77 results on '"Niknafs N"'
Search Results
2. Corrigendum to “HLA class II immunogenic mutation burden predicts response to immune checkpoint blockade”
- Author
-
Shao, X.M., primary, Huang, J., additional, Niknafs, N., additional, Balan, A., additional, Cherry, C., additional, White, J., additional, Velculescu, V.E., additional, Anagnostou, V., additional, and Karchin, R., additional
- Published
- 2023
- Full Text
- View/download PDF
3. OA12.01 Genomic and Immune Cell Landscape of Response to Chemo-Immunotherapy in Malignant Pleural Mesothelioma
- Author
-
Niknafs, N., primary, Forde, P., additional, Lanis, M., additional, Belcaid, Z., additional, Smith, K., additional, Sun, Z., additional, Balan, A., additional, White, J., additional, Cherry, C., additional, Shivakumar, A., additional, Shao, X., additional, Kindler, H., additional, Purcell, T., additional, Santana-Davila, R., additional, Dudek, A., additional, Borghaei, H., additional, Illei, P., additional, Velculescu, V., additional, Karchin, R., additional, Brahmer, J., additional, Ramalingam, S., additional, and Anagnostou, V., additional
- Published
- 2021
- Full Text
- View/download PDF
4. Vomiting in Pediatric Patients
- Author
-
Wray, A, Towle, D, Lucas, A, Thompson, S, Rebillot, K, and Niknafs, N
- Published
- 2020
- Full Text
- View/download PDF
5. Post-termination Hemorrhage
- Author
-
Wray, A and Niknafs, N
- Published
- 2019
- Full Text
- View/download PDF
6. Pediatric Both Bone Forearm Fracture
- Author
-
Wray, A and Niknafs, N
- Published
- 2019
- Full Text
- View/download PDF
7. Genome-wide cell-free DNA fragmentation in patients with cancer
- Author
-
Cristiano, S., Leal, A., Phallen, J., Fiksel, J., Adleff, V., Bruhm, D.C., Jensen, S.O., Medina, J.E., Hruban, C., White, J.R., Palsgrove, D.N., Niknafs, N., Anagnostou, V., Forde, P., Naidoo, J., Marrone, K., Brahmer, J., Woodward, B.D., Husain, H., Rooijen, K.L. van, Orntoft, M.W., Madsen, A.H., Velde, C.J. van de, Verheij, M., Cats, A., Punt, C.J.A., Vink, G.R., Grieken, N.C. van, Koopman, M., Fijneman, R.J., Johansen, J.S., Nielsen, H.J., Meijer, G.A., Andersen, C.L., Scharpf, R.B., Velculescu, V.E., Cristiano, S., Leal, A., Phallen, J., Fiksel, J., Adleff, V., Bruhm, D.C., Jensen, S.O., Medina, J.E., Hruban, C., White, J.R., Palsgrove, D.N., Niknafs, N., Anagnostou, V., Forde, P., Naidoo, J., Marrone, K., Brahmer, J., Woodward, B.D., Husain, H., Rooijen, K.L. van, Orntoft, M.W., Madsen, A.H., Velde, C.J. van de, Verheij, M., Cats, A., Punt, C.J.A., Vink, G.R., Grieken, N.C. van, Koopman, M., Fijneman, R.J., Johansen, J.S., Nielsen, H.J., Meijer, G.A., Andersen, C.L., Scharpf, R.B., and Velculescu, V.E.
- Abstract
Item does not contain fulltext, Cell-free DNA in the blood provides a non-invasive diagnostic avenue for patients with cancer(1). However, characteristics of the origins and molecular features of cell-free DNA are poorly understood. Here we developed an approach to evaluate fragmentation patterns of cell-free DNA across the genome, and found that profiles of healthy individuals reflected nucleosomal patterns of white blood cells, whereas patients with cancer had altered fragmentation profiles. We used this method to analyse the fragmentation profiles of 236 patients with breast, colorectal, lung, ovarian, pancreatic, gastric or bile duct cancer and 245 healthy individuals. A machine learning model that incorporated genome-wide fragmentation features had sensitivities of detection ranging from 57% to more than 99% among the seven cancer types at 98% specificity, with an overall area under the curve value of 0.94. Fragmentation profiles could be used to identify the tissue of origin of the cancers to a limited number of sites in 75% of cases. Combining our approach with mutation-based cell-free DNA analyses detected 91% of patients with cancer. The results of these analyses highlight important properties of cell-free DNA and provide a proof-of-principle approach for the screening, early detection and monitoring of human cancer.
- Published
- 2019
8. In Flight Emergency: Altered Mental Status Secondary to Hypoglycemia
- Author
-
Niknafs, N, Katzer, R, and Wray, A
- Published
- 2018
- Full Text
- View/download PDF
9. Pathologic features of response to neoadjuvant anti-PD-1 in resected non-small-cell lung carcinoma: a proposal for quantitative immune-related pathologic response criteria (irPRC)
- Author
-
Cottrell, T.R., primary, Thompson, E.D., additional, Forde, P.M., additional, Stein, J.E., additional, Duffield, A.S., additional, Anagnostou, V., additional, Rekhtman, N., additional, Anders, R.A., additional, Cuda, J.D., additional, Illei, P.B., additional, Gabrielson, E., additional, Askin, F.B., additional, Niknafs, N., additional, Smith, K.N., additional, Velez, M.J., additional, Sauter, J.L., additional, Isbell, J.M., additional, Jones, D.R., additional, Battafarano, R.J., additional, Yang, S.C., additional, Danilova, L., additional, Wolchok, J.D., additional, Topalian, S.L., additional, Velculescu, V.E., additional, Pardoll, D.M., additional, Brahmer, J.R., additional, Hellmann, M.D., additional, Chaft, J.E., additional, Cimino-Mathews, A., additional, and Taube, J.M., additional
- Published
- 2018
- Full Text
- View/download PDF
10. Ethical and legal aspects of patient’s safety: A clinical case report
- Author
-
Kadivar, M., Manookian, A., Fariba Asghari, Niknafs, N., Okazi, A., and Zarvani, A.
- Subjects
Ethics ,Patient safety ,lcsh:R723-726 ,Risk management ,lcsh:History of medicine. Medical expeditions ,education ,Legislation ,Case study ,lcsh:Medical philosophy. Medical ethics ,lcsh:R131-687 ,humanities - Abstract
Since patient safety is multidimensional and grounded in ethical and legal imperatives, both ethical and legal challenges should be taken into account. In this regard, a falling incident case of a 12-day-old newborn was raised in the monthly ethics round in the Children's Medical Center of Tehran University of Medical Sciences, Iran, and the ethical and legal dimensions of patient safety were discussed by experts in various fields. This report presents different aspects of patient safety in terms of root cause analysis (RCA) and risk management, the role of human resources, the role of professionalism, the necessity of informing the parents (disclosure of medical errors), and forensic medicine with focus on ethical aspects.
11. Early detection of ovarian cancer using cell-free DNA fragmentomes and protein biomarkers.
- Author
-
Medina JE, Annapragada AV, Lof P, Short S, Bartolomucci AL, Mathios D, Koul S, Niknafs N, Noe M, Foda ZH, Bruhm DC, Hruban C, Vulpescu NA, Jung E, Dua R, Canzoniero JV, Cristiano S, Adleff V, Symecko H, van den Broek D, Sokoll LJ, Baylin SB, Press MF, Slamon DJ, Konecny GE, Therkildsen C, Carvalho B, Meijer GA, Andersen CL, Domchek SM, Drapkin R, Scharpf RB, Phallen J, Lok CAR, and Velculescu VE
- Abstract
Ovarian cancer is a leading cause of death for women worldwide in part due to ineffective screening methods. In this study, we used whole-genome cell-free DNA (cfDNA) fragmentome and protein biomarker (CA-125 and HE4) analyses to evaluate 591 women with ovarian cancer, benign adnexal masses, or without ovarian lesions. Using a machine learning model with the combined features, we detected ovarian cancer with specificity >99% and sensitivity of 72%, 69%, 87%, and 100% for stages I-IV, respectively. At the same specificity, CA-125 alone detected 34%, 62%, 63%, and 100% of ovarian cancers for stages I-IV. Our approach differentiated benign masses from ovarian cancers with high accuracy (AUC=0.88, 95% CI=0.83-0.92). These results were validated in an independent population. These findings show that integrated cfDNA fragmentome and protein analyses detect ovarian cancers with high performance, enabling a new accessible approach for noninvasive ovarian cancer screening and diagnostic evaluation.
- Published
- 2024
- Full Text
- View/download PDF
12. DNA methylation and gene expression as determinants of genome-wide cell-free DNA fragmentation.
- Author
-
Noë M, Mathios D, Annapragada AV, Koul S, Foda ZH, Medina JE, Cristiano S, Cherry C, Bruhm DC, Niknafs N, Adleff V, Ferreira L, Easwaran H, Baylin S, Phallen J, Scharpf RB, and Velculescu VE
- Subjects
- Humans, Animals, Mice, Epigenesis, Genetic, Female, Isocitrate Dehydrogenase genetics, Male, Gene Expression Regulation, Neoplastic, DNA Methylation, Cell-Free Nucleic Acids genetics, Cell-Free Nucleic Acids blood, DNA Fragmentation, CpG Islands genetics, Neoplasms genetics
- Abstract
Circulating cell-free DNA (cfDNA) is emerging as an avenue for cancer detection, but the characteristics of cfDNA fragmentation in the blood are poorly understood. We evaluate the effect of DNA methylation and gene expression on genome-wide cfDNA fragmentation through analysis of 969 individuals. cfDNA fragment ends more frequently contained CCs or CGs, and fragments ending with CGs or CCGs are enriched or depleted, respectively, at methylated CpG positions. Higher levels and larger sizes of cfDNA fragments are associated with CpG methylation and reduced gene expression. These effects are validated in mice with isogenic tumors with or without the mutant IDH1, and are associated with genome-wide changes in cfDNA fragmentation in patients with cancer. Tumor-related hypomethylation and increased gene expression are associated with decrease in cfDNA fragment size that may explain smaller cfDNA fragments in human cancers. These results provide a connection between epigenetic changes and cfDNA fragmentation with implications for disease detection., (© 2024. The Author(s).)
- Published
- 2024
- Full Text
- View/download PDF
13. 3D genomic mapping reveals multifocality of human pancreatic precancers.
- Author
-
Braxton AM, Kiemen AL, Grahn MP, Forjaz A, Parksong J, Mahesh Babu J, Lai J, Zheng L, Niknafs N, Jiang L, Cheng H, Song Q, Reichel R, Graham S, Damanakis AI, Fischer CG, Mou S, Metz C, Granger J, Liu XD, Bachmann N, Zhu Y, Liu Y, Almagro-Pérez C, Jiang AC, Yoo J, Kim B, Du S, Foster E, Hsu JY, Rivera PA, Chu LC, Liu F, Fishman EK, Yuille A, Roberts NJ, Thompson ED, Scharpf RB, Cornish TC, Jiao Y, Karchin R, Hruban RH, Wu PH, Wirtz D, and Wood LD
- Subjects
- Adult, Female, Humans, Male, Clone Cells metabolism, Clone Cells pathology, Exome Sequencing, Machine Learning, Mutation, Pancreas anatomy & histology, Pancreas cytology, Pancreas metabolism, Pancreas pathology, Workflow, Disease Progression, Early Detection of Cancer, Oncogenes genetics, Genetic Heterogeneity, Genomics, Imaging, Three-Dimensional, Pancreatic Neoplasms genetics, Pancreatic Neoplasms pathology, Precancerous Conditions genetics, Precancerous Conditions pathology, Single-Cell Analysis
- Abstract
Pancreatic intraepithelial neoplasias (PanINs) are the most common precursors of pancreatic cancer, but their small size and inaccessibility in humans make them challenging to study
1 . Critically, the number, dimensions and connectivity of human PanINs remain largely unknown, precluding important insights into early cancer development. Here, we provide a microanatomical survey of human PanINs by analysing 46 large samples of grossly normal human pancreas with a machine-learning pipeline for quantitative 3D histological reconstruction at single-cell resolution. To elucidate genetic relationships between and within PanINs, we developed a workflow in which 3D modelling guides multi-region microdissection and targeted and whole-exome sequencing. From these samples, we calculated a mean burden of 13 PanINs per cm3 and extrapolated that the normal intact adult pancreas harbours hundreds of PanINs, almost all with oncogenic KRAS hotspot mutations. We found that most PanINs originate as independent clones with distinct somatic mutation profiles. Some spatially continuous PanINs were found to contain multiple KRAS mutations; computational and in situ analyses demonstrated that different KRAS mutations localize to distinct cell subpopulations within these neoplasms, indicating their polyclonal origins. The extensive multifocality and genetic heterogeneity of PanINs raises important questions about mechanisms that drive precancer initiation and confer differential progression risk in the human pancreas. This detailed 3D genomic mapping of molecular alterations in human PanINs provides an empirical foundation for early detection and rational interception of pancreatic cancer., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2024
- Full Text
- View/download PDF
14. Genome-wide repeat landscapes in cancer and cell-free DNA.
- Author
-
Annapragada AV, Niknafs N, White JR, Bruhm DC, Cherry C, Medina JE, Adleff V, Hruban C, Mathios D, Foda ZH, Phallen J, Scharpf RB, and Velculescu VE
- Subjects
- Male, Humans, DNA Transposable Elements, Cell-Free Nucleic Acids, Liver Neoplasms genetics
- Abstract
Genetic changes in repetitive sequences are a hallmark of cancer and other diseases, but characterizing these has been challenging using standard sequencing approaches. We developed a de novo kmer finding approach, called ARTEMIS (Analysis of RepeaT EleMents in dISease), to identify repeat elements from whole-genome sequencing. Using this method, we analyzed 1.2 billion kmers in 2837 tissue and plasma samples from 1975 patients, including those with lung, breast, colorectal, ovarian, liver, gastric, head and neck, bladder, cervical, thyroid, or prostate cancer. We identified tumor-specific changes in these patients in 1280 repeat element types from the LINE, SINE, LTR, transposable element, and human satellite families. These included changes to known repeats and 820 elements that were not previously known to be altered in human cancer. Repeat elements were enriched in regions of driver genes, and their representation was altered by structural changes and epigenetic states. Machine learning analyses of genome-wide repeat landscapes and fragmentation profiles in cfDNA detected patients with early-stage lung or liver cancer in cross-validated and externally validated cohorts. In addition, these repeat landscapes could be used to noninvasively identify the tissue of origin of tumors. These analyses reveal widespread changes in repeat landscapes of human cancers and provide an approach for their detection and characterization that could benefit early detection and disease monitoring of patients with cancer.
- Published
- 2024
- Full Text
- View/download PDF
15. Elucidating the Heterogeneity of Immunotherapy Response and Immune-Related Toxicities by Longitudinal ctDNA and Immune Cell Compartment Tracking in Lung Cancer.
- Author
-
Murray JC, Sivapalan L, Hummelink K, Balan A, White JR, Niknafs N, Rhymee L, Pereira G, Rao N, Weksler B, Bahary N, Phallen J, Leal A, Bartlett DL, Marrone KA, Naidoo J, Goel A, Levy B, Rosner S, Hann CL, Scott SC, Feliciano J, Lam VK, Ettinger DS, Li QK, Illei PB, Monkhorst K, Scharpf RB, Brahmer JR, Velculescu VE, Zaidi AH, Forde PM, and Anagnostou V
- Subjects
- Humans, Immunotherapy adverse effects, Biomarkers, Tumor genetics, Biomarkers, Tumor therapeutic use, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung genetics, Circulating Tumor DNA genetics
- Abstract
Purpose: Although immunotherapy is the mainstay of therapy for advanced non-small cell lung cancer (NSCLC), robust biomarkers of clinical response are lacking. The heterogeneity of clinical responses together with the limited value of radiographic response assessments to timely and accurately predict therapeutic effect-especially in the setting of stable disease-calls for the development of molecularly informed real-time minimally invasive approaches. In addition to capturing tumor regression, liquid biopsies may be informative in capturing immune-related adverse events (irAE)., Experimental Design: We investigated longitudinal changes in circulating tumor DNA (ctDNA) in patients with metastatic NSCLC who received immunotherapy-based regimens. Using ctDNA targeted error-correction sequencing together with matched sequencing of white blood cells and tumor tissue, we tracked serial changes in cell-free tumor load (cfTL) and determined molecular response. Peripheral T-cell repertoire dynamics were serially assessed and evaluated together with plasma protein expression profiles., Results: Molecular response, defined as complete clearance of cfTL, was significantly associated with progression-free (log-rank P = 0.0003) and overall survival (log-rank P = 0.01) and was particularly informative in capturing differential survival outcomes among patients with radiographically stable disease. For patients who developed irAEs, on-treatment peripheral blood T-cell repertoire reshaping, assessed by significant T-cell receptor (TCR) clonotypic expansions and regressions, was identified on average 5 months prior to clinical diagnosis of an irAE., Conclusions: Molecular responses assist with the interpretation of heterogeneous clinical responses, especially for patients with stable disease. Our complementary assessment of the peripheral tumor and immune compartments provides an approach for monitoring of clinical benefits and irAEs during immunotherapy., (©2023 The Authors; Published by the American Association for Cancer Research.)
- Published
- 2024
- Full Text
- View/download PDF
16. Fluid overload in newborns undergoing abdominal surgery: a retrospective study.
- Author
-
Niknafs N, Kuan MTY, Mammen C, Skarsgard E, and Ting JY
- Subjects
- Infant, Humans, Infant, Newborn, Retrospective Studies, Intensive Care Units, Neonatal, Gestational Age, Body Weight, Water-Electrolyte Imbalance complications
- Abstract
Background: Fluid management in newborns undergoing surgery can be challenging due to difficulties in accurately assessing volume status in context of high fluid needs perioperatively and postoperative third-space fluid loss. Fluid overload can be associated with an increase in neonatal morbidity and mortality., Objective: Our objective was to determine the burden of fluid overload and to evaluate their associations with adverse effects among infants undergoing abdominal surgery at a tertiary perinatal center., Methods: Patients from our Neonatal Intensive Care Unit who underwent abdominal surgery from January 2017 to June 2019 were included in this retrospective cohort study. Fluid balance was assessed based on the maximum percentage change in body weight at 3- and 7-postoperative days., Results: Sixty infants were included, with a median [interquartile range] gestational age (GA) of 29 [25-36] weeks and birth weight of 1240 [721-2871] grams. The median daily actual fluid intake was significantly higher than the prescribed fluid intake in the first 7 postoperative days (163 vs. 145 mL/kg, p < .01). The median maximum change of body weight by postoperative days 3 and 7 were 6% [3-13] and 11% [5-17], respectively. A 1% increase in weight within the first 3 postoperative days was associated with a 0.6-day increase for invasive ventilatory support ( p = .012). The correlation was still significant after adjusting for GA ( p = .033)., Conclusion: Fluid overload within the first 3 postoperative days was associated with an increase in ventilator support among infants. Careful attention to fluid management may affect the optimization of outcomes for newborns undergoing abdominal surgery.
- Published
- 2023
- Full Text
- View/download PDF
17. ctDNA response after pembrolizumab in non-small cell lung cancer: phase 2 adaptive trial results.
- Author
-
Anagnostou V, Ho C, Nicholas G, Juergens RA, Sacher A, Fung AS, Wheatley-Price P, Laurie SA, Levy B, Brahmer JR, Balan A, Niknafs N, Avrutin E, Zhu L, Sausen M, Bradbury PA, O'Donnell-Tormey J, Gaudreau PO, Ding K, and Dancey J
- Subjects
- Humans, Antibodies, Monoclonal, Humanized, Progression-Free Survival, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung pathology, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Lung Neoplasms pathology
- Abstract
Circulating tumor DNA (ctDNA) has shown promise in capturing primary resistance to immunotherapy. BR.36 is a multi-center, randomized, ctDNA-directed, phase 2 trial of molecular response-adaptive immuno-chemotherapy for patients with lung cancer. In the first of two independent stages, 50 patients with advanced non-small cell lung cancer received pembrolizumab as standard of care. The primary objectives of stage 1 were to ascertain ctDNA response and determine optimal timing and concordance with radiologic Response Evaluation Criteria in Solid Tumors (RECIST) response. Secondary endpoints included the evaluation of time to ctDNA response and correlation with progression-free and overall survival. Maximal mutant allele fraction clearance at the third cycle of pembrolizumab signified molecular response (mR). The trial met its primary endpoint, with a sensitivity of ctDNA response for RECIST response of 82% (90% confidence interval (CI): 52-97%) and a specificity of 75% (90% CI: 56.5-88.5%). Median time to ctDNA response was 2.1 months (90% CI: 1.5-2.6), and patients with mR attained longer progression-free survival (5.03 months versus 2.6 months) and overall survival (not reached versus 7.23 months). These findings are incorporated into the ctDNA-driven interventional molecular response-adaptive second stage of the BR.36 trial in which patients at risk of progression are randomized to treatment intensification or continuation of therapy. ClinicalTrials.gov ID: NCT04093167 ., (© 2023. The Author(s).)
- Published
- 2023
- Full Text
- View/download PDF
18. Elucidating the heterogeneity of immunotherapy response and immune-related toxicities by longitudinal ctDNA and immune cell compartment tracking in lung cancer.
- Author
-
Murray JC, Sivapalan L, Hummelink K, Balan A, White JR, Niknafs N, Rhymee L, Pereira G, Rao N, Phallen J, Leal A, Bartlett DL, Marrone KA, Naidoo J, Levy B, Rosner S, Hann CL, Scott SC, Feliciano J, Lam VK, Ettinger DS, Li QK, Illei PB, Monkhorst K, Zaidi AH, Scharpf RB, Brahmer JR, Velculescu VE, Forde PM, and Anagnostou V
- Abstract
Purpose: Although immunotherapy is the mainstay of therapy for advanced non-small cell lung cancer (NSCLC), robust biomarkers of clinical response are lacking. The heterogeneity of clinical responses together with the limited value of radiographic response assessments to timely and accurately predict therapeutic effect -especially in the setting of stable disease-call for the development of molecularly-informed real-time minimally invasive predictive biomarkers. In addition to capturing tumor regression, liquid biopsies may be informative in evaluating immune-related adverse events (irAEs)., Experimental Design: We investigated longitudinal changes in circulating tumor DNA (ctDNA) in patients with metastatic NSCLC who received immunotherapy-based regimens. Using ctDNA targeted error-correction sequencing together with matched sequencing of white blood cells and tumor tissue, we tracked serial changes in cell-free tumor load (cfTL) and determined molecular response for each patient. Peripheral T-cell repertoire dynamics were serially assessed and evaluated together with plasma protein expression profiles., Results: Molecular response, defined as complete clearance of cfTL, was significantly associated with progression-free (log-rank p=0.0003) and overall survival (log-rank p=0.01) and was particularly informative in capturing differential survival outcomes among patients with radiographically stable disease. For patients who developed irAEs, peripheral blood T-cell repertoire reshaping, assessed by significant TCR clonotypic expansions and regressions were noted on-treatment., Conclusions: Molecular responses assist with interpretation of heterogeneous clinical responses especially for patients with stable disease. Our complementary assessment of the tumor and immune compartments by liquid biopsies provides an approach for monitoring of clinical benefit and immune-related toxicities for patients with NSCLC receiving immunotherapy., Statement of Translational Relevance: Longitudinal dynamic changes in cell-free tumor load and reshaping of the peripheral T-cell repertoire capture clinical outcomes and immune-related toxicities during immunotherapy for patients with non-small cell lung cancer.
- Published
- 2023
- Full Text
- View/download PDF
19. Dynamics of Sequence and Structural Cell-Free DNA Landscapes in Small-Cell Lung Cancer.
- Author
-
Sivapalan L, Iams WT, Belcaid Z, Scott SC, Niknafs N, Balan A, White JR, Kopparapu P, Cann C, Landon BV, Pereira G, Velculescu VE, Hann CL, Lovly CM, and Anagnostou V
- Subjects
- Humans, Prognosis, Neoplasm Recurrence, Local, Mutation, Circulating Tumor DNA genetics, Small Cell Lung Carcinoma, Lung Neoplasms drug therapy, Carcinoma, Non-Small-Cell Lung drug therapy, Cell-Free Nucleic Acids
- Abstract
Purpose: Patients with small-cell lung cancer (SCLC) have an exceptionally poor prognosis, calling for improved real-time noninvasive biomarkers of therapeutic response., Experimental Design: We performed targeted error-correction sequencing on 171 serial plasmas and matched white blood cell (WBC) DNA from 33 patients with metastatic SCLC who received treatment with chemotherapy (n = 16) or immunotherapy-containing (n = 17) regimens. Tumor-derived sequence alterations and plasma aneuploidy were evaluated serially and combined to assess changes in total cell-free tumor load (cfTL). Longitudinal dynamic changes in cfTL were monitored to determine circulating cell-free tumor DNA (ctDNA) molecular response during therapy., Results: Combined tiered analyses of tumor-derived sequence alterations and plasma aneuploidy allowed for the assessment of ctDNA molecular response in all patients. Patients classified as molecular responders (n = 9) displayed sustained elimination of cfTL to undetectable levels. For 14 patients, we observed initial molecular responses, followed by ctDNA recrudescence. A subset of patients (n = 10) displayed a clear pattern of molecular progression, with persistence of cfTL across all time points. Molecular responses captured the therapeutic effect and long-term clinical outcomes in a more accurate and rapid manner compared with radiographic imaging. Patients with sustained molecular responses had longer overall (log-rank P = 0.0006) and progression-free (log-rank P < 0.0001) survival, with molecular responses detected on average 4 weeks earlier than imaging., Conclusions: ctDNA analyses provide a precise approach for the assessment of early on-therapy molecular responses and have important implications for the management of patients with SCLC, including the development of improved strategies for real-time tumor burden monitoring. See related commentary by Pellini and Chaudhuri, p. 2176., (©2023 The Authors; Published by the American Association for Cancer Research.)
- Published
- 2023
- Full Text
- View/download PDF
20. Tracing the genetic fingerprints of tumour evolution: The pursuit of identifying mutations with differential weights within the overall tumour mutation burden and their role in therapeutic responses with immune checkpoint blockade.
- Author
-
Niknafs N, Conroy M, and Anagnostou V
- Subjects
- Humans, Mutation genetics, Biomarkers, Tumor, Immune Checkpoint Inhibitors pharmacology, Immune Checkpoint Inhibitors therapeutic use, Neoplasms drug therapy, Neoplasms genetics
- Published
- 2023
- Full Text
- View/download PDF
21. Human Milk Calorie Guide: A Novel Color-Based Tool to Estimate the Calorie Content of Human Milk for Preterm Infants.
- Author
-
Pillai A, Albersheim S, Niknafs N, Maugo B, Rasmussen B, Lam M, Grewal G, Albert A, and Elango R
- Subjects
- Infant, Female, Humans, Infant, Newborn, Reproducibility of Results, Energy Intake, Mothers, Infant, Very Low Birth Weight, Milk, Human, Infant, Premature
- Abstract
Fixed-dose fortification of human milk (HM) is insufficient to meet the nutrient requirements of preterm infants. Commercial human milk analyzers (HMA) to individually fortify HM are unavailable in most centers. We describe the development and validation of a bedside color-based tool called the 'human milk calorie guide'(HMCG) for differentiating low-calorie HM using commercial HMA as the gold standard. Mothers of preterm babies (birth weight ≤ 1500 g or gestation ≤ 34 weeks) were enrolled. The final color tool had nine color shades arranged as three rows of three shades each (rows A, B, and C). We hypothesized that calorie values for HM samples would increase with increasing 'yellowness' predictably from row A to C. One hundred thirty-one mother's own milk (MOM) and 136 donor human milk (DHM) samples (total n = 267) were color matched and analyzed for macronutrients. The HMCG tool performed best in DHM samples for predicting lower calories (<55 kcal/dL) (AUC 0.87 for category A DHM) with modest accuracy for >70 kcal/dL (AUC 0.77 for category C DHM). For MOM, its diagnostic performance was poor. The tool showed good inter-rater reliability (Krippendorff's alpha = 0.80). The HMCG was reliable in predicting lower calorie ranges for DHM and has the potential for improving donor HM fortification practices.
- Published
- 2023
- Full Text
- View/download PDF
22. Detecting Liver Cancer Using Cell-Free DNA Fragmentomes.
- Author
-
Foda ZH, Annapragada AV, Boyapati K, Bruhm DC, Vulpescu NA, Medina JE, Mathios D, Cristiano S, Niknafs N, Luu HT, Goggins MG, Anders RA, Sun J, Meta SH, Thomas DL, Kirk GD, Adleff V, Phallen J, Scharpf RB, Kim AK, and Velculescu VE
- Subjects
- Humans, Liver Cirrhosis genetics, Liver Cirrhosis pathology, Liver Neoplasms diagnosis, Liver Neoplasms genetics, Liver Neoplasms pathology, Carcinoma, Hepatocellular diagnosis, Carcinoma, Hepatocellular genetics, Carcinoma, Hepatocellular pathology, Cell-Free Nucleic Acids genetics
- Abstract
Liver cancer is a major cause of cancer mortality worldwide. Screening individuals at high risk, including those with cirrhosis and viral hepatitis, provides an avenue for improved survival, but current screening methods are inadequate. In this study, we used whole-genome cell-free DNA (cfDNA) fragmentome analyses to evaluate 724 individuals from the United States, the European Union, or Hong Kong with hepatocellular carcinoma (HCC) or who were at average or high-risk for HCC. Using a machine learning model that incorporated multifeature fragmentome data, the sensitivity for detecting cancer was 88% in an average-risk population at 98% specificity and 85% among high-risk individuals at 80% specificity. We validated these results in an independent population. cfDNA fragmentation changes reflected genomic and chromatin changes in liver cancer, including from transcription factor binding sites. These findings provide a biological basis for changes in cfDNA fragmentation in patients with liver cancer and provide an accessible approach for noninvasive cancer detection., Significance: There is a great need for accessible and sensitive screening approaches for HCC worldwide. We have developed an approach for examining genome-wide cfDNA fragmentation features to provide a high-performing and cost-effective approach for liver cancer detection. See related commentary Rolfo and Russo, p. 532. This article is highlighted in the In This Issue feature, p. 517., (©2022 The Authors; Published by the American Association for Cancer Research.)
- Published
- 2023
- Full Text
- View/download PDF
23. Persistent mutation burden drives sustained anti-tumor immune responses.
- Author
-
Niknafs N, Balan A, Cherry C, Hummelink K, Monkhorst K, Shao XM, Belcaid Z, Marrone KA, Murray J, Smith KN, Levy B, Feliciano J, Hann CL, Lam V, Pardoll DM, Karchin R, Seiwert TY, Brahmer JR, Forde PM, Velculescu VE, and Anagnostou V
- Subjects
- Humans, Mutation, Biomarkers, Tumor genetics, Immunity, Immunotherapy, Tumor Microenvironment, Carcinoma, Non-Small-Cell Lung pathology, Lung Neoplasms pathology, Melanoma
- Abstract
Tumor mutation burden is an imperfect proxy of tumor foreignness and has therefore failed to consistently demonstrate clinical utility in predicting responses in the context of immunotherapy. We evaluated mutations in regions of the genome that are unlikely to undergo loss in a pan-cancer analysis across 31 tumor types (n = 9,242) and eight immunotherapy-treated cohorts of patients with non-small-cell lung cancer, melanoma, mesothelioma, and head and neck cancer (n = 524). We discovered that mutations in single-copy regions and those present in multiple copies per cell constitute a persistent tumor mutation burden (pTMB) which is linked with therapeutic response to immune checkpoint blockade. Persistent mutations were retained in the context of tumor evolution under selective pressure of immunotherapy and tumors with a high pTMB content were characterized by a more inflamed tumor microenvironment. pTMB imposes an evolutionary bottleneck that cancer cells cannot overcome and may thus drive sustained immunologic tumor control in the context of immunotherapy., (© 2023. The Author(s).)
- Published
- 2023
- Full Text
- View/download PDF
24. Three-dimensional genomic mapping of human pancreatic tissue reveals striking multifocality and genetic heterogeneity in precancerous lesions.
- Author
-
Braxton AM, Kiemen AL, Grahn MP, Forjaz A, Babu JM, Zheng L, Jiang L, Cheng H, Song Q, Reichel R, Graham S, Damanakis AI, Fischer CG, Mou S, Metz C, Granger J, Liu XD, Bachmann N, Almagro-Pérez C, Jiang AC, Yoo J, Kim B, Du S, Foster E, Hsu JY, Rivera PA, Chu LC, Liu F, Niknafs N, Fishman EK, Yuille A, Roberts NJ, Thompson ED, Scharpf RB, Cornish TC, Jiao Y, Karchin R, Hruban RH, Wu PH, Wirtz D, and Wood LD
- Abstract
Pancreatic intraepithelial neoplasia (PanIN) is a precursor to pancreatic cancer and represents a critical opportunity for cancer interception. However, the number, size, shape, and connectivity of PanINs in human pancreatic tissue samples are largely unknown. In this study, we quantitatively assessed human PanINs using CODA, a novel machine-learning pipeline for 3D image analysis that generates quantifiable models of large pieces of human pancreas with single-cell resolution. Using a cohort of 38 large slabs of grossly normal human pancreas from surgical resection specimens, we identified striking multifocality of PanINs, with a mean burden of 13 spatially separate PanINs per cm
3 of sampled tissue. Extrapolating this burden to the entire pancreas suggested a median of approximately 1000 PanINs in an entire pancreas. In order to better understand the clonal relationships within and between PanINs, we developed a pipeline for CODA-guided multi-region genomic analysis of PanINs, including targeted and whole exome sequencing. Multi-region assessment of 37 PanINs from eight additional human pancreatic tissue slabs revealed that almost all PanINs contained hotspot mutations in the oncogene KRAS , but no gene other than KRAS was altered in more than 20% of the analyzed PanINs. PanINs contained a mean of 13 somatic mutations per region when analyzed by whole exome sequencing. The majority of analyzed PanINs originated from independent clonal events, with distinct somatic mutation profiles between PanINs in the same tissue slab. A subset of the analyzed PanINs contained multiple KRAS mutations, suggesting a polyclonal origin even in PanINs that are contiguous by rigorous 3D assessment. This study leverages a novel 3D genomic mapping approach to describe, for the first time, the spatial and genetic multifocality of human PanINs, providing important insights into the initiation and progression of pancreatic neoplasia., Competing Interests: Competing Interests Statement: A pending patent application “COMPUTATIONAL TECHNIQUES FOR THREE-DIMENSIONAL RECONSTRUCTION AND MULTI-LABELING OF SERIALLY SECTIONED TISSUE” was filed on 6/24/2022 by authors AK, RHH, PHW, DW, and LDW. The other authors report no competing interests.- Published
- 2023
- Full Text
- View/download PDF
25. Sex-specific differences in immunogenomic features of response to immune checkpoint blockade.
- Author
-
Scott SC, Shao XM, Niknafs N, Balan A, Pereira G, Marrone KA, Lam VK, Murray JC, Feliciano JL, Levy BP, Ettinger DS, Hann CL, Brahmer JR, Forde PM, Karchin R, Naidoo J, and Anagnostou V
- Abstract
Introduction: The magnitude of response to immune checkpoint inhibitor (ICI) therapy may be sex-dependent, as females have lower response rates and decreased survival after ICI monotherapy. The mechanisms underlying this sex dimorphism in ICI response are unknown, and may be related to sex-driven differences in the immunogenomic landscape of tumors that shape anti-tumor immune responses in the context of therapy., Methods: To investigate the association of immunogenic mutations with HLA haplotypes, we leveraged whole exome sequence data and HLA genotypes from 482 non-small cell lung cancer (NSCLC) tumors from The Cancer Genome Atlas (TCGA). To explore sex-specific genomic features linked with ICI response, we analyzed whole exome sequence data from patients with NSCLC treated with ICI. Tumor mutational burden (TMB), HLA class I and II restricted immunogenic missense mutation (IMM) load, and mutational smoking signature were defined for each tumor. IMM load was combined with HLA class I and II haplotypes and correlated with therapeutic response and survival following ICI treatment. We examined rates of durable clinical benefit (DCB) for at least six months from ICI treatment initiation. Findings were validated utilizing whole exome sequence data from an independent cohort of ICI treated NSCLC., Results: Analysis of whole exome sequence data from NSCLC tumors of females and males revealed that germline HLA class II diversity (≥9 unique HLA alleles) was associated with higher tumor class II IMM load in females (p=0.01) and not in males (p=0.64). Similarly, in tumors of female patients, somatic HLA class II loss of heterozygosity was associated with increased IMM load (p=0.01) while this association was not observed in tumors in males (p=0.20). In females, TMB (p=0.005), class I IMM load (p=0.005), class II IMM load (p=0.004), and mutational smoking signature (p<0.001) were significantly higher in tumors responding to ICI as compared to non-responding tumors. In contrast, among males, there was no significant association between DCB and any of these features. When IMM was considered in the context of HLA zygosity, high MHC-II restricted IMM load and high HLA class II diversity was significantly associated with overall survival in males (p=0.017)., Conclusions: Inherent sex-driven differences in immune surveillance affect the immunogenomic determinants of response to ICI and likely mediate the dimorphic outcomes with ICI therapy. Deeper understanding of the selective pressures and mechanisms of immune escape in tumors in males and females can inform patient selection strategies and can be utilized to further hone immunotherapy approaches in cancer., Competing Interests: VA receives research funding to the institution from Astra Zeneca and has received research funding to her institution from Bristol-Myers Squibb in the past 5 years. SS has served in a consulting role for Genentech/Roche. KM has received research funding to the institution from Mirati and Bristol Myers Squibb, and she has served in a consulting role for Amgen, Janssen, Mirati, AstraZeneca and Puma. VL has received research funding to the institution from GlaxoSmithKline, Bristol Myers Squibb, Merck, and SeaGen and he has served in a consulting role for Takeda, SeaGen, Bristol Myers Squibb, AstraZeneca, Guardant Health and Takeda. JM has received research funding to the institution from Merck via the Conquer Cancer Young Investigators Award, and has served in a consulting role for MJH Life Sciences, Johnson & Johnson, and Doximity. JF has received research funding to the institution from AstraZeneca, Pfizer, and Bristol Myers Squibb, and has served in a consulting role for Genentech/Roche, Eli Lilly, AstraZeneca, Merck, Takeda, Coherus, Regeneron, and Pfizer. BL has served in a consulting role for AstraZeneca, Daiichi Sankyo, Janssen, Pfizer, Amgen, Takeda, Genentech/Roche, Eli Lilly, Mirati Therapeutics, and Guardant. DE has served in a consulting role for Beyond Spring Pharmaceuticals. CH has received research funding to the institution from AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, and GlaxoSmithKline, and has served in a consulting role for AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Genentech/Roche, Jannsen and GlaxoSmithKline. JB has received research funding to the institution from AstraZeneca, Bristol Myers Squibb, Genentech/Roche, Merck, RAPT Therapeutics Inc and Revolution Medicines, has served in a consulting role for Amgen, AstraZeneca, BMS, Genentech/Roche, Eli Lilly, GlaxoSmithKline, Merck, Sanofi and Regeneron, and is in the Data and Safety Monitoring Board/Committees of GlaxoSmithKline and Sanofi. PF has received research funding to the institution from AstraZeneca, Bristol Myers Squibb, Novartis, Corvus, Kyowa, and has served as a consultant for Amgen, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Iteos, Janssen, and as a data safety monitoring board member for Polaris and Flame Therapeutics. JN has received research funding from MSD, AstraZeneca, Bristol Myers Squibb, Amgen, Genentech/Roche, Novartis, has served in a consultant/advisory role for Merck, MSD, AstraZeneca, Bristol Myers Squibb, Genentech/Roche, Pfizer, Takeda, Daiichi Sankyo, Kaleido Biosciences, Amgen and Mirati Therapeutics, and is in the Data and Safety Monitoring Board/Committee of Daiichi Sankyo. Under a license agreement between Genentech and the Johns Hopkins University, XS and RK and the University are entitled to royalty distributions related to technology described in the study discussed in this publication. This arrangement has been reviewed and approved by the Johns Hopkins University in accordance with its conflict of interest policies. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest., (Copyright © 2022 Scott, Shao, Niknafs, Balan, Pereira, Marrone, Lam, Murray, Feliciano, Levy, Ettinger, Hann, Brahmer, Forde, Karchin, Naidoo and Anagnostou.)
- Published
- 2022
- Full Text
- View/download PDF
26. Estimation of cancer cell fractions and clone trees from multi-region sequencing of tumors.
- Author
-
Zheng L, Niknafs N, Wood LD, Karchin R, and Scharpf RB
- Subjects
- Humans, Bayes Theorem, Cross-Sectional Studies, Sequence Analysis, Mutation, Clone Cells, Phylogeny, Software, Neoplasms genetics
- Abstract
Motivation: Multi-region sequencing of solid tumors can improve our understanding of intratumor subclonal diversity and the evolutionary history of mutational events. Due to uncertainty in clonal composition and the multitude of possible ancestral relationships between clones, elucidating the most probable relationships from bulk tumor sequencing poses statistical and computational challenges., Results: We developed a Bayesian hierarchical model called PICTograph to model uncertainty in assigning mutations to subclones, to enable posterior distributions of cancer cell fractions (CCFs) and to visualize the most probable ancestral relationships between subclones. Compared with available methods, PICTograph provided more consistent and accurate estimates of CCFs and improved tree inference over a range of simulated clonal diversity. Application of PICTograph to multi-region whole-exome sequencing of tumors from individuals with pancreatic cancer precursor lesions confirmed known early-occurring mutations and indicated substantial molecular diversity, including 6-12 distinct subclones and intra-sample mixing of subclones. Using ensemble-based visualizations, we highlight highly probable evolutionary relationships recovered in multiple models. PICTograph provides a useful approximation to evolutionary inference from cross-sectional multi-region sequencing, particularly for complex cases., Availability and Implementation: https://github.com/KarchinLab/pictograph. The data underlying this article will be shared on reasonable request to the corresponding author., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2022
- Full Text
- View/download PDF
27. Peripheral blood immune cell dynamics reflect antitumor immune responses and predict clinical response to immunotherapy.
- Author
-
Hwang M, Canzoniero JV, Rosner S, Zhang G, White JR, Belcaid Z, Cherry C, Balan A, Pereira G, Curry A, Niknafs N, Zhang J, Smith KN, Sivapalan L, Chaft JE, Reuss JE, Marrone K, Murray JC, Li QK, Lam V, Levy BP, Hann C, Velculescu VE, Brahmer JR, Forde PM, Seiwert T, and Anagnostou V
- Subjects
- B7-H1 Antigen, Biomarkers, Tumor genetics, Ecosystem, Humans, Immune Checkpoint Inhibitors, Immunity, Immunologic Factors therapeutic use, Immunotherapy, Tumor Microenvironment, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung genetics, Circulating Tumor DNA genetics, Lung Neoplasms drug therapy, Lung Neoplasms genetics
- Abstract
Background: Despite treatment advancements with immunotherapy, our understanding of response relies on tissue-based, static tumor features such as tumor mutation burden (TMB) and programmed death-ligand 1 (PD-L1) expression. These approaches are limited in capturing the plasticity of tumor-immune system interactions under selective pressure of immune checkpoint blockade and predicting therapeutic response and long-term outcomes. Here, we investigate the relationship between serial assessment of peripheral blood cell counts and tumor burden dynamics in the context of an evolving tumor ecosystem during immune checkpoint blockade., Methods: Using machine learning, we integrated dynamics in peripheral blood immune cell subsets, including neutrophil-lymphocyte ratio (NLR), from 239 patients with metastatic non-small cell lung cancer (NSCLC) and predicted clinical outcome with immune checkpoint blockade. We then sought to interpret NLR dynamics in the context of transcriptomic and T cell repertoire trajectories for 26 patients with early stage NSCLC who received neoadjuvant immune checkpoint blockade. We further determined the relationship between NLR dynamics, pathologic response and circulating tumor DNA (ctDNA) clearance., Results: Integrated dynamics of peripheral blood cell counts, predominantly NLR dynamics and changes in eosinophil levels, predicted clinical outcome, outperforming both TMB and PD-L1 expression. As early changes in NLR were a key predictor of response, we linked NLR dynamics with serial RNA sequencing deconvolution and T cell receptor sequencing to investigate differential tumor microenvironment reshaping during therapy for patients with reduction in peripheral NLR. Reductions in NLR were associated with induction of interferon-γ responses driving the expression of antigen presentation and proinflammatory gene sets coupled with reshaping of the intratumoral T cell repertoire. In addition, NLR dynamics reflected tumor regression assessed by pathological responses and complemented ctDNA kinetics in predicting long-term outcome. Elevated peripheral eosinophil levels during immune checkpoint blockade were correlated with therapeutic response in both metastatic and early stage cohorts., Conclusions: Our findings suggest that early dynamics in peripheral blood immune cell subsets reflect changes in the tumor microenvironment and capture antitumor immune responses, ultimately reflecting clinical outcomes with immune checkpoint blockade., Competing Interests: Competing interests: VA receives research funding to her institution from Bristol-Myers Squibb and Astra Zeneca. PMF has received research funding to his institution from AstraZeneca, Bristol-Myers Squibb, Novartis, Corvus, Kyowa. He has also served as a consultant for Amgen, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Iteos, Janssen, Mirati, Novartis, Sanofi and as a DSMB member for Polaris and Flame Therapeutics. KNS receives research funding to her institution from Bristol-Myers Squibb, Astra Zeneca, and Enara Bio, and holds founder’s equity in manaT Bio. VEV is a founder of Delfi Diagnostics and Personal Genome Diagnostics, serves on the Board of Directors and as a consultant for both organizations, and owns Delfi Diagnostics and Personal Genome Diagnostics stock, which are subject to certain restrictions under university policy. Additionally, Johns Hopkins University owns equity in Delfi Diagnostics and Personal Genome Diagnostics. VEV is an inventor of multiple licensed patents related to technologies from Johns Hopkins University. Some of these licenses and relationships are associated with equity or royalty payments directly to Johns Hopkins and VEV. VEV is an advisor to Bristol-Myers Squibb, Danaher, Genentech, and Takeda Pharmaceuticals. Within the last five years, VEV has been an advisor to Merck and Ignyta. These arrangements have been reviewed and approved by the Johns Hopkins University in accordance with its conflict of interest policies. JW is a consultant for Personal Genome Diagnostics, is the founder and owner of Resphera Biosciences and holds patents, royalties or other intellectual property from Personal Genomic Diagnostics. JER is in the advisory board/consultant of Oncocyte, receives speaking fees for Astrazeneca, and has received research funding to his institution from Genetech/Roche, and Verastem. JB is in the advisory board/consultant of Amgen, AstraZeneca, BMS, Genentech/Roche, Eli Lilly, GlaxoSmithKline, Merck, Sanofi and Regeneron, receives grant research funding from AstraZeneca, BMS, Genentech/Roche, Merck, RAPT Therapeutics, Inc and Revolution Medicines and is in the Data and Safety Monitoring Board/Committees of GlaxoSmithKline, Sanofi and Janssen. TS is in the advisory board/consultant of Cue Biopharma, Dracen, Innate, Nanobiotix, Merck, Sanofi, Synthekine, receives grant research funding from AstraZeneca, BMS, Cue Biopharma, Genentech/Roche, Merck, Nanobiotix, Synthekine, and is in the Data and Safety Monitoring Board/Committees of Astra Zeneca, and Nektar. VL has received research funding to his institution from AstraZeneca, Bristol-Myers Squibb, Merck, SeaGen. He has also served as a consultant for Takeda, SeaGen, Bristol-Myers Squibb, AstraZeneca, and Guardant Health., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2022
- Full Text
- View/download PDF
28. Durvalumab with platinum-pemetrexed for unresectable pleural mesothelioma: survival, genomic and immunologic analyses from the phase 2 PrE0505 trial.
- Author
-
Forde PM, Anagnostou V, Sun Z, Dahlberg SE, Kindler HL, Niknafs N, Purcell T, Santana-Davila R, Dudek AZ, Borghaei H, Lanis M, Belcaid Z, Smith KN, Balan A, White JR, Cherry C, Ashok Sivakumar IK, Shao XM, Chan HY, Singh D, Thapa S, Illei PB, Pardoll DM, Karchin R, Velculescu VE, Brahmer JR, and Ramalingam SS
- Subjects
- Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal adverse effects, Antineoplastic Agents, Immunological adverse effects, Antineoplastic Combined Chemotherapy Protocols adverse effects, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Carboplatin therapeutic use, DNA Repair genetics, Female, Genetic Predisposition to Disease genetics, Germ-Line Mutation genetics, Humans, Male, Mesothelioma, Malignant genetics, Mesothelioma, Malignant mortality, Middle Aged, Nucleic Acid Synthesis Inhibitors adverse effects, Pemetrexed adverse effects, Progression-Free Survival, Tumor Suppressor Proteins genetics, Ubiquitin Thiolesterase genetics, Antibodies, Monoclonal therapeutic use, Antineoplastic Agents, Immunological therapeutic use, Cisplatin therapeutic use, Mesothelioma, Malignant drug therapy, Nucleic Acid Synthesis Inhibitors therapeutic use, Pemetrexed therapeutic use
- Abstract
Mesothelioma is a rare and fatal cancer with limited therapeutic options until the recent approval of combination immune checkpoint blockade. Here we report the results of the phase 2 PrE0505 trial ( NCT02899195 ) of the anti-PD-L1 antibody durvalumab plus platinum-pemetrexed chemotherapy for 55 patients with previously untreated, unresectable pleural mesothelioma. The primary endpoint was overall survival compared to historical control with cisplatin and pemetrexed chemotherapy; secondary and exploratory endpoints included safety, progression-free survival and biomarkers of response. The combination of durvalumab with chemotherapy met the pre-specified primary endpoint, reaching a median survival of 20.4 months versus 12.1 months with historical control. Treatment-emergent adverse events were consistent with known side effects of chemotherapy, and all adverse events due to immunotherapy were grade 2 or lower. Integrated genomic and immune cell repertoire analyses revealed that a higher immunogenic mutation burden coupled with a more diverse T cell repertoire was linked to favorable clinical outcome. Structural genome-wide analyses showed a higher degree of genomic instability in responding tumors of epithelioid histology. Patients with germline alterations in cancer predisposing genes, especially those involved in DNA repair, were more likely to achieve long-term survival. Our findings indicate that concurrent durvalumab with platinum-based chemotherapy has promising clinical activity and that responses are driven by the complex genomic background of malignant pleural mesothelioma., (© 2021. The Author(s).)
- Published
- 2021
- Full Text
- View/download PDF
29. Detection and characterization of lung cancer using cell-free DNA fragmentomes.
- Author
-
Mathios D, Johansen JS, Cristiano S, Medina JE, Phallen J, Larsen KR, Bruhm DC, Niknafs N, Ferreira L, Adleff V, Chiao JY, Leal A, Noe M, White JR, Arun AS, Hruban C, Annapragada AV, Jensen SØ, Ørntoft MW, Madsen AH, Carvalho B, de Wit M, Carey J, Dracopoli NC, Maddala T, Fang KC, Hartman AR, Forde PM, Anagnostou V, Brahmer JR, Fijneman RJA, Nielsen HJ, Meijer GA, Andersen CL, Mellemgaard A, Bojesen SE, Scharpf RB, and Velculescu VE
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Apoptosis, Carcinoma, Non-Small-Cell Lung diagnosis, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung pathology, Cell Line, Tumor, Diagnosis, Differential, Early Detection of Cancer, Female, Genome, Human, Humans, Lung Neoplasms pathology, Male, Middle Aged, Models, Biological, Neoplasm Metastasis, Neoplasm Staging, Small Cell Lung Carcinoma diagnosis, Small Cell Lung Carcinoma genetics, Small Cell Lung Carcinoma pathology, Young Adult, Circulating Tumor DNA metabolism, DNA Fragmentation, Lung Neoplasms diagnosis, Lung Neoplasms genetics
- Abstract
Non-invasive approaches for cell-free DNA (cfDNA) assessment provide an opportunity for cancer detection and intervention. Here, we use a machine learning model for detecting tumor-derived cfDNA through genome-wide analyses of cfDNA fragmentation in a prospective study of 365 individuals at risk for lung cancer. We validate the cancer detection model using an independent cohort of 385 non-cancer individuals and 46 lung cancer patients. Combining fragmentation features, clinical risk factors, and CEA levels, followed by CT imaging, detected 94% of patients with cancer across stages and subtypes, including 91% of stage I/II and 96% of stage III/IV, at 80% specificity. Genome-wide fragmentation profiles across ~13,000 ASCL1 transcription factor binding sites distinguished individuals with small cell lung cancer from those with non-small cell lung cancer with high accuracy (AUC = 0.98). A higher fragmentation score represented an independent prognostic indicator of survival. This approach provides a facile avenue for non-invasive detection of lung cancer., (© 2021. The Author(s).)
- Published
- 2021
- Full Text
- View/download PDF
30. Sensory processing and cortisol at age 4 years: Procedural pain-related stress in children born very preterm.
- Author
-
McLean MA, Niknafs N, Scoten OC, Chau CMY, MacKay M, Weinberg J, Synnes A, Miller SP, and Grunau RE
- Subjects
- Child, Child, Preschool, Female, Humans, Infant, Infant, Extremely Premature, Infant, Newborn, Male, Perception, Prospective Studies, Hydrocortisone metabolism, Pain, Procedural
- Abstract
Children born preterm display altered sensory processing, which may manifest as hyper- and/or hypo-sensitivity to sensory information. In this vulnerable population, exposure to neonatal pain-related stress is associated with altered stress regulation, as indexed by alterations in cortisol levels. It is unknown whether sensory processing behaviors are also affected by early life adversity, and whether dysregulated cortisol is related to sensory processing problems in preterm children. We examined relationships between neonatal pain-related stress, sensory processing profiles and cortisol levels at age 4 years, and whether pathways were sex-specific. In a longitudinal prospective cohort study, N = 146 infants born 24-32 weeks gestational age were recruited from BC Women's Hospital, Vancouver, BC, Canada; neonatal factors were collected from daily chart review. At age 4 years, saliva to assay cortisol was collected three times across cognitive assessment (pre-test, during, end) and parents completed the Short Sensory Profile questionnaire. Using generalized linear modeling, independent of other neonatal factors, higher number of invasive procedures (pain/stress) was associated with more sensory processing problems (total, hypo- and hyper-sensitivity) for girls only. After accounting for neonatal factors, greater cortisol output across the assessment was associated with more total sensory processing problems in girls only, and hypersensitivity to sensory input in both boys and girls. Findings suggest that in children born very preterm, how a child responds to sensory input and cortisol reactivity to stress are related but may have different precursors. Girls may be somewhat more susceptible to neonatal pain-related stress exposure in relation to sensory processing at preschool age., (© 2020 Wiley Periodicals LLC.)
- Published
- 2021
- Full Text
- View/download PDF
31. Integrative Tumor and Immune Cell Multi-omic Analyses Predict Response to Immune Checkpoint Blockade in Melanoma.
- Author
-
Anagnostou V, Bruhm DC, Niknafs N, White JR, Shao XM, Sidhom JW, Stein J, Tsai HL, Wang H, Belcaid Z, Murray J, Balan A, Ferreira L, Ross-Macdonald P, Wind-Rotolo M, Baras AS, Taube J, Karchin R, Scharpf RB, Grasso C, Ribas A, Pardoll DM, Topalian SL, and Velculescu VE
- Subjects
- B-Lymphocytes drug effects, B-Lymphocytes immunology, Gene Expression drug effects, Gene Expression genetics, Gene Expression immunology, Gene Expression Profiling methods, Genomics methods, Humans, Immunotherapy methods, Melanoma immunology, Mutation drug effects, Mutation genetics, Mutation immunology, Prospective Studies, T-Lymphocytes drug effects, T-Lymphocytes immunology, Transcription, Genetic drug effects, Transcription, Genetic genetics, Transcription, Genetic immunology, Transcriptome drug effects, Transcriptome genetics, Transcriptome immunology, Immune Checkpoint Inhibitors pharmacology, Melanoma drug therapy, Melanoma genetics
- Abstract
In this study, we incorporate analyses of genome-wide sequence and structural alterations with pre- and on-therapy transcriptomic and T cell repertoire features in immunotherapy-naive melanoma patients treated with immune checkpoint blockade. Although tumor mutation burden is associated with improved treatment response, the mutation frequency in expressed genes is superior in predicting outcome. Increased T cell density in baseline tumors and dynamic changes in regression or expansion of the T cell repertoire during therapy distinguish responders from non-responders. Transcriptome analyses reveal an increased abundance of B cell subsets in tumors from responders and patterns of molecular response related to expressed mutation elimination or retention that reflect clinical outcome. High-dimensional genomic, transcriptomic, and immune repertoire data were integrated into a multi-modal predictor of response. These findings identify genomic and transcriptomic characteristics of tumors and immune cells that predict response to immune checkpoint blockade and highlight the importance of pre-existing T and B cell immunity in therapeutic outcomes., Competing Interests: V.A. and J.T. receive research funding from Bristol-Myers Squibb. J.T. serves as a consultant/advisory board member to Bristol-Myers Squibb, Merck, Astra Zeneca, and Compugen. J.R.W. is a consultant for Personal Genome Diagnostics; is the founder and owner of Resphera Biosciences; and holds patents, royalties, or other intellectual property from Personal Genomic Diagnostics. A.B. receives honoraria from Proscia and Corista; is a consultant of Bristol-Myers Squibb, Genentech, and Bayer; and receives research funding from Genentech. C.G. has patents, royalties, or other intellectual property from Karyopharm and Arcus. A.R. has received honoraria from consulting with Amgen, Bristol-Myers Squibb, Chugai, Genentech, Merck, Novartis, Roche, and Sanofi; is or has been a member of the scientific advisory board and holds stock in Advaxis, Arcus Biosciences, Bioncotech Therapeutics, Compugen, CytomX, Five Prime, FLX-Bio, ImaginAb, Isoplexis, Kite-Gilead, Lutris Pharma, Merus, PACT Pharma, Rgenix, and Tango Therapeutics; and has received research funding from Agilent and from Bristol-Myers Squibb through Stand Up to Cancer (SU2C). P.R.-M. and M.W.-R. are employees of Bristol-Myers Squibb. D.M.P. and S.L.T. report stock and other ownership interests in Aduro Biotech, DNAtrix, Dracen Pharmaceuticals, Dragonfly Therapeutics, Ervaxx, Five Prime Therapeutics, Potenza Therapeutics, RAPT, Tizona Therapeutics, Trieza Therapeutics, and WindMIL; a consulting or advisory role in Amgen, DNAtrix, Dragonfly Therapeutics, Dynavax, Ervaxx, Five Prime Therapeutics, Immunocore, Immunomic Therapeutics, Janssen Pharmaceuticals, MedImmune/AstraZeneca, Merck, RAPT, and WindMIL; research grants from Bristol-Myers Squibb and Compugen; patents, royalties, and/or other intellectual property through their institution with Aduro Biotech, Arbor Pharmaceuticals, Bristol-Myers Squibb, Immunomic Therapeutics, NexImmune, and WindMIL; and travel, accommodations, and expenses from Bristol-Myers Squibb and Five Prime Therapeutics. V.E.V. is a founder of Delfi Diagnostics and Personal Genome Diagnostics, serves on the Board of Directors and as a consultant for both organizations, and owns Delfi Diagnostics and Personal Genome Diagnostics stock, which are subject to certain restrictions under university policy. Additionally, Johns Hopkins University owns equity in Delfi Diagnostics and Personal Genome Diagnostics. V.E.V. is an advisor to Bristol-Myers Squibb, Genentech, Merck, and Takeda Pharmaceuticals. Within the last 5 years, V.E.V. has been an advisor to Daiichi Sankyo, Janssen Diagnostics, and Ignyta. These arrangements have been reviewed and approved by the Johns Hopkins University in accordance with its conflict of interest policies., (© 2020 The Authors.)
- Published
- 2020
- Full Text
- View/download PDF
32. Genomic characterization of malignant progression in neoplastic pancreatic cysts.
- Author
-
Noë M, Niknafs N, Fischer CG, Hackeng WM, Beleva Guthrie V, Hosoda W, Debeljak M, Papp E, Adleff V, White JR, Luchini C, Pea A, Scarpa A, Butturini G, Zamboni G, Castelli P, Hong SM, Yachida S, Hiraoka N, Gill AJ, Samra JS, Offerhaus GJA, Hoorens A, Verheij J, Jansen C, Adsay NV, Jiang W, Winter J, Albores-Saavedra J, Terris B, Thompson ED, Roberts NJ, Hruban RH, Karchin R, Scharpf RB, Brosens LAA, Velculescu VE, and Wood LD
- Subjects
- Carcinogenesis genetics, Cell Transformation, Neoplastic genetics, Exome genetics, Gene Dosage, Humans, Mutation, Pancreatic Cyst pathology, Receptor, Transforming Growth Factor-beta Type II genetics, Smad4 Protein genetics, Disease Progression, Genomics, Pancreatic Cyst genetics, Pancreatic Neoplasms genetics
- Abstract
Intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs) are non-invasive neoplasms that are often observed in association with invasive pancreatic cancers, but their origins and evolutionary relationships are poorly understood. In this study, we analyze 148 samples from IPMNs, MCNs, and small associated invasive carcinomas from 18 patients using whole exome or targeted sequencing. Using evolutionary analyses, we establish that both IPMNs and MCNs are direct precursors to pancreatic cancer. Mutations in SMAD4 and TGFBR2 are frequently restricted to invasive carcinoma, while RNF43 alterations are largely in non-invasive lesions. Genomic analyses suggest an average window of over three years between the development of high-grade dysplasia and pancreatic cancer. Taken together, these data establish non-invasive IPMNs and MCNs as origins of invasive pancreatic cancer, identifying potential drivers of invasion, highlighting the complex clonal dynamics prior to malignant transformation, and providing opportunities for early detection and intervention.
- Published
- 2020
- Full Text
- View/download PDF
33. Multimodal genomic features predict outcome of immune checkpoint blockade in non-small-cell lung cancer.
- Author
-
Anagnostou V, Niknafs N, Marrone K, Bruhm DC, White JR, Naidoo J, Hummelink K, Monkhorst K, Lalezari F, Lanis M, Rosner S, Reuss JE, Smith KN, Adleff V, Rodgers K, Belcaid Z, Rhymee L, Levy B, Feliciano J, Hann CL, Ettinger DS, Georgiades C, Verde F, Illei P, Li QK, Baras AS, Gabrielson E, Brock MV, Karchin R, Pardoll DM, Baylin SB, Brahmer JR, Scharpf RB, Forde PM, and Velculescu VE
- Subjects
- Biomarkers, Tumor genetics, Humans, Immune Checkpoint Inhibitors pharmacology, Immunotherapy methods, Carcinoma, Non-Small-Cell Lung drug therapy, Lung Neoplasms drug therapy
- Abstract
Despite progress in immunotherapy, identifying patients that respond has remained a challenge. Through analysis of whole-exome and targeted sequence data from 5,449 tumors, we found a significant correlation between tumor mutation burden (TMB) and tumor purity, suggesting that low tumor purity tumors are likely to have inaccurate TMB estimates. We developed a new method to estimate a corrected TMB (cTMB) that was adjusted for tumor purity and more accurately predicted outcome to immune checkpoint blockade (ICB). To identify improved predictive markers together with cTMB, we performed whole-exome sequencing for 104 lung tumors treated with ICB. Through comprehensive analyses of sequence and structural alterations, we discovered a significant enrichment in activating mutations in receptor tyrosine kinase (RTK) genes in nonresponding tumors in three immunotherapy treated cohorts. An integrated multivariable model incorporating cTMB, RTK mutations, smoking-related mutational signature and human leukocyte antigen status provided an improved predictor of response to immunotherapy that was independently validated.
- Published
- 2020
- Full Text
- View/download PDF
34. The Effects of a Peer-Counseling Program on Increase Rate and Continuity of Lactation in Tehran Nursing Mothers.
- Author
-
Nayeri F, Farrokhzad N, Esmaeilnia T, Niknafs N, Dalili H, Atarod L, Charousaei H, and Shariat M
- Abstract
Objective: The practice of breastfeeding is considered a blessing since its effects on health are well recognized and applies to both mothers and infants. The objective of this study was to evaluate the effectiveness of peer support and training on breastfeeding initiation, duration and exclusivity. Materials and methods: This community-based clinical trial, (IRCT No: 201504049568N12), was conducted during 2015 in the Municipality of Tehran 19 District. First, a total of 150 mothers with their infants from 4 to 20 months of age were asked to complete a questionnaire, which included the demographic characteristics, educational level, and the type of lactation, the initial age of infant for breastfeeding, and the duration of exclusive breastfeeding. Afterwards, 25 volunteer women were selected for lactation counseling. After 6 months, another sample of 116 nursing mothers in the region who had received peer counseling was selected and questioned through the previously mentioned questionnaire. Finally, the results, which were collected from the behavior of the target population before and after the intervention, were compared. Results: The results of the present study indicated that the nursing mothers who received peer counseling proved to have longer durations of breastfeeding (P-value = 0.039), and higher frequency of first hour initiation of breastfeeding (P-value = 0.003) however, the volunteer counselors were mainly housewives who had lower levels of education (P-value = 0.009) and were younger (P-value = 0.009) than those of untrained control group. Conclusion: The study demonstrated the significant effect of peer counseling on breastfeeding initiation and continuation. It is suggested that lactation training could be initiated during the prenatal period along with the conventional methods of training., (Copyright © Vali-e-Asr Reproductive Health Research Center, Tehran University of Medical Sciences.)
- Published
- 2019
35. Characterization of genetic subclonal evolution in pancreatic cancer mouse models.
- Author
-
Niknafs N, Zhong Y, Moral JA, Zhang L, Shao MX, Lo A, Makohon-Moore A, Iacobuzio-Donahue CA, and Karchin R
- Subjects
- Animals, Clonal Evolution genetics, DNA Copy Number Variations genetics, Disease Models, Animal, Evolution, Molecular, Mice, Mice, Transgenic, Mutation, Proto-Oncogene Proteins p21(ras) genetics, Receptor, Transforming Growth Factor-beta Type II genetics, Tumor Suppressor Protein p53 genetics, Adenocarcinoma genetics, Pancreatic Neoplasms genetics
- Abstract
The KPC mouse model, driven by the Kras and Trp53 transgenes, is well regarded for faithful recapitulation of human pancreatic cancer biology. However, the extent that this model recapitulates the subclonal evolution of this tumor type is unknown. Here we report evidence of continuing subclonal evolution after tumor initiation that largely reflect copy number alterations that target cellular processes of established significance in human pancreatic cancer. The evolutionary trajectories of the mouse tumors show both linear and branching patterns as well as clonal mixing. We propose the KPC model and derivatives have unexplored utility as a functional system to model the mechanisms and modifiers of tumor evolution.
- Published
- 2019
- Full Text
- View/download PDF
36. Intraductal Papillary Mucinous Neoplasms Arise From Multiple Independent Clones, Each With Distinct Mutations.
- Author
-
Fischer CG, Beleva Guthrie V, Braxton AM, Zheng L, Wang P, Song Q, Griffin JF, Chianchiano PE, Hosoda W, Niknafs N, Springer S, Dal Molin M, Masica D, Scharpf RB, Thompson ED, He J, Wolfgang CL, Hruban RH, Roberts NJ, Lennon AM, Jiao Y, Karchin R, and Wood LD
- Subjects
- Aged, Aged, 80 and over, Cell Transformation, Neoplastic pathology, Chromogranins genetics, Clonal Evolution, DNA Mutational Analysis, DNA-Binding Proteins genetics, Evolution, Molecular, Female, GTP-Binding Protein alpha Subunits, Gs genetics, Genetic Predisposition to Disease, Humans, Male, Middle Aged, Mutation Rate, Neoplasm Staging, Oncogene Proteins genetics, Pancreatic Intraductal Neoplasms pathology, Pancreatic Neoplasms pathology, Phenotype, Proto-Oncogene Proteins p21(ras) genetics, Retrospective Studies, Ubiquitin-Protein Ligases, Biomarkers, Tumor genetics, Cell Transformation, Neoplastic genetics, Mutation, Pancreatic Intraductal Neoplasms genetics, Pancreatic Neoplasms genetics
- Abstract
Background & Aims: Intraductal papillary mucinous neoplasms (IPMNs) are lesions that can progress to invasive pancreatic cancer and constitute an important system for studies of pancreatic tumorigenesis. We performed comprehensive genomic analyses of entire IPMNs to determine the diversity of somatic mutations in genes that promote tumorigenesis., Methods: We microdissected neoplastic tissues from 6-24 regions each of 20 resected IPMNs, resulting in 227 neoplastic samples that were analyzed by capture-based targeted sequencing. Somatic mutations in genes associated with pancreatic tumorigenesis were assessed across entire IPMN lesions, and the resulting data were supported by evolutionary modeling, whole-exome sequencing, and in situ detection of mutations., Results: We found a high prevalence of heterogeneity among mutations in IPMNs. Heterogeneity in mutations in KRAS and GNAS was significantly more prevalent in IPMNs with low-grade dysplasia than in IPMNs with high-grade dysplasia (P < .02). Whole-exome sequencing confirmed that IPMNs contained multiple independent clones, each with distinct mutations, as originally indicated by targeted sequencing and evolutionary modeling. We also found evidence for convergent evolution of mutations in RNF43 and TP53, which are acquired during later stages of tumorigenesis., Conclusions: In an analysis of the heterogeneity of mutations throughout IPMNs, we found that early-stage IPMNs contain multiple independent clones, each with distinct mutations, indicating their polyclonal origin. These findings challenge the model in which pancreatic neoplasms arise from a single clone. Increasing our understanding of the mechanisms of IPMN polyclonality could lead to strategies to identify patients at increased risk for pancreatic cancer., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
37. Iranian neonatal diabetes mellitus due to mutation in PDX1 gene: a case report.
- Author
-
Sahebi L, Niknafs N, Dalili H, Amini E, Esmaeilnia T, Amoli M, and Farrokhzad N
- Subjects
- Diabetes Mellitus blood, Diabetes Mellitus drug therapy, Humans, Hyperglycemia blood, Hyperglycemia drug therapy, Infant, Infant, Newborn, Infant, Newborn, Diseases, Insulin administration & dosage, Iran, Male, Mutation, Diabetes Mellitus genetics, Homeodomain Proteins, Hyperglycemia genetics, Trans-Activators
- Abstract
Background: Neonatal diabetes mellitus with hyperglycemia during the first 6 months of life is a rare disorder that can occur in all races and societies., Case Presentation: In this study, we introduced an Iranian (Persian) 65-day-old patient with neonatal diabetes mellitus with novel homozygous mutation in the pancreatic and duodenal homeobox 1, PDX1, gene, which is also known as IPF1 gene, located in exon 2. This case was a newborn boy born in Vali-Asr Hospital, Tehran; he was diagnosed as having hyperglycemia on 28th day. Genetic analysis detected a homozygous mutation on PDX1 gene on chromosome 13. It is a novel homozygous mutation in the PDX1 gene (NM_000209.3), p.Phe167Val. This mutation was confirmed by Sanger sequencing. There was no evidence of agenesis of the pancreas., Conclusions: We reported a case of neonatal diabetes mellitus due to novel homozygous mutation in the PDX1 gene without exocrine pancreas manifestations.
- Published
- 2019
- Full Text
- View/download PDF
38. Genome-wide cell-free DNA fragmentation in patients with cancer.
- Author
-
Cristiano S, Leal A, Phallen J, Fiksel J, Adleff V, Bruhm DC, Jensen SØ, Medina JE, Hruban C, White JR, Palsgrove DN, Niknafs N, Anagnostou V, Forde P, Naidoo J, Marrone K, Brahmer J, Woodward BD, Husain H, van Rooijen KL, Ørntoft MW, Madsen AH, van de Velde CJH, Verheij M, Cats A, Punt CJA, Vink GR, van Grieken NCT, Koopman M, Fijneman RJA, Johansen JS, Nielsen HJ, Meijer GA, Andersen CL, Scharpf RB, and Velculescu VE
- Subjects
- Case-Control Studies, Cohort Studies, DNA Mutational Analysis, Humans, Machine Learning, Mutation, Neoplasms blood, Neoplasms pathology, Circulating Tumor DNA blood, Circulating Tumor DNA genetics, DNA Fragmentation, Genome, Human genetics, Neoplasms diagnosis, Neoplasms genetics
- Abstract
Cell-free DNA in the blood provides a non-invasive diagnostic avenue for patients with cancer
1 . However, characteristics of the origins and molecular features of cell-free DNA are poorly understood. Here we developed an approach to evaluate fragmentation patterns of cell-free DNA across the genome, and found that profiles of healthy individuals reflected nucleosomal patterns of white blood cells, whereas patients with cancer had altered fragmentation profiles. We used this method to analyse the fragmentation profiles of 236 patients with breast, colorectal, lung, ovarian, pancreatic, gastric or bile duct cancer and 245 healthy individuals. A machine learning model that incorporated genome-wide fragmentation features had sensitivities of detection ranging from 57% to more than 99% among the seven cancer types at 98% specificity, with an overall area under the curve value of 0.94. Fragmentation profiles could be used to identify the tissue of origin of the cancers to a limited number of sites in 75% of cases. Combining our approach with mutation-based cell-free DNA analyses detected 91% of patients with cancer. The results of these analyses highlight important properties of cell-free DNA and provide a proof-of-principle approach for the screening, early detection and monitoring of human cancer.- Published
- 2019
- Full Text
- View/download PDF
39. Dynamics of Tumor and Immune Responses during Immune Checkpoint Blockade in Non-Small Cell Lung Cancer.
- Author
-
Anagnostou V, Forde PM, White JR, Niknafs N, Hruban C, Naidoo J, Marrone K, Sivakumar IKA, Bruhm DC, Rosner S, Phallen J, Leal A, Adleff V, Smith KN, Cottrell TR, Rhymee L, Palsgrove DN, Hann CL, Levy B, Feliciano J, Georgiades C, Verde F, Illei P, Li QK, Gabrielson E, Brock MV, Isbell JM, Sauter JL, Taube J, Scharpf RB, Karchin R, Pardoll DM, Chaft JE, Hellmann MD, Brahmer JR, and Velculescu VE
- Subjects
- Antineoplastic Agents, Immunological therapeutic use, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung pathology, Circulating Tumor DNA genetics, Cohort Studies, DNA, Neoplasm genetics, Follow-Up Studies, Humans, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Lung Neoplasms pathology, Neoplasm, Residual drug therapy, Neoplasm, Residual genetics, Neoplasm, Residual pathology, Prognosis, Survival Rate, Carcinoma, Non-Small-Cell Lung immunology, Circulating Tumor DNA analysis, DNA, Neoplasm analysis, Lung Neoplasms immunology, Neoplasm, Residual immunology, Nivolumab therapeutic use
- Abstract
Despite the initial successes of immunotherapy, there is an urgent clinical need for molecular assays that identify patients more likely to respond. Here, we report that ultrasensitive measures of circulating tumor DNA (ctDNA) and T-cell expansion can be used to assess responses to immune checkpoint blockade in metastatic lung cancer patients ( N = 24). Patients with clinical response to therapy had a complete reduction in ctDNA levels after initiation of therapy, whereas nonresponders had no significant changes or an increase in ctDNA levels. Patients with initial response followed by acquired resistance to therapy had an initial drop followed by recrudescence in ctDNA levels. Patients without a molecular response had shorter progression-free and overall survival compared with molecular responders [5.2 vs. 14.5 and 8.4 vs. 18.7 months; HR 5.36; 95% confidence interval (CI), 1.57-18.35; P = 0.007 and HR 6.91; 95% CI, 1.37-34.97; P = 0.02, respectively], which was detected on average 8.7 weeks earlier and was more predictive of clinical benefit than CT imaging. Expansion of T cells, measured through increases of T-cell receptor productive frequencies, mirrored ctDNA reduction in response to therapy. We validated this approach in an independent cohort of patients with early-stage non-small cell lung cancer ( N = 14), where the therapeutic effect was measured by pathologic assessment of residual tumor after anti-PD1 therapy. Consistent with our initial findings, early ctDNA dynamics predicted pathologic response to immune checkpoint blockade. These analyses provide an approach for rapid determination of therapeutic outcomes for patients treated with immune checkpoint inhibitors and have important implications for the development of personalized immune targeted strategies. Significance: Rapid and sensitive detection of circulating tumor DNA dynamic changes and T-cell expansion can be used to guide immune targeted therapy for patients with lung cancer. See related commentary by Zou and Meyerson, p. 1038 ., (©2018 American Association for Cancer Research.)
- Published
- 2019
- Full Text
- View/download PDF
40. Association of SP-B gene 9306 A/G polymorphism (rs7316) and risk of RDS.
- Author
-
Fatahi N, Niknafs N, Kalani M, Dalili H, Shariat M, Amini E, Esmaeilnia Shirvani T, Hardani AK, Taheritafti R, Ghasemi-Fakhr N, Ghadami M, Tavakkoly-Bazzaz J, Rashidi-Nezhad R, Nayeri F, and Rashidi-Nezhad A
- Subjects
- Case-Control Studies, Female, Genetic Predisposition to Disease, Humans, Infant, Newborn, Infant, Premature, Iran epidemiology, Male, Polymorphism, Genetic, Respiratory Distress Syndrome, Newborn mortality, Pulmonary Surfactant-Associated Protein B genetics, Respiratory Distress Syndrome, Newborn genetics
- Abstract
Background: Respiratory distress syndrome (RDS) is a severe pulmonary disease predominantly affects preterm newborns. Polymorphisms of surfactant-protein genes have been mostly evaluated as the candidate contributors in genetics of RDS. However the results are divers in different studies. We aimed at investigating the association of surfactant protein B (SPB) gene 9306 A/G polymorphism (rs7316) with RDS development., Method: Three hundred and eighty newborns with gestational age of less than 34 weeks were included in a multicenter case-control study. Respiratory distress (RD) was scored according to Downes' scoring system. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used for genotyping., Result: One hundred and eighty-four neonates showed RDS and 196 did not. Gestational age (GA) was significantly lower in the RDS group compared with the controls. AA genotype and A allele were found more frequently in the RDS group than the controls (96.2% versus 63.8% and 98.1% versus 80.6%, respectively) (p =.0001)., Conclusions: This is the first report of association of SFTPB rs7316 polymorphism with RDS development in Iranian newborns. The current study suggests that GA <28-weeks is the most important factor in predisposition to RDS. Genetic background in terms of SP-B gene might be involved in predisposition to RDS in premature neonates.
- Published
- 2018
- Full Text
- View/download PDF
41. Tranexamic Acid in Civilian Trauma Care in the California Prehospital Antifibrinolytic Therapy Study.
- Author
-
Neeki MM, Dong F, Toy J, Vaezazizi R, Powell J, Wong D, Mousselli M, Rabiei M, Jabourian A, Niknafs N, Burgett-Moreno M, Vara R, Kissel S, Luo-Owen X, O'Bosky KR, Ludi D, Sporer K, Pennington T, Lee T, Borger R, and Kwong E
- Subjects
- Adolescent, Adult, California epidemiology, Emergency Medical Services methods, Female, Glasgow Outcome Scale, Humans, Incidence, Injury Severity Score, Male, Middle Aged, Prospective Studies, Shock, Hemorrhagic etiology, Time Factors, Young Adult, Antifibrinolytic Agents administration & dosage, Shock, Hemorrhagic mortality, Shock, Hemorrhagic therapy, Tranexamic Acid administration & dosage, Wounds and Injuries complications
- Abstract
Introduction: Hemorrhage is one of the leading causes of death in trauma victims. Historically, paramedics have not had access to medications that specifically target the reversal of trauma-induced coagulopathies. The California Prehospital Antifibrinolytic Therapy (Cal-PAT) study seeks to evaluate the safety and efficacy of tranexamic acid (TXA) use in the civilian prehospital setting in cases of traumatic hemorrhagic shock., Methods: The Cal-PAT study is a multi-centered, prospective, observational cohort study with a retrospective comparison. From March 2015 to July 2017, patients ≥ 18 years-old who sustained blunt or penetrating trauma with signs of hemorrhagic shock identified by first responders in the prehospital setting were considered for TXA treatment. A control group was formed of patients seen in the five years prior to data collection cessation (June 2012 to July 2017) at each receiving center who were not administered TXA. Control group patients were selected through propensity score matching based on gender, age, Injury Severity Scores, and mechanism of injury. The primary outcome assessed was mortality recorded at 24 hours, 48 hours, and 28 days. Additional variables assessed included total blood products transfused, the hospital and intensive care unit length of stay, systolic blood pressure taken prior to TXA administration, Glasgow Coma Score observed prior to TXA administration, and the incidence of known adverse events associated with TXA administration., Results: We included 724 patients in the final analysis, with 362 patients in the TXA group and 362 in the control group. Reduced mortality was noted at 28 days in the TXA group in comparison to the control group (3.6% vs. 8.3% for TXA and control, respectively, odds ratio [OR]=0.41 with 95% confidence interval [CI] [0.21 to 0.8]). This mortality difference was greatest in severely injured patients with ISS >15 (6% vs 14.5% for TXA and control, respectively, OR=0.37 with 95% CI [0.17 to 0.8]). Furthermore, a significant reduction in total blood product transfused was observed after TXA administration in the total cohort as well as in severely injured patients. No significant increase in known adverse events following TXA administration were observed., Conclusion: Findings from the Cal-PAT study suggest that TXA use in the civilian prehospital setting may safely improve survival outcomes in patients who have sustained traumatic injury with signs of hemorrhagic shock., Competing Interests: Conflicts of Interest: By the WestJEM article submission agreement, all authors are required to disclose all affiliations, funding sources and financial or management relationships that could be perceived as potential sources of bias. No author has professional or financial relationships with any companies that are relevant to this study. There are no conflicts of interest or sources of funding to declare.
- Published
- 2018
- Full Text
- View/download PDF
42. A machine learning approach for somatic mutation discovery.
- Author
-
Wood DE, White JR, Georgiadis A, Van Emburgh B, Parpart-Li S, Mitchell J, Anagnostou V, Niknafs N, Karchin R, Papp E, McCord C, LoVerso P, Riley D, Diaz LA Jr, Jones S, Sausen M, Velculescu VE, and Angiuoli SV
- Subjects
- Exome genetics, High-Throughput Nucleotide Sequencing, Humans, Immunotherapy, Neoplasms genetics, Neoplasms immunology, Neoplasms therapy, Software, Exome Sequencing, Machine Learning, Mutation genetics
- Abstract
Variability in the accuracy of somatic mutation detection may affect the discovery of alterations and the therapeutic management of cancer patients. To address this issue, we developed a somatic mutation discovery approach based on machine learning that outperformed existing methods in identifying experimentally validated tumor alterations (sensitivity of 97% versus 90 to 99%; positive predictive value of 98% versus 34 to 92%). Analysis of paired tumor-normal exome data from 1368 TCGA (The Cancer Genome Atlas) samples using this method revealed concordance for 74% of mutation calls but also identified likely false-positive and false-negative changes in TCGA data, including in clinically actionable genes. Determination of high-quality somatic mutation calls improved tumor mutation load-based predictions of clinical outcome for melanoma and lung cancer patients previously treated with immune checkpoint inhibitors. Integration of high-quality machine learning mutation detection in clinical next-generation sequencing (NGS) analyses increased the accuracy of test results compared to other clinical sequencing analyses. These analyses provide an approach for improved identification of tumor-specific mutations and have important implications for research and clinical management of cancer patients., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
- Published
- 2018
- Full Text
- View/download PDF
43. Ipilimumab plus nivolumab and DNA-repair defects in AR-V7-expressing metastatic prostate cancer.
- Author
-
Boudadi K, Suzman DL, Anagnostou V, Fu W, Luber B, Wang H, Niknafs N, White JR, Silberstein JL, Sullivan R, Dowling D, Harb R, Nirschl TR, Veeneman BA, Tomlins SA, Wang Y, Jendrisak A, Graf RP, Dittamore R, Carducci MA, Eisenberger MA, Haffner MC, Meeker AK, Eshleman JR, Luo J, Velculescu VE, Drake CG, and Antonarakis ES
- Abstract
AR-V7-expressing metastatic prostate cancer is an aggressive phenotype with poor progression-free survival (PFS) and overall survival (OS). Preliminary evidence suggests that AR-V7-positive tumors may be enriched for DNA-repair defects, perhaps rendering them more sensitive to immune-checkpoint blockade. We enrolled 15 metastatic prostate cancer patients with AR-V7-expressing circulating tumor cells into a prospective phase-2 trial. Patients received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses, then maintenance nivolumab 3 mg/kg every 2 weeks. Targeted next-generation sequencing was performed to determine DNA-repair deficiency (DRD) status. Outcomes included PSA response rates, objective response rates (ORR), PSA progression-free survival (PSA-PFS), clinical/radiographic PFS and OS. Median age of participants was 65, median PSA was 115 ng/mL, 67% had visceral metastases, and 60% had ≥4 prior systemic therapies. Six of 15 men (40%) had DRD mutations (three in BRCA2 , two in ATM , one in ERCC4 ; none had microsatellite instability). Overall, the PSA response rate was 2/15 (13%), ORR was 2/8 (25%) in those with measurable disease, median PSA-PFS was 3.0 (95%CI 2.1-NR) months, PFS was 3.7 (95%CI 2.8-7.5) months, and OS was 8.2 (95%CI 5.5-10.4) months. Outcomes appeared generally better in DRD+ vs. DRD- tumors with respect to PSA responses (33% vs. 0%; P =0.14, nonsignificant), ORR (40% vs. 0%; P =0.46, nonsignificant), PSA-PFS (HR 0.19; P <0.01, significant), PFS (HR 0.31; P =0.01, significant), and OS (HR 0.41; P =0.11, nonsignificant). There were no new safety concerns. Ipilimumab plus nivolumab demonstrated encouraging efficacy in AR-V7-positive prostate cancers with DRD mutations, but not in the overall study population., Competing Interests: CONFLICTS OF INTEREST E.S.A. is a paid consultant/advisor to Janssen, Astellas, Sanofi, Dendreon, Medivation, ESSA, AstraZeneca, Clovis and Merck; has received research funding to his institution from Janssen, Johnson & Johnson, Sanofi, Dendreon, Genentech, Novartis, Tokai, Bristol Myers-Squibb, AstraZeneca, Clovis and Merck; and is the co-inventor of a biomarker technology that has been licensed to Qiagen. S.A.T. has served as a consultant and received honoraria from Roche/ Ventana Medical Systems, Almac Diagnostics, Janssen, AbbVie and Astellas/Medivation; he is also a co-founder of, consultant for and Laboratory Director of Strata Oncology. Y.W., A.J., R.P.G. and R.D. are employees of Epic Sciences. V.E.V. is a founder of Personal Genome Diagnostics (PGDx), is a member of its Scientific Advisory Board and Board of Directors, and owns PGDx stock, which is subject to certain restrictions under university policy; he is also on the Scientific Advisory Board for Ignyta; the terms of these arrangements are managed by the Johns Hopkins University in accordance with its conflict of interest policies. The remaining authors disclose no relevant conflicts of interest.
- Published
- 2018
- Full Text
- View/download PDF
44. Ethical and legal aspects of patient's safety: a clinical case report.
- Author
-
Kadivar M, Manookian A, Asghari F, Niknafs N, Okazi A, and Zarvani A
- Abstract
Since patient safety is multidimensional and grounded in ethical and legal imperatives, both ethical and legal challenges should be taken into account. In this regard, a falling incident case of a 12-day-old newborn was raised in the monthly ethics round in the Children's Medical Center of Tehran University of Medical Sciences, Iran, and the ethical and legal dimensions of patient safety were discussed by experts in various fields. This report presents different aspects of patient safety in terms of root cause analysis (RCA) and risk management, the role of human resources, the role of professionalism, the necessity of informing the parents (disclosure of medical errors), and forensic medicine with focus on ethical aspects.
- Published
- 2017
45. Epigenetic Therapy Ties MYC Depletion to Reversing Immune Evasion and Treating Lung Cancer.
- Author
-
Topper MJ, Vaz M, Chiappinelli KB, DeStefano Shields CE, Niknafs N, Yen RC, Wenzel A, Hicks J, Ballew M, Stone M, Tran PT, Zahnow CA, Hellmann MD, Anagnostou V, Strissel PL, Strick R, Velculescu VE, and Baylin SB
- Subjects
- Animals, Antigen Presentation drug effects, Antineoplastic Agents therapeutic use, Azacitidine therapeutic use, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung immunology, Cell Line, Tumor, Histone Deacetylase Inhibitors therapeutic use, Hydroxamic Acids therapeutic use, Immunotherapy, Lung Neoplasms genetics, Lung Neoplasms immunology, Mice, T-Lymphocytes immunology, Transcriptome, Tumor Microenvironment, Carcinoma, Non-Small-Cell Lung therapy, Drug Therapy, Combination, Lung Neoplasms therapy, Tumor Escape drug effects
- Abstract
Combining DNA-demethylating agents (DNA methyltransferase inhibitors [DNMTis]) with histone deacetylase inhibitors (HDACis) holds promise for enhancing cancer immune therapy. Herein, pharmacologic and isoform specificity of HDACis are investigated to guide their addition to a DNMTi, thus devising a new, low-dose, sequential regimen that imparts a robust anti-tumor effect for non-small-cell lung cancer (NSCLC). Using in-vitro-treated NSCLC cell lines, we elucidate an interferon α/β-based transcriptional program with accompanying upregulation of antigen presentation machinery, mediated in part through double-stranded RNA (dsRNA) induction. This is accompanied by suppression of MYC signaling and an increase in the T cell chemoattractant CCL5. Use of this combination treatment schema in mouse models of NSCLC reverses tumor immune evasion and modulates T cell exhaustion state towards memory and effector T cell phenotypes. Key correlative science metrics emerge for an upcoming clinical trial, testing enhancement of immune checkpoint therapy for NSCLC., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2017
- Full Text
- View/download PDF
46. Association of SP-C gene codon 186 polymorphism (rs1124) and risk of RDS.
- Author
-
Fatahi N, Dalili H, Kalani M, Niknafs N, Shariat M, Tavakkoly-Bazzaz J, Amini E, Esmaeilnia Shirvani T, Hardani AK, Taheritafti R, Ghasemi-Fakhr N, Ghadami M, Nayeri F, and Rashidi-Nezhad A
- Subjects
- Case-Control Studies, Female, Genetic Predisposition to Disease, Humans, Infant, Newborn, Male, Polymorphism, Single Nucleotide, Pulmonary Surfactant-Associated Protein C genetics, Respiratory Distress Syndrome, Newborn genetics
- Abstract
Background: Respiratory distress syndrome (RDS) is a severe pulmonary disease that mainly affects preterm neonates. Surfactant-protein genes' polymorphisms have been mostly evaluated as the candidate contributors in genetics of RDS. However, the results are diverse in different populations. We aimed at investigating the association of rs1124 with RDS development., Method: Three hundred and thirty five preterm neonates were enrolled in a multicenter case-control study. Respiratory distress (RD) was scored according to Downes' scoring system. Genotyping was performed by PCR-RFLP method., Result: One hundred and sixty six neonates showed RDS and 169 did not. Gestational age (GA) was significantly lower in RDS group compared to the controls. In female preterm newborns, AA genotype was found more frequently in RDS group. In RDS group, AA genotype was also associated with milder RD irrespective of gender. In neonates who were born 28-34 weeks, RD appeared to be more severe in the RDS group and males., Conclusions: This is the first report of association of SFTPC rs1124 polymorphism with RDS development in Iranian newborns. The current study suggests that GA <28-weeks is the most important factor in predisposition to RDS. AA genotype is also, a predisposing factor for the development of RDS in female preterm infants.
- Published
- 2017
- Full Text
- View/download PDF
47. High grade serous ovarian carcinomas originate in the fallopian tube.
- Author
-
Labidi-Galy SI, Papp E, Hallberg D, Niknafs N, Adleff V, Noe M, Bhattacharya R, Novak M, Jones S, Phallen J, Hruban CA, Hirsch MS, Lin DI, Schwartz L, Maire CL, Tille JC, Bowden M, Ayhan A, Wood LD, Scharpf RB, Kurman R, Wang TL, Shih IM, Karchin R, Drapkin R, and Velculescu VE
- Subjects
- Alleles, DNA Copy Number Variations genetics, Fallopian Tube Neoplasms metabolism, Fallopian Tubes metabolism, Female, Humans, Immunohistochemistry, Laser Capture Microdissection, Neoplasms, Cystic, Mucinous, and Serous metabolism, Cystadenocarcinoma, Serous genetics, Fallopian Tube Neoplasms pathology, Fallopian Tubes pathology, Neoplasms, Cystic, Mucinous, and Serous pathology, Ovarian Neoplasms genetics
- Abstract
High-grade serous ovarian carcinoma (HGSOC) is the most frequent type of ovarian cancer and has a poor outcome. It has been proposed that fallopian tube cancers may be precursors of HGSOC but evolutionary evidence for this hypothesis has been limited. Here, we perform whole-exome sequence and copy number analyses of laser capture microdissected fallopian tube lesions (p53 signatures, serous tubal intraepithelial carcinomas (STICs), and fallopian tube carcinomas), ovarian cancers, and metastases from nine patients. The majority of tumor-specific alterations in ovarian cancers were present in STICs, including those affecting TP53, BRCA1, BRCA2 or PTEN. Evolutionary analyses reveal that p53 signatures and STICs are precursors of ovarian carcinoma and identify a window of 7 years between development of a STIC and initiation of ovarian carcinoma, with metastases following rapidly thereafter. Our results provide insights into the etiology of ovarian cancer and have implications for prevention, early detection and therapeutic intervention of this disease.
- Published
- 2017
- Full Text
- View/download PDF
48. Matching phenotypes to whole genomes: Lessons learned from four iterations of the personal genome project community challenges.
- Author
-
Cai B, Li B, Kiga N, Thusberg J, Bergquist T, Chen YC, Niknafs N, Carter H, Tokheim C, Beleva-Guthrie V, Douville C, Bhattacharya R, Yeo HTG, Fan J, Sengupta S, Kim D, Cline M, Turner T, Diekhans M, Zaucha J, Pal LR, Cao C, Yu CH, Yin Y, Carraro M, Giollo M, Ferrari C, Leonardi E, Tosatto SCE, Bobe J, Ball M, Hoskins RA, Repo S, Church G, Brenner SE, Moult J, Gough J, Stanke M, Karchin R, and Mooney SD
- Subjects
- Area Under Curve, Genetic Predisposition to Disease, Human Genome Project, Humans, Phenotype, Quantitative Trait Loci, High-Throughput Nucleotide Sequencing methods, Whole Genome Sequencing methods
- Abstract
The advent of next-generation sequencing has dramatically decreased the cost for whole-genome sequencing and increased the viability for its application in research and clinical care. The Personal Genome Project (PGP) provides unrestricted access to genomes of individuals and their associated phenotypes. This resource enabled the Critical Assessment of Genome Interpretation (CAGI) to create a community challenge to assess the bioinformatics community's ability to predict traits from whole genomes. In the CAGI PGP challenge, researchers were asked to predict whether an individual had a particular trait or profile based on their whole genome. Several approaches were used to assess submissions, including ROC AUC (area under receiver operating characteristic curve), probability rankings, the number of correct predictions, and statistical significance simulations. Overall, we found that prediction of individual traits is difficult, relying on a strong knowledge of trait frequency within the general population, whereas matching genomes to trait profiles relies heavily upon a small number of common traits including ancestry, blood type, and eye color. When a rare genetic disorder is present, profiles can be matched when one or more pathogenic variants are identified. Prediction accuracy has improved substantially over the last 6 years due to improved methodology and a better understanding of features., (© 2017 Wiley Periodicals, Inc.)
- Published
- 2017
- Full Text
- View/download PDF
49. Evolution of Neoantigen Landscape during Immune Checkpoint Blockade in Non-Small Cell Lung Cancer.
- Author
-
Anagnostou V, Smith KN, Forde PM, Niknafs N, Bhattacharya R, White J, Zhang T, Adleff V, Phallen J, Wali N, Hruban C, Guthrie VB, Rodgers K, Naidoo J, Kang H, Sharfman W, Georgiades C, Verde F, Illei P, Li QK, Gabrielson E, Brock MV, Zahnow CA, Baylin SB, Scharpf RB, Brahmer JR, Karchin R, Pardoll DM, and Velculescu VE
- Subjects
- Adult, Antibodies, Monoclonal pharmacology, Antibodies, Monoclonal therapeutic use, Antigens, Neoplasm immunology, Antineoplastic Agents, Immunological pharmacology, CTLA-4 Antigen genetics, CTLA-4 Antigen immunology, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung immunology, Carcinoma, Non-Small-Cell Lung pathology, Cell Cycle Checkpoints drug effects, Cell Cycle Checkpoints immunology, Cohort Studies, Drug Resistance, Neoplasm genetics, Female, Humans, Immunotherapy, Ipilimumab pharmacology, Ipilimumab therapeutic use, Janus Kinase 1 genetics, Janus Kinase 2 genetics, Lung Neoplasms genetics, Lung Neoplasms immunology, Lung Neoplasms pathology, Male, Middle Aged, Mutation, Nivolumab, Programmed Cell Death 1 Receptor antagonists & inhibitors, Programmed Cell Death 1 Receptor genetics, Programmed Cell Death 1 Receptor immunology, Receptors, Antigen, T-Cell immunology, Receptors, Antigen, T-Cell metabolism, Antineoplastic Agents, Immunological therapeutic use, Carcinoma, Non-Small-Cell Lung therapy, Drug Resistance, Neoplasm immunology, Lung Neoplasms therapy, Receptors, Antigen, T-Cell genetics
- Abstract
Immune checkpoint inhibitors have shown significant therapeutic responses against tumors containing increased mutation-associated neoantigen load. We have examined the evolving landscape of tumor neoantigens during the emergence of acquired resistance in patients with non-small cell lung cancer after initial response to immune checkpoint blockade with anti-PD-1 or anti-PD-1/anti-CTLA-4 antibodies. Analyses of matched pretreatment and resistant tumors identified genomic changes resulting in loss of 7 to 18 putative mutation-associated neoantigens in resistant clones. Peptides generated from the eliminated neoantigens elicited clonal T-cell expansion in autologous T-cell cultures, suggesting that they generated functional immune responses. Neoantigen loss occurred through elimination of tumor subclones or through deletion of chromosomal regions containing truncal alterations, and was associated with changes in T-cell receptor clonality. These analyses provide insight into the dynamics of mutational landscapes during immune checkpoint blockade and have implications for the development of immune therapies that target tumor neoantigens. Significance: Acquired resistance to immune checkpoint therapy is being recognized more commonly. This work demonstrates for the first time that acquired resistance to immune checkpoint blockade can arise in association with the evolving landscape of mutations, some of which encode tumor neoantigens recognizable by T cells. These observations imply that widening the breadth of neoantigen reactivity may mitigate the development of acquired resistance. Cancer Discov; 7(3); 264-76. ©2017 AACR. See related commentary by Yang, p. 250 This article is highlighted in the In This Issue feature, p. 235 ., (©2017 American Association for Cancer Research.)
- Published
- 2017
- Full Text
- View/download PDF
50. Exome-Scale Discovery of Hotspot Mutation Regions in Human Cancer Using 3D Protein Structure.
- Author
-
Tokheim C, Bhattacharya R, Niknafs N, Gygax DM, Kim R, Ryan M, Masica DL, and Karchin R
- Subjects
- Biomarkers, Tumor metabolism, Computational Biology, High-Throughput Nucleotide Sequencing, Humans, Protein Conformation, Biomarkers, Tumor chemistry, Biomarkers, Tumor genetics, Exome genetics, Genomics methods, Mutation genetics, Neoplasms genetics
- Abstract
The impact of somatic missense mutation on cancer etiology and progression is often difficult to interpret. One common approach for assessing the contribution of missense mutations in carcinogenesis is to identify genes mutated with statistically nonrandom frequencies. Even given the large number of sequenced cancer samples currently available, this approach remains underpowered to detect drivers, particularly in less studied cancer types. Alternative statistical and bioinformatic approaches are needed. One approach to increase power is to focus on localized regions of increased missense mutation density or hotspot regions, rather than a whole gene or protein domain. Detecting missense mutation hotspot regions in three-dimensional (3D) protein structure may also be beneficial because linear sequence alone does not fully describe the biologically relevant organization of codons. Here, we present a novel and statistically rigorous algorithm for detecting missense mutation hotspot regions in 3D protein structures. We analyzed approximately 3 × 10(5) mutations from The Cancer Genome Atlas (TCGA) and identified 216 tumor-type-specific hotspot regions. In addition to experimentally determined protein structures, we considered high-quality structural models, which increase genomic coverage from approximately 5,000 to more than 15,000 genes. We provide new evidence that 3D mutation analysis has unique advantages. It enables discovery of hotspot regions in many more genes than previously shown and increases sensitivity to hotspot regions in tumor suppressor genes (TSG). Although hotspot regions have long been known to exist in both TSGs and oncogenes, we provide the first report that they have different characteristic properties in the two types of driver genes. We show how cancer researchers can use our results to link 3D protein structure and the biologic functions of missense mutations in cancer, and to generate testable hypotheses about driver mechanisms. Our results are included in a new interactive website for visualizing protein structures with TCGA mutations and associated hotspot regions. Users can submit new sequence data, facilitating the visualization of mutations in a biologically relevant context. Cancer Res; 76(13); 3719-31. ©2016 AACR., (©2016 American Association for Cancer Research.)
- Published
- 2016
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.