Hernando , Valero Vicente , Litton Jennifer Keating , Tripathy Debu 
Published: May 2020

1544 Background: There are limited large prospective single institution studies on outcome of breast cancer in patients with germline BRCA1 and BRCA2 mutation. The primary aim of this study was to determine the effect of a germline BRCA1 or BRCA2 mutation on recurrence-free survival (RFS) and overall survival (OS) in patients with breast cancer. Methods: This is a prospective cohort study of patients with invasive breast cancer recruited from the UT MD Anderson Cancer Center Breast Medical Oncology and Clinical Cancer Genetics Center. For the purpose of this analysis, newly diagnosed breast cancer patients who have had germline BRCA1 and BRCA2 testing within 12 months were included. Clinical and pathological data, and data regarding outcomes were collected in this prospective cohort. The Kaplan-Meier method and corresponding log-rank test were used to estimate OS and RFS and to compare survival by mutation status. Results: Between 1996 and 2015, 3026 patients were recruited. Median age at diagnosis was 45 (19-87) years. A germline BRCA mutation was detected in 361 (11.9%) patients (207 with BRCA1, 154 with BRCA2). After a median follow-up time of 5.3 (0.04-20.7) years, 437 (14.4%) patients recurred and 340 (11.2%) were deceased. At median follow-up time 5 years, 79.3% of BRCA1, 91.4% of BRCA2 and 89.6% of BRCA negative patients were disease free; this difference was significant (p = 0.0001). Difference in OS between BRCA1/2-positive and BRCA-negative patients was also significant (p = 0.0001), with 81.2% of BRCA1, 93.4% of BRCA2 and 90% of BRCA negative patients being alive at 5 years. Amongst 600 patients with triple negative breast cancer (TNBC) patients, DFS and OS were not significantly different between the 3 groups. Of those patients diagnosed under 40 years (n = 937), RFS and OS was significantly different between 3 groups at 5 years (0.001 for RFS and OS); 75% BRCA1, 92% BRCA2 and 86% BRCA negative patients were disease free and 77% BRCA1, 94% BRCA2 and 88% BRCA negative patients were alive. Conclusions: Patients with BRCA1 or BRCA2 mutations have different survival outcomes. The prognosis of the first cancer needs to be taken into consideration when deciding for preventive surgeries to prevent second primary breast cancers in these patients. Furthermore, for BRCA1 mutation carriers more effective therapy strategies need to be evaluated to improve outcome.
Tumor detection rates in screening carriers with SDHx-related hereditary paraganglioma-pheochromocytoma syndrome based on prior tumor history.
Authors: Greenberg Samantha , Jacobs Michelle , Wachtel Heather , Anson Amanda , Buchmann Luke , Cohen Debbie , Bonnani Maria , Bennett Bonita , Naumer Anne , Schaefer Amanda , Kohlmann Wendy , Nathanson Katherine , Else Tobias , Fishbein Lauren 
Published: May 2020

1545 Background: Patients with germline pathogenic variants (PVs) in the SDHx genes have increased risk for paragangliomas/pheochromocytomas (PGL/PCC), renal cell carcinomas, and gastrointestinal stromal tumors. Expert recommendation suggests individuals with SDHx PVs undergo biennial whole-body imaging and annual biochemical testing. This study aimed to evaluate tumor detection rate using standard biochemical and imaging protocols for individuals with SDHx PVs, particularly in those with and without SDHx-related tumor history, and in those with biochemical testing data. Methods: A retrospective longitudinal observational study at the Universities of Michigan, Pennsylvania, and Utah Huntsman Cancer Institute was conducted from the start of each center’s screening program through March 1, 2018. Individuals with SDHx PVs had clinical imaging with whole body MRI/CT and biochemical testing per expert recommendation. SDHx-related tumors identified during clinical screening were measured. Results: A total of 263 individuals with SDHx PVs completed 491 screens. Individuals with SDHB PVs were the most prevalent (n = 188, 71.5%). The average number of screens per subject was 1.87 (range 1-7). A majority (n = 194, 73.7%) of individuals did not have a prior history of PGL/PCC. Overall, SDHx-related tumors were detected in 17.1% (n = 45) of the cohort. Of the 46 scans that identified an SDHx-related tumor, 85% of them (n = 39) were baseline scans. SDHx-related tumors were identified in 18.6% (n = 36/194) of individuals that did not have a prior history of PGL/PCC, whereas they were identified in 13.0% (n = 9/69) of individuals that did have a prior history of PGL/PCC (p = 0.39). Biochemical testing was available for 70% (n = 343) of imaging screens, of which 18% (n = 61) had positive biochemistry. Of those with positive biochemistry, 19 tumors were identified on imaging (6%). Sixteen tumors were identified on imaging with negative biochemistry (5%) with a sensitivity of 54% and a specificity of 94%. Utilizing a cut-off of two times the upper limit of normal, 9.91% (n = 34) biochemical tests were positive, and 15 (44.12%) had an SDHx-related tumor on corresponding imaging. Conclusions: Current SDHx screening protocols are effective at identifying SDHx-related tumors. Tumors were detected in subjects with a prior history of PGL/PCC and those with no prior history. This suggests life-long screening is important for all SDHx carriers. Imaging is a crucial piece of SDHx screening given biochemical testing’s sensitivity and specificity.
Non-invasive detection of urothelial carcinoma (UC) by cost-effective low-coverage whole genome sequencing from urine exfoliated cells DNA.
Authors: Zeng Shuxiong , Nai Dongxing , Ye Yingdie , Ji Jiatao , Zhou Zunlin , Wang Baiyun , Ziliang Qian , Xu Changliang 
Published: May 2020

1552 Background: Urothelial carcinoma (UC) is a malignancy with frequent chromosomal aberrations. The FISH assays were more sensitive as compared to cytology tests. Here we investigated cost-effective whole genome sequencing technology, which is able to detect all chromosomal aberrations for UC diagnoses. Methods: UC patients and control group are prospectively recruited in trial NCT03998371. First-morning-voided urine were freshly collected before TURBT or cystectomy. Urine Exfoliated Cells DNA was analyzed by illumina HiSeq X10, followed by genotyping by bioinformatics workflow UCAD. Results: 195 individuals were prospectively recruited. 121 UC patients and 67 non-tumor diseases were included in this study. 7 other malignancies as confirmed by pathological testing were excluded. Frequent chromosome copy number changes were found in cancer patients as compared non-tumor controls, including chromosome 3 gain, 17 gain, 7 gain and 9p loss used in FISH assays were found. In addition to that, chr9q loss, 8q gain, 5q loss, 17p loss, 11p loss, 1q gain, 8p loss, 10q loss, 6q loss, 4q loss and 11q loss were also frequent in cancer patients (AUC > 0.65). Metacentric chromosomes showed better AUC compared to acrocentric and telocentric chromosomes (P = 1.7e-03). A novel diagnosis model UCAD was built by incorporating all the chromosomal changes. The model reached performance of AUC = 0.933. At the optimal cutoff |Z| > = 3.16, the sensitivity, specificity and accuracy were 84.7%, 97.9% and 89.0% respectively. The prediction positivity was found correlated with urine microscopy visible epithelial cells (P = 0.00069), tumor invasiveness (Ta/Tis vs the other, P = 0.0048) and tumor grade (P = 0.0030), but not microscopy RBC/WBC findings, urine culture findings, smoke and drinking history. The UCAD model outperformed cytology tests by predicting all 16-cytology positive and 12 cytology negative tumors with comparable specificity. The model found 75.0% more tumors. And UCAD identified more upper urinary tract cancer (P = 0.012) and smaller tumors ( < 3cm, P = 5.9e-04). The adding of cytology to UCAD did not improve diagnosing sensitivity and specificity. UCAD reproduce the diagnoses among morning - void urine, morning, afternoon urine samples with correlation coefficient R2> 0.98. All the urine samples showed high concordances with matched tumor samples (R2> 0.85). Conclusions: UCAD could be a high specific, robust UC diagnoses method with improved sensitivity as compared to cytology tests. Clinical trial information: NCT03998371.