Ludwig Center for Cancer Genetics and Therapeutics

Baltimore, MD, United States

Ludwig Center for Cancer Genetics and Therapeutics

Baltimore, MD, United States
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Tomasetti C.,Johns Hopkins University | Marchionni L.,Johns Hopkins University | Nowak M.A.,Harvard University | Parmigiani G.,Dana-Farber Cancer Institute | And 2 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2015

Cancer arises through the sequential accumulation of mutations in oncogenes and tumor suppressor genes. However, how many such mutations are required for a normal human cell to progress to an advanced cancer? The best estimates for this number have been provided by mathematical models based on the relation between age and incidence. For example, the classic studies of Nordling [Nordling CO (1953) Br J Cancer 7(1):68-72] and Armitage and Doll [Armitage P, Doll R (1954) Br J Cancer 8(1):1-12] suggest that six or seven sequential mutations are required. Here, we describe a different approach to derive this estimate that combines conventional epidemiologic studies with genome-wide sequencing data: incidence data for different groups of patients with the same cancer type were compared with respect to their somatic mutation rates. In two well-documented cancer types (lung and colon adenocarcinomas), we find that only three sequential mutations are required to develop cancer. This conclusion deepens our understanding of the process of carcinogenesis and has important implications for the design of future cancer genome-sequencing efforts. © 2015, National Academy of Sciences. All rights reserved.


Izumchenko E.,Johns Hopkins University | Sun K.,Shanghai JiaoTong University | Jones S.,Personal Genome Diagnostics (PGD) | Brait M.,Johns Hopkins University | And 8 more authors.
Cancer Prevention Research | Year: 2015

Disruption of NOTCH1 signaling was recently discovered in head and neck cancer. This study aims to evaluate NOTCH1 alterations in the progression of oral squamous cell carcinoma (OSCC) and compare the occurrence of these mutations in Chinese and Caucasian populations. We used a high-throughput PCR-based enrichment technology and next-generation sequencing (NGS) to sequence NOTCH1 in 144 samples collected in China. Forty-nine samples were normal oralmucosa from patients undergoing oral surgery, 45 were oral leukoplakia biopsies, and 50 were chemoradiation-naïve OSCCsamples with 22 paired-normal tissues from the adjacent unaffected areas. NOTCH1 mutations were found in 54% of primary OSCC and 60% of premalignant lesions. Importantly, almost 60% of patients with leukoplakia with mutated NOTCH1 carried mutations that were also identified in OSCC, indicating an important role of these clonal events in the progression of early neoplasms. We then compared all known NOTCH1 mutations identified in Chinese patients with OSCC with those reported in Caucasians to date. Although we found obvious overlaps in critical regulatory NOTCH1 domains alterations and identified specific mutations shared by both groups, possible gain-of-function mutations were predominantly seen in Chinese population. Our findings demonstrate that premalignant lesions display NOTCH1 mutations at an early stage and are thus bona fide drivers of OSCCprogression. Moreover, our results reveal that NOTCH1 promotes distinct tumorigenic mechanisms in patients from different ethnical populations. ©2014 AACR.


Garralda E.,Spanish National Cancer Research Center | Paz K.,Hospital Universitario Madrid Sanchinarro | Lopez-Casas P.P.,Spanish National Cancer Research Center | Jones S.,Hospital Universitario Madrid Sanchinarro | And 14 more authors.
Clinical Cancer Research | Year: 2014

Background: Current technology permits anunbiasedmassive analysis of somatic genetic alterations from tumorDNA aswell as the generation of individualizedmouse xenografts (Avatarmodels). Thiswork aimed to evaluate our experience integrating these two strategies to personalize the treatment of patients with cancer. Methods: We performed whole-exome sequencing analysis of 25 patients with advanced solid tumors to identify putatively actionable tumor-specific genomic alterations. Avatar models were used as an in vivo platform to test proposed treatment strategies. Results: Successful exome sequencing analyses have been obtained for 23 patients. Tumor-specific mutations and copy-number variations were identified. All samples profiled contained relevant genomic alterations. Tumor was implanted to create an Avatar model from 14 patients and 10 succeeded. Occasionally, actionable alterations such as mutations in NF1, PI3KA, and DDR2 failed to provide any benefit when a targeted drug was tested in the Avatar and, accordingly, treatment of the patients with these drugs was not effective. To date, 13 patients have received a personalized treatment and 6 achieved durable partial remissions. Prior testing of candidate treatments in Avatar models correlated with clinical response and helped to select empirical treatments in some patients with no actionable mutations. Conclusion: The use of full genomic analysis for cancer care is encouraging but presents important challenges that will need to be solved for broad clinical application. Avatar models are a promising investigational platform for therapeutic decision making. While limitations still exist, this strategy should be further tested. © 2014 AACR.


Yang J.,Ludwig Center for Cancer Genetics and Therapeutics | Yang J.,Howard Hughes Medical Institute | Yang J.,Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Hendricks W.,Ludwig Center for Cancer Genetics and Therapeutics | And 16 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2013

Nanoparticle gene therapy holds great promise for the treatment of malignant disease in light of the large number of potent, tumor-specific therapeutic payloads potentially available for delivery. To be effective, gene therapy vehicles must be able to deliver their therapeutic payloads to metastatic lesions after systemic administration. Here we describe nanoparticles comprised of a core of high molecular weight linear polyethylenimine (LPEI) complexed with DNA and surrounded by a shell of polyethyleneglycol-modified (PEGylated) low molecular weight LPEI. Compared with a state-of-the-art commercially available in vivo gene delivery formulation, i.v. delivery of the core/PEGylated shell (CPS) nanoparticles provided more than a 16,000-fold increase in the ratio of tumor to nontumor transfection. The vast majority of examined liver and lung metastases derived from a colorectal cancer cell line showed transgene expression after i.v. CPS injection in an animal model of metastasis. Histological examination of tissues from transfected mice revealed that the CPS nanoparticles selectively transfected neoplastic cells rather than stromal cells within primary and metastatic tumors. However, only a small fraction of neoplastic cells (<1%) expressed the transgene, and the extent of delivery varied with the tumor cell line, tumor site, and host mouse strain used. Our results demonstrate that these CPS nanoparticles offer substantial advantages over previously described formulations for in vivo nanoparticle gene therapeutics. At the same time, they illustrate that major increases in the effectiveness of such approaches are needed for utility in patients with metastatic cancer.


Kinde I.,Ludwig Center for Cancer Genetics and Therapeutics | Munari E.,Johns Hopkins University | Faraj S.F.,Johns Hopkins University | Hruban R.H.,Johns Hopkins University | And 13 more authors.
Cancer Research | Year: 2013

Activating mutations occur in the promoter of the telomerase reverse transcriptase (TERT) gene in 66% of muscle-invasive urothelial carcinomas. To explore their role in bladder cancer development and to assess their utility as urine markers for early detection, we sequenced the TERT promoter in 76 well-characterized papillary and flat noninvasive urothelial carcinomas, including 28 pTa low-grade transitional cell carcinomas (TCC), 31 pTa high-grade TCCs, and 17 pTis carcinoma in situ lesions. We also evaluated the sequence of the TERT promoter in a separate series of 14 early bladder neoplasms and matched follow-up urine samples to determine whether urine TERT status was an indicator of disease recurrence. A high rate of TERT promoter mutation was observed in both papillary and flat lesions, as well as in low- and high-grade noninvasive urothelial neoplasms (mean: 74%). In addition, among patients whose tumors harbored TERT promoter mutations, the same mutations were present in follow-up urines in seven of eight patients that recurred but in none of the six patients that did not recur (P 0.001). TERT promoter mutations occur in both papillary and flat lesions, are the most frequent genetic alterations identified to date in noninvasive precursor lesions of the bladder, are detectable in urine, and seem to be strongly associated with bladder cancer recurrence. These provocative results suggest that TERT promoter mutations may offer a useful urinary biomarker for both early detection and monitoring of bladder neoplasia. © 2013 American Association for Cancer Research.


Cardenas-Navia L.I.,Human Genome Research Institutes | Cruz P.,U.S. National Institutes of Health | Lin J.C.,Ludwig Center for Cancer Genetics and Therapeutics | Rosenberg S.A.,U.S. National Cancer Institute | Samuels Y.,Human Genome Research Institutes
Cancer Biology and Therapy | Year: 2010

Heterotrimeric guanine nucleotide-binding proteins (G proteins) mediate signals between G-protein coupled receptors and their downstream pathways, and have been shown to be mutated in cancer. In particular, GNAQ was found to be frequently mutated in blue nevi of the skin and uveal melanoma, acting as an oncogene in its mutated form. To further examine the role of heterotrimeric G proteins in melanoma, we performed a comprehensive mutational analysis of the 35 genes in the heterotrimeric G protein gene family in a panel of 80 melanoma samples. somatic alterations in a G protein subunit were detected in 17% of samples spanning 7 genes. The highest rates of somatic, non-synonymous mutations were found in GNG10 and GNAZ, neither of which has been previously reported to be mutated in melanoma. Our study is the first systematic analysis of the heterotrimeric G proteins in melanoma and indicates that multiple mutated heterotrimeric G proteins may be involved in melanoma progression. © 2010 Landes Bioscience.


Lovejoy C.A.,Rockefeller University | Li W.,Rockefeller University | Reisenweber S.,Rockefeller University | Thongthip S.,Rockefeller University | And 25 more authors.
PLoS Genetics | Year: 2012

The Alternative Lengthening of Telomeres (ALT) pathway is a telomerase-independent pathway for telomere maintenance that is active in a significant subset of human cancers and in vitro immortalized cell lines. ALT is thought to involve templated extension of telomeres through homologous recombination, but the genetic or epigenetic changes that unleash ALT are not known. Recently, mutations in the ATRX/DAXX chromatin remodeling complex and histone H3.3 were found to correlate with features of ALT in pancreatic neuroendocrine cancers, pediatric glioblastomas, and other tumors of the central nervous system, suggesting that these mutations might contribute to the activation of the ALT pathway in these cancers. We have taken a comprehensive approach to deciphering ALT by applying genomic, molecular biological, and cell biological approaches to a panel of 22 ALT cell lines, including cell lines derived in vitro. Here we show that loss of ATRX protein and mutations in the ATRX gene are hallmarks of ALT-immortalized cell lines. In addition, ALT is associated with extensive genome rearrangements, marked micronucleation, defects in the G2/M checkpoint, and altered double-strand break (DSB) repair. These attributes will facilitate the diagnosis and treatment of ALT positive human cancers. © 2012 Lovejoy et al.


Reese J.B.,Johns Hopkins University | Porter L.S.,Duke University | Regan K.R.,Widener University | Keefe F.J.,Duke University | And 5 more authors.
Psycho-Oncology | Year: 2014

Background: We previously developed and piloted a telephone-based intimacy enhancement (IE) intervention addressing sexual concerns of colorectal cancer patients and their partners in an uncontrolled study. The current study tested the feasibility, acceptability, and preliminary efficacy of the IE intervention in a randomized, controlled trial. Methods: Twenty-three couples were randomized to either the four-session IE condition or to a wait list control condition and completed sexual and relationship outcomes measures. The IE intervention teaches skills for coping with sexual concerns and improving intimacy. Feasibility and acceptability were assessed through enrollment and post-treatment program evaluations, respectively. Effect sizes were calculated by comparing differences in average pre/post change scores across completers in the two groups (n = 18 couples). Results: Recruitment and attrition data supported feasibility. Program evaluations for process (e.g., ease of participation) and content (e.g., relevance) demonstrated acceptability. Engaging in intimacy-building activities and communication were the skills rated as most commonly practiced and most helpful. For patients, positive effects of the IE intervention were found for female and male sexual function, medical impact on sexual function, and self-efficacy for enjoying intimacy (≥.58); no effects were found on sexual distress or intimacy and small negative effects for sexual communication, and two self-efficacy items. For partners, positive IE effects were found for all outcomes; the largest were for sexual distress (.69), male sexual function (1.76), communication (.97), and two self-efficacy items (≥.87). Conclusions: The telephone-based IE intervention shows promise for couples facing colorectal cancer. Larger multi-site intervention studies are necessary to replicate findings. Copyright © 2014 John Wiley & Sons, Ltd.


Sausen M.,Ludwig Center for Cancer Genetics and Therapeutics | Leary R.J.,Ludwig Center for Cancer Genetics and Therapeutics | Jones S.,Ludwig Center for Cancer Genetics and Therapeutics | Jones S.,Hopkins Inc. | And 15 more authors.
Nature Genetics | Year: 2013

Neuroblastomas are tumors of peripheral sympathetic neurons and are the most common solid tumor in children. To determine the genetic basis for neuroblastoma, we performed whole-genome sequencing (6 cases), exome sequencing (16 cases), genome-wide rearrangement analyses (32 cases) and targeted analyses of specific genomic loci (40 cases) using massively parallel sequencing. On average, each tumor had 19 somatic alterations in coding genes (range of 3-70). Among genes not previously known to be involved in neuroblastoma, chromosomal deletions and sequence alterations of the chromatin-remodeling genes ARID1A and ARID1B were identified in 8 of 71 tumors (11%) and were associated with early treatment failure and decreased survival. Using tumor-specific structural alterations, we developed an approach to identify rearranged DNA fragments in sera, providing personalized biomarkers for minimal residual disease detection and monitoring. These results highlight the dysregulation of chromatin remodeling in pediatric tumorigenesis and provide new approaches for the management of patients with neuroblastoma. © 2013 Nature America, Inc. All rights reserved.


Velculescu V.E.,Ludwig Center for Cancer Genetics and Therapeutics | Diaz Jr. L.A.,Ludwig Center for Cancer Genetics and Therapeutics
Science Translational Medicine | Year: 2011

In this issue of Science Translational Medicine, Tanas and colleagues describe a disease defining genetic alteration for the vascular cancer epithelioid hemangioendothelioma (EHE). The resulting EHE-associated fusion gene encodes an aberrantly expressed putative transcription factor. This molecular information is the latest in a series of genetic discoveries that aid in cancer diagnosis and may pave the way to targeted therapeutic agents.

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