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  • American Association for Cancer Research (AACR)  (6)
  • 1
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 8_Supplement ( 2012-04-15), p. 5114-5114
    Abstract: The Cancer Cell Line Encyclopedia (CCLE) represents a collaborative effort to assemble a comprehensive resource of human cancer models for basic and translational research. It contains a detailed genetic profiling of approximately 1,000 human cancer cell lines spanning many tumor types. Thus far, high-density SNP array data, gene expression microarray data and mutation data from hybrid capture sequencing of 1,650 cancer genes has been obtained. Additionally, we have assessed the sensitivity of these same cell lines using a series of pharmacological compounds that represent both conventional cytotoxic and targeted agents. On major goal of the CCLE effort involves systematic integration of the genomic and pharmacologic datasets in order to identify putative targets of prevalent genetic alterations as well as predictors and modifiers of pharmacologic sensitivity and resistance. The availability of high-quality data generated by uniform criteria across hundreds of cell lines markedly enhances the statistical power to discover genetic alterations involved in carcinogenesis and molecular predictors of pharmacologic vulnerability. We developed a framework based on an elastic net machine-learning regression algorithm, and combined with a bootstrapping procedure, to derive predictive models of the sensitivity to each compound, using all genetic features of the cell lines in the collection. Through this computational prediction approach, we have both rediscovered molecular features predicting response to most drugs in our set but also uncovered novel potential biomarkers of sensitivity and resistance to targeted agents and chemotherapy drugs. For instance, we have found that response to topoisomerase 1 inhibitors seems to be linked to the expression of a single gene. We have also observed that tissue lineage is a key predictor for sensitivity to certain compounds, providing rationale for clinical trials of these drugs in particular cancer types and we identified potential stratifiers for existing EGFR targeted therapies. Finally, we have found an additional target for a certain chemotype of MEK inhibitors, and shown that this interaction was responsible for growth suppression, which might be a new indication for this kind of drug. Our cell line-based platform provides a valuable tool for the development of personalized cancer medicine, revealing critical tumor dependencies and helping to stratify patients for clinical trials. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5114. doi:1538-7445.AM2012-5114
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
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  • 2
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 4601-4601
    Abstract: The analysis of exonic DNA from prostate cancers has identified recurrently mutated genes, but the spectrum of alterations across the entire genome has not been profiled extensively in this disease. We sequenced the genomes of 55 primary prostate tumors and matched normal tissues to catalogue somatic alterations and to study how they accumulate during oncogenesis and progression. By implementing an algorithm to identify genomic alterations that arise together, we found abundant sets of DNA rearrangements and deletions that may occur simultaneously in a single cell. This phenomenon, which we term “chromoplexy," frequently accounts for the dysregulation of prostate cancer genes including PTEN, NKX3-1, TP53 and CDKN1B. The somatic fusion of TMPRSS2 and ERG, which occurs in approximately half of prostate cancers, predominantly arises with additional genomic rearrangements in the context of chromoplexy. We further demonstrate that TMPRSS2-ERG fusion-positive tumors display a unique profile of chromoplexy, with complex chains of rearrangements that may fuse DNA from four or more distinct chromosomes. In prostate cancer and other neoplasms, chromoplexy induces considerable genomic derangement in a series of relatively few events. In several instances, multiple cancer genes from non-contiguous regions of the genome appear to be disrupted simultaneously by this process, suggesting a model of punctuated progression during cancer evolution. By characterizing the clonal hierarchy of genomic lesions in prostate tumors, we constructed a path of oncogenic events along which chromoplexy drives prostate carcinogenesis. Citation Format: Sylvan C. Baca, Davide Prandi, Michael S. Lawrence, Juan Miguel Mosquera, Alessandro Romanel, Yotam Drier, Kyung Park, Naoki Kitabayashi, Theresa Y. MacDonald, Eliezer Van Allen, Gregory V. Kryukov, Jean-Philippe Theurillat, T. David Soong, Elizabeth Nickerson, Daniel Auclair, Ashutosh Tewari, Himisha Beltran, Robert C. Onofrio, Gunther Boysen, Candace Guiducci, Christopher E. Barbieri, Kristian Cibulskis, Andrey Sivachenko, Scott L. Carter, Douglas Voet, Gordon Saksena, Michelle R. Cipicchio, Kristin Ardlie, Philip W. Kantoff, Michael F. Berger, Stacey B. Gabriel, Todd R. Golub, Matthew Meyerson, Eric S. Lander, Olivier Elemento, Gad Getz, Francesca Demichelis, Mark A. Rubin, Levi A. Garraway. Punctuated evolution of prostate cancer genomes. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4601. doi:10.1158/1538-7445.AM2013-4601
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 3
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. LB-136-LB-136
    Abstract: Background: Circulating cell-free DNA (cfDNA) has largely been used to monitor blood for specific tumor mutations, but genome-wide discovery from cfDNA has not been well established. Here, we establish a scalable approach for whole-exome sequencing (WES) of cfDNA, making it possible to perform comprehensive genomic characterization of metastatic cancer in a routine and minimally-invasive manner. Comprehensive genomic characterization of metastatic cancer stands to uncover novel alterations of clinical significance. A major challenge is that metastatic tumors are infrequently biopsied. Cell-free DNA is shed abundantly into the bloodstream from metastatic tumors, presenting an opportunity for genomic discovery in advanced cancers that are rarely biopsied in routine clinical care. We report an efficient process to qualify and sequence whole-exomes from cfDNA at scale and systematically compare the somatic mutations, indels, and copy number alterations detected in WES of cfDNA to WES of matched tumor biopsies. Methods: We consented 86 patients with metastatic breast or prostate cancers for blood collection. We isolated cfDNA and germline DNA from blood and performed low coverage sequencing to estimate tumor content based on genome-wide copy number. We screened patient blood samples and prioritized those with higher tumor fractions for WES. In parallel, we analyzed cfDNA and germline DNA from healthy donors to calibrate our methods and assess false positive rate for genomic alterations. Results: We found the vast majority of patients with metastatic prostate or breast cancer to have detectable tumor-derived cfDNA. WES of cfDNA from healthy donors revealed very low false positive rates for somatic mutations, indels and copy number alterations (SCNAs). By analyzing WES of cfDNA and tumor biopsies from dozens of patients with metastatic breast or prostate cancers, we established guidelines for the coverage and tumor fraction required for mutation discovery in WES of cfDNA. We found WES of cfDNA to uncover 91% of the clonal mutations, 59% of the subclonal mutations, and 75% of the SCNAs detected in WES of matched tumor biopsies. In several cases, we observed mutations exclusive to cfDNA that were confirmed in later blood draws, suggesting that cfDNA-exclusive mutations may be derived from unsampled metastases. In some cases, cfDNA revealed clinically actionable mutations that were not detected in matched tumor biopsies. Conclusions: WES of cfDNA uncovers the majority of somatic mutations, indels, and SCNAs found in matched tumor biopsies of metastatic cancer. The high degree of concordance suggests that comprehensive sequencing of cfDNA can be leveraged for genomic discovery in settings where conventional biopsies are difficult to access. Furthermore, the detection of mutations in cfDNA that are not detected in concurrent biopsies suggests that cfDNA may be complementary to tumor biopsies for both translational studies and precision cancer medicine. Citation Format: Viktor A. Adalsteinsson, Gavin Ha, Sam Freeman, Atish D. Choudhury, Daniel G. Stover, Heather A. Parsons, Gregory Gydush, Sarah Reed, Denis Loginov, Dimitri Livitz, Daniel Rosebrock, Ignat Leshchiner, Ofir Cohen, Coyin Oh, Jaegil Kim, Chip Stewart, Mara Rosenberg, Huiming Ding, Maxwell R. Lloyd, Sairah Mahmud, Karla E. Helvie, Margaret S. Merrill, Rebecca A. Santiago, Edward P. O’Connor, Seong H. Jeong, Joseph F. Kramkowski, Jens G. Lohr, Laura Polacek, Nelly Oliver, Lori Marini, Joshua Francis, Lauren C. Harshman, Eliezer M. Van Allen, Eric P. Winer, Nancy U. Lin, Mari Nakabayashi, Mary-Ellen Taplin, Levi A. Garraway, Todd R. Golub, Jesse S. Boehm, Nikhil Wagle, Gad Getz, Matthew Meyerson, Christopher J. Love. High concordance of whole-exome sequencing of cell-free DNA and matched biopsies enables genomic discovery in metastatic cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-136.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 4
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 32, No. 1_Supplement ( 2023-01-01), p. C070-C070
    Abstract: Background: Lack of representation in genomic databases limits the generalizability of study findings, predictive models, and therapeutics. In cancer, the development of nearly 75% of cancer drugs have been informed by genomic data,1 yet there is persistent lack of diversity of genomic testing databases that inform clinical trials and lead to drug approval.2,3 The PROFILE project at Dana-Farber Cancer Institute (DFCI) is available to all adult cancer patients, offering free genomic testing for inclusion in their genomic database. Herein, we describe the enrollment ratios in PROFILE delineated by demographic group and cancer type. Methods: We conducted a cross-sectional analysis of the prevalence of PROFILE enrollment 7/8/2011 – 1/1/2022. Over this time period 177,788. Enrollment processes vary in each DFCI disease center, but all solid tumor patients are meant to be approached for enrollment around the time of their first visit. The electronic health record was queried to identify demographics, which are collected by registration staff at intake. Queried demographics included gender, age ( & lt;70/≥70 years old), race, ethnicity, marital status, English proficiency, and primary language; cancer type was also queried. Prevalence was calculated from the number of patients enrolled each year and the total patients for that year. The association between PROFILE enrollment and demographic groups were determined with χ2 tests. Results: Across DFCI, 41% of adult patients are enrolled in PROFILE (73,730 enrolled). Enrollment was most common in the following groups (% of DFCI population, % of enrolled): female (57, 54), younger (78, 79), white (90, 93), non-Hispanic (97, 98), married (68, 70), English proficient (96, 98), hematologic malignancy (20, 18). Differences were statisticially significant for each category (p-value & lt;0.0001). Conclusion: This data suggests that, despite the universal availability of genomic testing for DFCI patients, disparities still result in underenrollment of certain groups, particularly by race and English proficiency. Ongoing projects at DFCI aim to increase enrollment with decision-making support through a patient navigator and informational video among key patient groups, including older adults, racial minorities, Latinx, and limited English proficient. 1. Marquart J, Chen EY, Prasad V. Estimation of the percentage of US patients with cancer who benefit from genome-driven oncology. JAMA oncology. 2018;4(8):1093-1098. 2. Guerrero S, López-Cortés A, Indacochea A, et al. Analysis of racial/ethnic representation in select basic and applied cancer research studies. Scientific reports. 2018;8(1):1-8. 3. Zavala VA, Bracci PM, Carethers JM, et al. Cancer health disparities in racial/ethnic minorities in the United States. British journal of cancer. 2021;124(2):315-332. Citation Format: Nadine Jackson McCleary, Ellana K. Haakenstad, Bridget Neville, Arrien A. Bertram, Wendy Loeser, Joseph Grider, Andea Kruse, Alissa Gentile, Olga Kozyreva, Pedro Sanz-Altamira, Christopher Lathan, Michael J. Hassett, Ethan Cerami, Annette S. Kim, Marios Giannakis, R. Coleman Lindsley, Neal I. Lindeman, William C. Hahn, Janina Longtine, Barrett Rollins, Levi Garraway, Bruce E. Johnson. REAL variance in genomic testing by sex, age, race, ethnicity, and language: PROFILE database 7/2011 - 1/2022 [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Un derserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C070.
    Type of Medium: Online Resource
    ISSN: 1538-7755
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 5
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 5524-5524
    Abstract: Purpose: Tumor genomic testing and cancer clinical trial enrollment provide key access to precision cancer therapeutics and supportive care options to enhance the patient experience. However, physician and patient barriers limit participation of patients who are historically underrepresented in genomic studies and clinical trials [historically underrepresented patients (HUP)], thereby decreasing generalizability for those most negatively affected by cancer diagnosis. We interviewed patients to identify factors impacting genomic testing uptake and clinical trial enrollment. Methods: From 09/2021 - 12/2021 we interviewed 16 patients diagnosed with cancer seen at an ambulatory oncology center. Patients were HUP (Black, American Indian or Alaska Native, Native Hawaiian or other Pacific Islander, Hispanic/Latinx, or older adult [70 years or older], or from a low-income zip code). From non-inclusive groups, patients identified as: 3 primarily spoke a language other than English, 9 Black, 3 other race, 6 Hispanic, and 3 aged 70 years or older. One-on-one interviews utilized a structured interview guide and lasted approximately 45 minutes. Participants were recruited until thematic saturation was reached then transcripts coded for major patterns and themes. Results: Regarding tumor genomic testing, many patients were unsure if they received testing or if testing was recommended (citing possible confusion with medical terminology or overwhelm with information). Cited barriers included education (not understanding the benefit of participating, investigational drug/device identity, the procedures and processes involved), mistrust of research (specifically concerns over data privacy); and logistical accessibility (cost, time away from work, transportation). Those tested found it to be an easy process. Several cited that a patient advocate or social worker would be beneficial to navigate the process. Barriers around clinical trial enrollment included education (the risks of participating/side effects, size of the study, investigational drug/device identity), mistrust of research (data privacy, inclusion of HUP in trial, loss of autonomy in decision making), and logistical accessibility (time commitment). HUP who participated in a clinical trial appreciated the additional psychosocial support and clinical monitoring. Patients were emphatically interested in participating in genomic testing and cancer clinical trials when presented as the best course of care, though concerns about side effects from clinical trials persisted. Conclusion: Patient barriers to tumor genomic testing and cancer clinical trials center around education, mistrust in research, and logistical accessibility. Patients who participated in genomic testing and clinical trials did have a positive experience. Barriers may be addressed with personalized education and coaching, including supportive resources referral. Citation Format: Ellana K. Haakenstad, Jane Roberts, Anna C. Revette, Wendy Loeser, Joseph Grider, Andrea Kruse, Alissa Gentile, Rachel Freedman, Neal I. Lindeman, Olga Kozyreva, Pedro Sanz-Altamira, Christopher S. Lathan, Michael Hassett, Ethan Cerami, Annette S. Kim, Danielle K. Manning, Jonathan Nowak, Marios Giannakis, R Coleman Lindsley, William C. Hahn, Barrett J. Rollins, Levi Garraway, Bruce E. Johnson, Nadine Jackson McCleary. Persistent patient barriers to genomic testing in ambulatory oncology. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5524.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 6
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 4017-4017
    Abstract: Characterizing the genomic evolution of cancer is critical to understanding disease progression and identifying potential therapeutic targets. By examining the clonal hierarchy of genomic lesions in common tumors, it would be possible to reconstruct the path of oncogenic events that drive carcinogenesis. Reliable assessment of such paths from high-throughput genome sequencing data is complicated by the admixture of normal DNA in tumor samples and by reduced data signal for highly subclonal events. We introduce an approach that exploits individuals’ genetic background by using the abundant germline SNP genotype data provided by whole genome sequence coverage to assess the clonality of genomic alterations, including copy number changes, rearrangements, and point mutations. We developed a novel algorithm, CLONET (CLONality Estimate in Tumors), which analyzes patient-specific heterozygous SNP loci (informative SNPs) and mono-allelic somatic deletions to assess levels of stromal DNA admixture and infer the clonal status of each aberration. For every mono allelic deletion, CLONET assesses the allelic fractions of informative SNPs to determine the apparent proportion of normal cells DNA. Next, through a conservative use of simulation-based error estimates, deletions with the lowest proportions of normal DNA reads are considered clonal. For point mutations, the tumor allelic fraction is corrected for stromal DNA admixture level and subclonality is inferred when it differs significantly from the expected value for clonal lesions. Similarly, the proportions of reads that span each side of a putative breakpoint involved in a rearrangement are matched against the expected values. CLONET also addresses tumor aneuploidy by searching for chromosomes with coverage and allelic fractions of informative SNPs not consistent with a diploid genome. CLONET was tested on 55 whole genome sequences from prostate cancers, a highly heterogeneous tumor type, to catalogue the accumulation of somatic alterations during oncogenesis and progression. In 98% of the cases CLONET made confident assessment of admixture and clonality. We observed consistent clonal lesions involving NKX3-1, the 3Mb region between TMPRSS2 and ERG and FOXP1, as well as early point mutations in SPOP and FOXA1. Overall, we observed a higher rate of subclonal protein-coding point mutation versus deletions (p-value & lt; 10−7). We validated this approach by IHC and FISH for predicted clonal and sub-clonal events. A predicted subclonal homozygous deletion of CHD1 was confirmed by FISH that demonstrated the presence of both nuclei with homozygous and with hemizygous deletion of CHD1. Finally, to assess the general validity of CLONET, we analyzed data from 53 additional tumor genomes, including 25 melanomas and 28 lung adenocarcinomas. In summary, our results imply the existence of consensus paths of tumor carcinogenesis that favor dysregulation of cancer genes in a defined sequence. Citation Format: Davide Prandi, Sylvan C. Baca, Michael S. Lawrence, Juan Miguel Mosquera, Alessandro Romanel, Yotam Drier, Kyung Park, Naoki Kitabayashi, Theresa Y. MacDonald, Eliezer Van Allen, Gregory V. Kryukov, Jean-Philippe Theurillat, T. David Soong, Elizabeth Nickerson, Daniel Auclair, Ashutosh Tewari, Himisha Beltran, Robert C. Onofrio, Gunther Boysen, Candace Guiducci, Christopher E. Barbieri, Kristian Cibulskis, Andrey Sivachenko, Scott L. Carter, Gordon Saksena, Douglas Voet, Alex H. Ramos, Wendy Winckler, Michelle Cipicchio, Kristin Ardlie, Philip W. Kantoff, Michael F. Berger, Stacey B. Gabriel, Todd R. Golub, Matthew Meyerson, Eric S. Lander, Olivier Elemento, Gad Getz, Francesca Demichelis, Mark A. Rubin, Levi A. Garraway. Dissecting the clonal hierarchy of cancer-driving genomic lesions. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4017. doi:10.1158/1538-7445.AM2013-4017
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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