Laura E Macconaill

Dana-Farber Cancer Institute, Boston, Massachusetts, United States

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Publications (44)443.61 Total impact

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    ABSTRACT: The ERK signaling pathway is activated in Langerhans cell histiocytosis (LCH) histiocytes but only 60% of cases carry somatic activating mutations of BRAF. To identify other genetic causes of ERK pathway activation, we performed whole exome sequencing on purified LCH cells in three cases. One patient with wild type BRAF alleles in his histiocytes had compound mutations in the kinase domain of ARAF. Unlike wild type ARAF, this mutant was a highly active MEK kinase in vitro and was capable of transforming mouse embryo fibroblasts. Mutant ARAF activity was inhibited by vemurafenib, a BRAF inhibitor, indicating the importance of fully evaluating ERK pathway abnormalities in selecting LCH patients for targeted inhibitor therapy.
    Blood 03/2014; · 9.06 Impact Factor
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    ABSTRACT: Cervical cancer is the second leading cause of cancer deaths among women worldwide. The objective of this study was to describe the most common oncogenic mutations in cervical cancers and to explore genomic differences between the 2 most common histologic subtypes: adenocarcinoma and squamous cell carcinoma. A high-throughput genotyping platform, termed Oncomap, was used to interrogate 80 cervical tumors for 1250 known mutations in 139 cancer genes. Samples were analyzed using a mass spectrometry-based genotyping platform and were validated using orthogonal chemistry. Epidermal growth factor receptor (EGFR) mutations were further validated by massive parallel sequencing. Human papilloma virus (HPV) genotyping also was performed. Validated mutations were detected in 48 of 80 tumors (60%) examined. The highest mutation rates were in the genes phosphatidylinositol 3-kinase, catalytic subunit α (PIK3CA) (31.3%); Kirsten rat sarcoma viral oncogene homolog (KRAS) (8.8%); and EGFR (3.8%). PIK3CA mutation rates did not differ significantly between adenocarcinomas and squamous cell carcinomas (25% vs 37.5%, respectively; P = .33). In contrast, KRAS mutations were identified only in adenocarcinomas (17.5% vs 0%; P = .01), and a novel EGFR mutation was detected only in squamous cell carcinomas (0% vs 7.5%; P = .24). There were no associations between HPV-16 or HPV-18 and somatic mutations or overall survival. In adjusted analyses, PIK3CA mutations were associated with shorter survival (67.1 months vs 90.3 months; hazard ratio, 9.1; 95% confidence interval, 2.8-29.5 months; P < .001). Cervical cancers harbor high rates of potentially targetable oncogenic mutations. In addition, cervical squamous cell carcinoma and adenocarcinoma have distinct molecular profiles, suggesting that clinical outcomes may be improved with the use of more tailored treatment strategies, including PI3K and MEK inhibitors. Cancer 2013. © 2013 American Cancer Society.
    Cancer 08/2013; · 5.20 Impact Factor
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    ABSTRACT: Ligand-independent, constitutive activation of Hedgehog signaling in mice expressing a mutant, activated SmoM2 allele results in the development of multifocal, highly differentiated tumors that express myogenic markers (including desmin, actin, MyoD and myogenin). The histopathology of these tumors, commonly classified as rhabdomyosarcomas, more closely resembles human fetal rhabdomyoma (FRM), a benign tumor that can be difficult to distinguish from highly differentiated rhabdomyosarcomas. We evaluated the spectrum of Hedgehog (HH) pathway gene mutations in a cohort of human FRM tumors by targeted Illumina sequencing and fluorescence in-situ hybridization testing for PTCH1. Our studies identified functionally relevant aberrations at the PTCH1 locus in 3 out of 5 FRM tumors surveyed, including a PTCH1 frameshift mutation in one tumor and homozygous deletions of PTCH1 in 2 tumors. These data suggest that activated Hedgehog signaling contributes to the biology of human FRM.
    The Journal of Pathology 06/2013; · 7.59 Impact Factor
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    ABSTRACT: Pediatric low-grade gliomas (PLGGs) are among the most common solid tumors in children but, apart from BRAF kinase mutations or duplications in specific subclasses, few genetic driver events are known. Diffuse PLGGs comprise a set of uncommon subtypes that exhibit invasive growth and are therefore especially challenging clinically. We performed high-resolution copy-number analysis on 44 formalin-fixed, paraffin-embedded diffuse PLGGs to identify recurrent alterations. Diffuse PLGGs exhibited fewer such alterations than adult low-grade gliomas, but we identified several significantly recurrent events. The most significant event, 8q13.1 gain, was observed in 28% of diffuse astrocytoma grade IIs and resulted in partial duplication of the transcription factor MYBL1 with truncation of its C-terminal negative-regulatory domain. A similar recurrent deletion-truncation breakpoint was identified in two angiocentric gliomas in the related gene v-myb avian myeloblastosis viral oncogene homolog (MYB) on 6q23.3. Whole-genome sequencing of a MYBL1-rearranged diffuse astrocytoma grade II demonstrated MYBL1 tandem duplication and few other events. Truncated MYBL1 transcripts identified in this tumor induced anchorage-independent growth in 3T3 cells and tumor formation in nude mice. Truncated transcripts were also expressed in two additional tumors with MYBL1 partial duplication. Our results define clinically relevant molecular subclasses of diffuse PLGGs and highlight a potential role for the MYB family in the biology of low-grade gliomas.
    Proceedings of the National Academy of Sciences 04/2013; · 9.74 Impact Factor
  • Laura E Macconaill
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    ABSTRACT: Ongoing global genome characterization efforts are revolutionizing our knowledge of cancer genomics and tumor biology. In parallel, information gleaned from these studies on driver cancer gene alterations-mutations, copy number alterations, translocations, and/or chromosomal rearrangements-can be leveraged, in principle, to develop a cohesive framework for individualized cancer treatment. These possibilities have been enabled, to a large degree, by revolutionary advances in genomic technologies that facilitate systematic profiling for hallmark cancer genetic alterations at increasingly fine resolutions. Ongoing innovations in existing genomics technologies, as well as the many emerging technologies, will likely continue to advance translational cancer genomics and precision cancer medicine.
    Journal of Clinical Oncology 04/2013; · 18.04 Impact Factor
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    ABSTRACT: Meningiomas are the most common primary nervous system tumor. The tumor suppressor NF2 is disrupted in approximately half of all meningiomas, but the complete spectrum of genetic changes remains undefined. We performed whole-genome or whole-exome sequencing on 17 meningiomas and focused sequencing on an additional 48 tumors to identify and validate somatic genetic alterations. Most meningiomas had simple genomes, with fewer mutations, rearrangements and copy-number alterations than reported in other tumors in adults. However, several meningiomas harbored more complex patterns of copy-number changes and rearrangements, including one tumor with chromothripsis. We confirmed focal NF2 inactivation in 43% of tumors and found alterations in epigenetic modifiers in an additional 8% of tumors. A subset of meningiomas lacking NF2 alterations harbored recurrent oncogenic mutations in AKT1 (p.Glu17Lys) and SMO (p.Trp535Leu) and exhibited immunohistochemical evidence of activation of these pathways. These mutations were present in therapeutically challenging tumors of the skull base and higher grade. These results begin to define the spectrum of genetic alterations in meningiomas and identify potential therapeutic targets.
    Nature Genetics 01/2013; · 35.21 Impact Factor
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    ABSTRACT: It has been demonstrated for some cancers that the frequency of somatic oncogenic mutations may vary in ancestral populations. To determine whether key driver alterations might occur at different frequencies in colorectal cancer, we applied a high-throughput genotyping platform (OncoMap) to query 385 mutations across 33 known cancer genes in colorectal cancer DNA from 83 Asian, 149 Black and 195 White patients. We found that Asian patients had fewer canonical oncogenic mutations in the genes tested (60% vs Black 79% (P = 0.011) and White 77% (P = 0.015)), and that BRAF mutations occurred at a higher frequency in White patients (17% vs Asian 4% (P = 0.004) and Black 7% (P = 0.014)). These results suggest that the use of genomic approaches to elucidate the different ancestral determinants harbored by patient populations may help to more precisely and effectively treat colorectal cancer.
    PLoS ONE 01/2013; 8(9):e74950. · 3.73 Impact Factor
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    BMC proceedings 10/2012; 6(6).
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    ABSTRACT: Rhabdoid tumors (also called atypical teratoid/rhabdoid tumor (AT/RT) in the brain), are highly malignant, poor prognosis lesions arising in the kidneys, soft tissues, and central nervous system. Targeted therapy in this disease would benefit from advanced technologies detecting relevant actionable mutations. Here we report on the evaluation of 25 tumors, all with known SMARCB1/INI1 alterations, for the presence of 983 different mutations in 115 oncogenes and tumor-suppressor genes using OncoMap, a mass spectrometric method of allele detection. Other than mutations in SMARCB1, our results identified a single activating mutation in NRAS and complete absence of oncogenic mutations in all other genes tested. The absence of mutations in canonical pathways critical for development and progression of adult cancers suggests that distinct mechanisms drive these highly malignant pediatric tumors. This may limit the therapeutic utility of available targeted therapies and require a refocusing toward developmental and epigenetic pathways. Pediatr Blood Cancer 2012; 59: 1155-1157. © 2012 Wiley Periodicals, Inc.
    Pediatric Blood & Cancer 09/2012; 59(7):1155-7. · 2.35 Impact Factor
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    ABSTRACT: Purpose. We assessed for mutations in a large number of oncogenes and tumor suppressor genes in primary uveal melanomas using a high-throughput profiling system. Methods. DNA was extracted and purified from 134 tissue samples from fresh-frozen tissues (n = 87) or formalin-fixed, paraffin-embedded tissues (n = 47) from 124 large uveal melanomas that underwent primary treatment by enucleation. DNA was subjected to whole genome amplification and MALDI-TOF mass spectrometry-based mutation profiling (>1000 mutations tested across 120 oncogenes and tumor suppressor genes) using the OncoMap3 platform. All candidate mutations, as well as commonly occurring mutations in GNAQ and GNA11, were validated using homogeneous mass extension (hME) technology. Results. Of 123 samples, 97 (79%, representing 89 unique tumors) were amplified successfully, passed all quality control steps, and were assayed with the OncoMap platform. A total of 58 mutation calls was made for 49 different mutations across 26 different genes in 34/98 (35%) samples. Of 91 tumors that underwent hME validation, 83 (91%) harbored mutations in the GNAQ (47%) or GNA11 (44%) genes, while hME validation revealed two tumors with mutations in EGFR. These additional mutations occurred in tumors that also had mutations in GNAQ or GNA11. Conclusions. The vast majority of primary large uveal melanomas harbor mutually-exclusive mutations in GNAQ or GNA11, but very rarely have the oncogenic mutations that are reported commonly in other cancers. When present, these other mutations were found in conjunction with GNAQ/GNA11 mutations, suggesting that these other mutations likely are not the primary drivers of oncogenesis in uveal melanoma.
    Investigative ophthalmology & visual science 09/2012; 53(11):6991-6. · 3.43 Impact Factor
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    ABSTRACT: 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.
    PLoS Genetics 07/2012; 8(7):e1002772. · 8.52 Impact Factor
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    ABSTRACT: To illustrate the complex patterns that emerge when race/ethnicity, socioeconomic status (SES), and gender are considered simultaneously in health care disparities research and to outline the needed research to understand them by using disparities in lung cancer risks, treatment, and outcomes as an example. SES, gender, and race/ethnicity are social categories that are robust predictors of variations in health and health services utilization. These are usually considered separately, but intersectionality theory indicates that the impact of each depends on the others. Each reflects historically and culturally contingent variations in social, economic, and political status. Distinct patterns of risk and resilience emerge at the intersections of multiple social categories and shape the experience of health, health care access, utilization, quality, and outcomes where these categories intersect. Intersectional approaches call for greater attention to understand social processes at multiple levels of society and require the collection of relevant data and utilization of appropriate analytic approaches to understand how multiple risk factors and resources combine to affect the distribution of disease and its management. Understanding how race/ethnicity, gender, and SES are interactive, interdependent, and social identities can provide new knowledge to enhance our efforts to effectively address health disparities.
    Health Services Research 06/2012; 47(3 Pt 2):1255-77. · 2.29 Impact Factor
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    ABSTRACT: The disease course of chronic lymphocytic leukemia (CLL) varies significantly within cytogenetic groups. We hypothesized that high-resolution genomic analysis of CLL would identify additional recurrent abnormalities associated with short time-to-first therapy (TTFT). We undertook high-resolution genomic analysis of 161 prospectively enrolled CLLs using Affymetrix 6.0 SNP arrays, and integrated analysis of this data set with gene expression profiles. Copy number analysis (CNA) of nonprogressive CLL reveals a stable genotype, with a median of only 1 somatic CNA per sample. Progressive CLL with 13q deletion was associated with additional somatic CNAs, and a greater number of CNAs was predictive of TTFT. We identified other recurrent CNAs associated with short TTFT: 8q24 amplification focused on the cancer susceptibility locus near MYC in 3.7%; 3q26 amplifications focused on PIK3CA in 5.6%; and 8p deletions in 5% of patients. Sequencing of MYC further identified somatic mutations in two CLLs. We determined which catalytic subunits of phosphoinositide 3-kinase (PI3K) were in active complex with the p85 regulatory subunit and showed enrichment for the α subunit in three CLLs carrying PIK3CA amplification. Our findings implicate amplifications of 3q26 focused on PIK3CA and 8q24 focused on MYC in CLL.
    Clinical Cancer Research 05/2012; 18(14):3791-802. · 7.84 Impact Factor
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    ABSTRACT: The systematic translation of cancer genomic data into knowledge of tumour biology and therapeutic possibilities remains challenging. Such efforts should be greatly aided by robust preclinical model systems that reflect the genomic diversity of human cancers and for which detailed genetic and pharmacological annotation is available. Here we describe the Cancer Cell Line Encyclopedia (CCLE): a compilation of gene expression, chromosomal copy number and massively parallel sequencing data from 947 human cancer cell lines. When coupled with pharmacological profiles for 24 anticancer drugs across 479 of the cell lines, this collection allowed identification of genetic, lineage, and gene-expression-based predictors of drug sensitivity. In addition to known predictors, we found that plasma cell lineage correlated with sensitivity to IGF1 receptor inhibitors; AHR expression was associated with MEK inhibitor efficacy in NRAS-mutant lines; and SLFN11 expression predicted sensitivity to topoisomerase inhibitors. Together, our results indicate that large, annotated cell-line collections may help to enable preclinical stratification schemata for anticancer agents. The generation of genetic predictions of drug response in the preclinical setting and their incorporation into cancer clinical trial design could speed the emergence of 'personalized' therapeutic regimens.
    Nature 03/2012; 483(7391):603-7. · 38.60 Impact Factor
  • Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 02/2012; 26(7):1710-3. · 10.16 Impact Factor
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    ABSTRACT: Gastric cancer is one of the leading cancer types in incidence and mortality, especially in Asia. In order to improve survival, identification of a catalogue of molecular alterations underlying gastric cancer is a critical step for developing and designing genome-directed therapies. The Center for Cancer Genome Discovery (CCGD) at the Dana-Farber Cancer Institute (DFCI) has adapted a high-throughput genotyping platform to determine the mutation status of a large panel of known cancer genes. The mutation detection platform, termed OncoMap v4, interrogates 474 "hotspot" mutations in 41 genes that are relevant for cancer. We performed OncoMap v4 in formalin-fixed paraffin-embedded (FFPE) tissue specimens from 237 gastric adenocarcinomas. Using OncoMap v4, we found that 34 (14.4%) of 237 gastric cancer patients harbored mutations. Among mutations we screened, PIK3CA mutations were the most frequent (5.1%) followed by p53 (4.6%), APC (2.5%), STK11 (2.1%), CTNNB1 (1.7%), and CDKN2A (0.8%). Six samples harbored concomitant somatic mutations. Mutations of CTNNB1 were significantly more frequent in EBV-associated gastric carcinoma (P = 0.046). Our study led to the detection of potentially druggable mutations in gastric cancer which may guide novel therapies in subsets of gastric cancer patients. Using high throughput mutation screening platform, we identified that PIK3CA mutations were the most frequently observed target for gastric adenocarcinoma.
    PLoS ONE 01/2012; 7(6):e38892. · 3.73 Impact Factor
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    ABSTRACT: Knowledge of "actionable" somatic genomic alterations present in each tumor (e.g., point mutations, small insertions/deletions, and copy-number alterations that direct therapeutic options) should facilitate individualized approaches to cancer treatment. However, clinical implementation of systematic genomic profiling has rarely been achieved beyond limited numbers of oncogene point mutations. To address this challenge, we utilized a targeted, massively parallel sequencing approach to detect tumor genomic alterations in formalin-fixed, paraffin-embedded (FFPE) tumor samples. Nearly 400-fold mean sequence coverage was achieved, and single-nucleotide sequence variants, small insertions/deletions, and chromosomal copynumber alterations were detected simultaneously with high accuracy compared with other methods in clinical use. Putatively actionable genomic alterations, including those that predict sensitivity or resistance to established and experimental therapies, were detected in each tumor sample tested. Thus, targeted deep sequencing of clinical tumor material may enable mutation-driven clinical trials and, ultimately, "personalized" cancer treatment. SIGNIFICANCE: Despite the rapid proliferation of targeted therapeutic agents, systematic methods to profile clinically relevant tumor genomic alterations remain underdeveloped. We describe a sequencingbased approach to identifying genomic alterations in FFPE tumor samples. These studies affirm the feasibility and clinical utility of targeted sequencing in the oncology arena and provide a foundation for genomics-based stratification of cancer patients.
    Cancer Discovery 01/2012; 2(1):82-93. · 10.14 Impact Factor
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    ABSTRACT: Given the high incidence of metastatic esophageal squamous cell carcinoma, especially in Asia, we screened for the presence of somatic mutations using OncoMap platform with the aim of defining subsets of patients who may be potential candidate for targeted therapy. We analyzed 87 tissue specimens obtained from 80 patients who were pathologically confirmed with esophageal squamous cell carcinoma and received 5-fluoropyrimidine/platinum-based chemotherapy. OncoMap 4.0, a mass-spectrometry based assay, was used to interrogate 471 oncogenic mutations in 41 commonly mutated genes. Tumor specimens were prepared from primary cancer sites in 70 patients and from metastatic sites in 17 patients. In order to test the concordance between primary and metastatic sites from the patient for mutations, we analyzed 7 paired (primary-metastatic) specimens. All specimens were formalin-fixed paraffin embedded tissues and tumor content was >70%. In total, we have detected 20 hotspot mutations out of 80 patients screened. The most frequent mutation was PIK3CA mutation (four E545K, five H1047R and one H1047L) (N = 10, 11.5%) followed by MLH1 V384D (N = 7, 8.0%), TP53 (R306, R175H and R273C) (N = 3, 3.5%), BRAF V600E (N = 1, 1.2%), CTNNB1 D32N (N = 1, 1.2%), and EGFR P733L (N = 1, 1.2%). Distributions of somatic mutations were not different according to anatomic sites of esophageal cancer (cervical/upper, mid, lower). In addition, there was no difference in frequency of mutations between primary-metastasis paired samples. Our study led to the detection of potentially druggable mutations in esophageal SCC which may guide novel therapies in small subsets of esophageal cancer patients.
    PLoS ONE 01/2012; 7(8):e41655. · 3.73 Impact Factor
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    ABSTRACT: Diffuse intrinsic pontine gliomas (DIPG) can not be cured with current treatment modalities. Targeted therapy in this disease would benefit from advanced technologies detecting relevant drugable mutations. Twenty patients with classic newly diagnosed DIPG underwent stereotactic biopsies and were analyzed for the presence of 983 different mutations in 115 oncogenes and tumor-suppressor genes using OncoMap, a mass spectrometric method of allele detection. Our results identified oncogenic mutations in TP53 (40%), PI3KCA (15%), and ATM/MPL (5%) while none were identified in a large number of other genes commonly mutated in malignant gliomas. The identification of oncogenic mutations in the PI3K pathway offers the potential of a therapeutic target at initial diagnosis in this devastating disease.
    Pediatric Blood & Cancer 12/2011; 58(4):489-91. · 2.35 Impact Factor
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    ABSTRACT: RAF inhibitors are effective against melanomas with BRAF V600E mutations but may induce keratoacanthomas (KAs) and cutaneous squamous cell carcinomas (cSCCs). The potential of these agents to promote secondary malignancies is concerning. We analyzed cSCC and KA lesions for genetic mutations in an attempt to identify an underlying mechanism for their formation. Four international centers contributed 237 KA or cSCC tumor samples from patients receiving an RAF inhibitor (either vemurafenib or sorafenib; n = 19) or immunosuppression therapy (n = 53) or tumors that developed spontaneously (n = 165). Each sample was profiled for 396 known somatic mutations across 33 cancer-related genes by using a mass spectrometric-based genotyping platform. Mutations were detected in 16% of tumors (38 of 237), with five tumors harboring two mutations. Mutations in TP53, CDKN2A, HRAS, KRAS, and PIK3CA were previously described in squamous cell tumors. Mutations in MYC, FGFR3, and VHL were identified for the first time. A higher frequency of activating RAS mutations was found in tumors from patients treated with an RAF inhibitor versus populations treated with a non-RAF inhibitor (21.1% v 3.2%; P < .01), although overall mutation rates between treatment groups were similar (RAF inhibitor, 21.1%; immunosuppression, 18.9%; and spontaneous, 17.6%; P = not significant). Tumor histology (KA v cSCC), tumor site (head and neck v other), patient age (≤ 70 v > 70 years), and sex had no significant impact on mutation rate or type. Squamous cell tumors from patients treated with an RAF inhibitor have a distinct mutational profile that supports a mechanism of therapy-induced tumorigenesis in RAS-primed cells. Conceivably, cotargeting of MEK together with RAF may reduce or prevent formation of these tumors.
    Journal of Clinical Oncology 11/2011; 30(3):316-21. · 18.04 Impact Factor

Publication Stats

2k Citations
443.61 Total Impact Points

Institutions

  • 2006–2013
    • Dana-Farber Cancer Institute
      • Department of Medical Oncology
      Boston, Massachusetts, United States
  • 2010–2012
    • Broad Institute of MIT and Harvard
      Cambridge, Massachusetts, United States
  • 2011
    • Massachusetts Institute of Technology
      Cambridge, Massachusetts, United States