Scott Carter

Dana-Farber Cancer Institute, Biostatistics and Computational Biology, Faculty Member

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PI at Dana-Farber Cancer Institute applying advanced statistical analysis to multi-omic characterization of human cancers in order to elucidate cancer initiation, drug resistance, and metastasis. My lab works closely with clinical researchers and drug-makers to rapidly translate genomic findings into patient-tailored clinical trials.
Address: Cambridge, MA, USA

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Jordi Vallverdú

Universitat Autònoma de Barcelona

Jayjit Majumdar

University of Kalyani

Jon R Sayers

The University of Sheffield

Prof. Mohamed Labib Salem

Tanta University

Jeffrey Townsend

Yale University

Viswanathan Chinnusamy

INDIAN AGRICULTURAL RESEARCH INSTITUTE, NEW DELHI, INDIA

Samit Chakrabarty

University of Leeds

Dhafer Malouche

The American University In Cairo

Fabio Cuzzolin

Oxford Brookes University

Michael J. Gonzalez

Universidad de Puerto Rico Rio

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Papers by Scott Carter

Prognostic Marker for Endometrial Carcinoma

Absolute quantification of somatic DNA alterations in human cancer

We describe a computational method that infers tumor purity and malignant cell ploidy directly fr... more We describe a computational method that infers tumor purity and malignant cell ploidy directly from analysis of somatic DNA alterations. The method, named ABSOLUTE, can detect subclonal heterogeneity and somatic homozygosity, and it can calculate statistical sensitivity for detection of specific aberrations. We used ABSOLUTE to analyze exome sequencing data from 214 ovarian carcinoma tumor-normal pairs. This analysis identified both pervasive subclonal somatic point-mutations and a small subset of predominantly clonal and homozygous mutations, which were overrepresented in the tumor suppressor genes TP53 and NF1 and in a candidate tumor suppressor gene CDK12. We also used ABSOLUTE to infer absolute allelic copy-number profiles from 3,155 diverse cancer specimens, revealing that genome-doubling events are common in human cancer, likely occur in cells that are already aneuploid, and influence pathways of tumor progression (for example, with recessive inactivation of NF1 being less common after genome doubling). ABSOLUTE will facilitate the design of clinical sequencing studies and studies of cancer genome evolution and intra-tumor heterogeneity.

Mutations driving CLL and their evolution in progression and relapse

Nature, 2015

Which genetic alterations drive tumorigenesis and how they evolve over the course of disease and ... more Which genetic alterations drive tumorigenesis and how they evolve over the course of disease and therapy are central questions in cancer biology. Here we identify 44 recurrently mutated genes and 11 recurrent somatic copy number variations through whole-exome sequencing of 538 chronic lymphocytic leukaemia (CLL) and matched germline DNA samples, 278 of which were collected in a prospective clinical trial. These include previously unrecognized putative cancer drivers (RPS15, IKZF3), and collectively identify RNA processing and export, MYC activity, and MAPK signalling as central pathways involved in CLL. Clonality analysis of this large data set further enabled reconstruction of temporal relationships between driver events. Direct comparison between matched pre-treatment and relapse samples from 59 patients demonstrated highly frequent clonal evolution. Thus, large sequencing data sets of clinically informative samples enable the discovery of novel genes associated with cancer, the network of relationships between the driver events, and their impact on disease relapse and clinical outcome.

Genomic Characterization of Brain Metastases Reveals Branched Evolution and Potential Therapeutic Targets

Cancer discovery, Jan 26, 2015

Brain metastases are associated with a dismal prognosis. Whether brain metastases harbor distinct... more Brain metastases are associated with a dismal prognosis. Whether brain metastases harbor distinct genetic alterations beyond those observed in primary tumors is unknown. We performed whole-exome sequencing of 86 matched brain metastases, primary tumors, and normal tissue. In all clonally related cancer samples, we observed branched evolution, where all metastatic and primary sites shared a common ancestor yet continued to evolve independently. In 53% of cases, we found potentially clinically informative alterations in the brain metastases not detected in the matched primary-tumor sample. In contrast, spatially and temporally separated brain metastasis sites were genetically homogenous. Distal extracranial and regional lymph node metastases were highly divergent from brain metastases. We detected alterations associated with sensitivity to PI3K/AKT/mTOR, CDK, and HER2/EGFR inhibitors in the brain metastases. Genomic analysis of brain metastases provides an opportunity to identify pote...

Paired exome analysis of Barrett's esophagus and adenocarcinoma

Nature genetics, Jan 20, 2015

Barrett's esophagus is thought to progress to esophageal adenocarcinoma (EAC) through a stepw... more Barrett's esophagus is thought to progress to esophageal adenocarcinoma (EAC) through a stepwise progression with loss of CDKN2A followed by TP53 inactivation and aneuploidy. Here we present whole-exome sequencing from 25 pairs of EAC and Barrett's esophagus and from 5 patients whose Barrett's esophagus and tumor were extensively sampled. Our analysis showed that oncogene amplification typically occurred as a late event and that TP53 mutations often occurred early in Barrett's esophagus progression, including in non-dysplastic epithelium. Reanalysis of additional EAC exome data showed that the majority (62.5%) of EACs emerged following genome doubling and that tumors with genomic doubling had different patterns of genomic alterations, with more frequent oncogenic amplification and less frequent inactivation of tumor suppressors, including CDKN2A. These data suggest that many EACs emerge not through the gradual accumulation of tumor-suppressor alterations but rather t...

Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas

The New England journal of medicine, Jan 25, 2015

Diffuse low-grade and intermediate-grade gliomas (which together make up the lower-grade gliomas,... more Diffuse low-grade and intermediate-grade gliomas (which together make up the lower-grade gliomas, World Health Organization grades II and III) have highly variable clinical behavior that is not adequately predicted on the basis of histologic class. Some are indolent; others quickly progress to glioblastoma. The uncertainty is compounded by interobserver variability in histologic diagnosis. Mutations in IDH, TP53, and ATRX and codeletion of chromosome arms 1p and 19q (1p/19q codeletion) have been implicated as clinically relevant markers of lower-grade gliomas. We performed genomewide analyses of 293 lower-grade gliomas from adults, incorporating exome sequence, DNA copy number, DNA methylation, messenger RNA expression, microRNA expression, and targeted protein expression. These data were integrated and tested for correlation with clinical outcomes. Unsupervised clustering of mutations and data from RNA, DNA-copy-number, and DNA-methylation platforms uncovered concordant classificat...

Abstract 3992: Modes of metastasis evolution in human and murine cancer revealed by whole exome sequencing

Cancer Research, 2014

Abstract 1724: Genomic mechanisms of exquisite sensitivity and acquired resistance to everolimus in a patient with anaplastic thyroid carcinoma

Cancer Research, 2014

Abstract NG03: Genomic characterization of 101 brain metastases and paired primary tumors reveals patterns of clonal evolution and selection of driver mutations

Cancer Research, 2014

Genomic Correlate of Exceptional Erlotinib Response in Head and Neck Squamous Cell Carcinoma

JAMA Oncology, 2015

Single-cell analysis reveals an adaptive, transiently heritable, slowly-dividing, drug-resistant ... more Single-cell analysis reveals an adaptive, transiently heritable, slowly-dividing, drug-resistant state inhibitable by drug combinations View project supplementary View project Eliezer Van Allen Broad Institute of MIT and Harvard 199 PUBLICATIONS 7,564 CITATIONS SEE PROFILE IMPORTANCE Randomized clinical trials demonstrate no benefit for epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in unselected patients with head and neck squamous cell carcinoma (HNSCC). However, a patient with stage IVA HNSCC received 13 days of neoadjuvant erlotinib and experienced a near-complete histologic response.

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Abstract 3925: Characterization of complex chromosomal aberrations in prostate cancer from whole genome sequencing

Cancer Research, 2011

Abstract 5135: Analysis of formalin-fixed paraffin-embedded (FFPE) samples

Cancer Research, 2013

Comprehensive molecular portraits of human breast tumours

by Mia Grifford, Cheng Fan, Scott Carter, Raju Kucherlapati, Jeff Gentry, Hai Hu, Bryan Hernandez, Ashley H Salazar, S M, Erik Zmuda, Rehan Akbani, and Gordon Saksena

Nature, 2012

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Sporadic hemangioblastomas are characterized by cryptic VHL inactivation

Acta Neuropathologica Communications, 2014

Hemangioblastomas consist of 10-20% neoplastic "stromal" cells within a vascular tumor cell mass ... more Hemangioblastomas consist of 10-20% neoplastic "stromal" cells within a vascular tumor cell mass of reactive pericytes, endothelium and lymphocytes. Familial cases of central nervous system hemangioblastoma uniformly result from mutations in the Von Hippel-Lindau (VHL) gene. In contrast, inactivation of VHL has been previously observed in only a minority of sporadic hemangioblastomas, suggesting an alternative genetic etiology. We performed deep-coverage DNA sequencing on 32 sporadic hemangioblastomas (whole exome discovery cohort n = 10, validation n = 22), followed by analysis of clonality, copy number alteration, and somatic mutation. We identified somatic mutation, loss of heterozygosity and/or deletion of VHL in 8 of 10 discovery cohort tumors. VHL inactivating events were ultimately detected in 78% (25/32) of cases. No other gene was significantly mutated. Overall, deep-coverage sequence analysis techniques uncovered VHL alterations within the neoplastic fraction of these tumors at higher frequencies than previously reported. Our findings support the central role of VHL inactivation in the molecular pathogenesis of both familial and sporadic hemangioblastomas.

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A Tumor Suppressor Complex with GAP Activity for the Rag GTPases That Signal Amino Acid Sufficiency to mTORC1

Science, 2013

The mTOR Complex 1 (mTORC1) pathway promotes cell growth in response to many cues, including amin... more The mTOR Complex 1 (mTORC1) pathway promotes cell growth in response to many cues, including amino acids, which act through the Rag GTPases to promote mTORC1 translocation to the lysosomal surface, its site of activation. Although progress has been made in identifying positive regulators of the Rags, it is unknown if negative factors also exist. Here, we identify GATOR as a complex that interacts with the Rags and is composed of two subcomplexes we call GATOR1 and 2. Inhibition of GATOR1 subunits (DEPDC5, Nprl2, and Nprl3) makes mTORC1 signaling resistant to amino acid deprivation. In contrast, inhibition of GATOR2 subunits (Mios, WDR24, WDR59, Seh1L, Sec13) suppresses mTORC1 signaling and epistasis analysis shows that GATOR2 negatively regulates DEPDC5. GATOR1 has GTPase activating protein (GAP) activity for RagA and RagB and its components are mutated in human cancer. In cancer cells with inactivating mutations in GATOR1, mTORC1 is hyperactive and insensitive to amino acid starvation and such cells are hypersensitive to rapamycin, an mTORC1 inhibitor. Thus, we identify a key negative regulator of the Rag GTPases and reveal that, like other mTORC1 regulators, Rag function can be deregulated in cancer.

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Pan-cancer patterns of somatic copy number alteration

by Scott Carter and Bryan Hernandez

Nature genetics, Jan 26, 2013

Determining how somatic copy number alterations (SCNAs) promote cancer is an important goal. We c... more Determining how somatic copy number alterations (SCNAs) promote cancer is an important goal. We characterized SCNA patterns in 4,934 cancers from The Cancer Genome Atlas Pan-Cancer data set. Whole-genome doubling, observed in 37% of cancers, was associated with higher rates of every other type of SCNA, TP53 mutations, CCNE1 amplifications and alterations of the PPP2R complex. SCNAs that were internal to chromosomes tended to be shorter than telomere-bounded SCNAs, suggesting different mechanisms underlying their generation. Significantly recurrent focal SCNAs were observed in 140 regions, including 102 without known oncogene or tumor suppressor gene targets and 50 with significantly mutated genes. Amplified regions without known oncogenes were enriched for genes involved in epigenetic regulation. When levels of genomic disruption were accounted for, 7% of region pairs were anticorrelated, and these regions tended to encompass genes whose proteins physically interact, suggesting rela...

Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer

by Michelle Redman and Scott Carter

Nature Genetics, 2012

Prostate cancer is the second most common cancer in men worldwide and causes over 250,000 deaths ... more Prostate cancer is the second most common cancer in men worldwide and causes over 250,000 deaths each year 1 . Overtreatment of indolent disease also results in significant morbidity 2 . Common genetic alterations in prostate cancer include losses of NKX3.1 (8p21) 3,4 and PTEN (10q23) 5,6 , gains of AR (the androgen receptor gene) 7,8 and fusion of ETS family transcription factor genes with androgen-responsive promoters 9-11 . Recurrent somatic base-pair substitutions are believed to be less contributory in prostate tumorigenesis 12,13 but have not been systematically analyzed in large cohorts. Here, we sequenced the exomes of 112 prostate tumor and normal tissue pairs. New recurrent mutations were identified in multiple genes, including MED12 and FOXA1. SPOP was the most frequently mutated gene, with mutations involving the SPOP substrate-binding cleft in 6-15% of tumors across multiple independent cohorts. Prostate cancers with mutant SPOP lacked ETS family gene rearrangements and showed a distinct pattern of genomic alterations. Thus, SPOP mutations may define a new molecular subtype of prostate cancer.

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Absolute quantification of somatic DNA alterations in human cancer

Nature Biotechnology, 2012

Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples

Nature Biotechnology, 2013

Detection of somatic point substitutions is a key step in characterizing the cancer genome. Mutat... more Detection of somatic point substitutions is a key step in characterizing the cancer genome. Mutations in cancer are rare (0.1-100/Mb) and often occur only in a subset of the sequenced cells, either due to contamination by normal cells or due to tumor heterogeneity. Consequently, mutation calling methods need to be both specific, avoiding false positives, and sensitive to detect clonal and sub-clonal mutations. The decreased sensitivity of existing methods for low allelic fraction mutations highlights the pressing need for improved and systematically evaluated mutation detection methods. Here we present MuTect, a method based on a Bayesian classifier designed to detect somatic mutations with very low allele-fractions, requiring only a few supporting reads, followed by a set of carefully tuned filters that ensure high specificity. We also describe novel benchmarking approaches, which use real sequencing data to evaluate the sensitivity and specificity as a function of sequencing depth, base quality and allelic fraction. Compared with other methods, MuTect has higher sensitivity with similar specificity, especially for mutations with allelic fractions as low as 0.1 and below, making MuTect particularly useful for studying cancer subclones and their evolution in standard exome and genome sequencing data.

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Clonal evolution in hematological malignancies and therapeutic implications

Leukemia, 2014

The ability of cancer to evolve and adapt is a principal challenge to therapy in general and to t... more The ability of cancer to evolve and adapt is a principal challenge to therapy in general and to the paradigm of targeted therapy in particular. This ability is fueled by the co-existence of multiple, genetically heterogeneous subpopulations within the cancer cell population. Increasing evidence has supported the idea that these subpopulations are selected in a Darwinian fashion, by which the genetic landscape of the tumor is continuously reshaped. Massively parallel sequencing has enabled a recent surge in our ability to study this process, adding to previous efforts using cytogenetic methods and targeted sequencing. Altogether, these studies reveal the complex evolutionary trajectories occurring across individual hematological malignancies. They also suggest that while clonal evolution may contribute to resistance to therapy, treatment may also hasten the evolutionary process. New insights into this process challenge us to understand the impact of treatment on clonal evolution and inspire the development of novel prognostic and therapeutic strategies.

Prognostic Marker for Endometrial Carcinoma

Absolute quantification of somatic DNA alterations in human cancer