Myc transcription factors are well-established drivers of human cancers. However, despite being a... more Myc transcription factors are well-established drivers of human cancers. However, despite being amongst the most frequently mutated, translocated and overexpressed oncogenes, no therapy targeting the Myc family members directly has been developed to date. To sustain uncontrolled cell proliferation and tumor growth, Myc-driven cancers are known to be addicted to protein translation. This addiction creates a dependency on critical components of the translational machinery providing in turn a unique opportunity for therapeutic intervention. We hypothesized that targeting the translational termination factor GSPT1, a key regulator of protein synthesis, would constitute a vulnerability for Myc-driven tumors. GSPT1 contains a well-defined degron allowing for the recruitment of the E3 ligase cereblon (CRBN) and subsequent proteasomal degradation in the presence of molecular glue degraders. Herein we describe a novel orally bioavailable GSPT1-directed small molecule degrader MRT-2359, which...
SL-401 is a novel targeted therapy comprised of recombinant interleukin 3 (IL3) fused to a trunca... more SL-401 is a novel targeted therapy comprised of recombinant interleukin 3 (IL3) fused to a truncated diphtheria toxin (DT) payload. SL-401 delivers DT to cells expressing the IL3 receptor (CD123). After internalization, DT catalyzes ADP ribosylation of eukaryotic elongation factor 2 (eEF2), blocking protein synthesis and killing target cells. SL-401 is currently in clinical trials for CD123+ cancers, including acute myeloid leukemia (AML) and blastic plasmacytoid dendritic cell neoplasm (BPDCN). Other than CD123 expression, the determinants of response are largely unknown. Our goal was to study mechanisms of de novo and acquired resistance to inform combination strategies and enhance the efficacy of SL-401. In 16 AML and BPDCN patients enrolled in a phase 1-2 trial, we did not see decreased expression of CD123 by flow cytometry during or after SL-401. To study alternative resistance mechanisms, we generated 3-6 independent SL-401 resistant clones from each of 4 CD123+ AML (THP1, NOM...
The Myc family of transcription factors is a well-established driver of human cancers. However, d... more The Myc family of transcription factors is a well-established driver of human cancers. However, despite being amongst the most frequently mutated, translocated and overexpressed oncogenes, no therapy directly targeting the Myc family members has been developed to date. Abnormal activation of Myc results in uncontrolled cell growth that is associated with high translational output and ramp up of the protein translational machinery. This creates a dependency to protein translation and in turn represents a potential therapeutic vulnerability for Myc-driven tumors. Based on these considerations, we hypothesized that targeting the translational termination factor GSPT1, a key player of protein synthesis, may constitute a vulnerability for Myc-driven tumors. Using our proprietary Quantitative and Engineered Elimination of Neosubstrates (QuEENTM) platform we characterized and explored the known G-loop degron in GSPT1 that renders it amenable to cereblon-induced degradation by molecular glu...
Highlights d Topology of junction copy number reveals novel classes of complex structural variant... more Highlights d Topology of junction copy number reveals novel classes of complex structural variants d Rigma are deletion ''chasms'' at fragile sites arising early in GI tumor evolution d Pyrgo are superenhancer-associated duplication ''towers'' in breast and ovarian cancer d Tyfonas are ''typhoons'' of amplified fold-back inversions in acral melanoma
We recently demonstrated that genetic heterogeneity contributes to evolution and clinical outcome... more We recently demonstrated that genetic heterogeneity contributes to evolution and clinical outcome in chronic lymphocytic leukemia (CLL) (Landau et al., Cell 2013). As both genetic and epigenetic alterations contribute to the cellular phenotype and its fitness for selection, we hypothesized that heterogeneity in DNA methylation impacts leukemic evolution as well. We analyzed existing CLL methylation data (Kulis et al., Nat Gen 2012), and found higher heterogeneity in 450K arrays of 139 CLLs compared to 23 normal B cell samples, with a higher proportion of sites having intermediate levels of methylation (13.7% vs 10.7%, P<0.0001). Next, we re-analyzed whole genome bisulfite sequencing data from 2 CLL and 3 normal B cell samples to distinguish between 2 possible explanations for heterogeneity: 1) a mixture of cell subpopulations with ordered but differing methylation states, and 2) increased proportion of cells with ‘noisy’ or disordered methylation states. We found that the bulk of...
Human cancer cell lines are the workhorse of cancer research. Although cell lines are known to ev... more Human cancer cell lines are the workhorse of cancer research. Although cell lines are known to evolve in culture, the extent of the resultant genetic and transcriptional heterogeneity and its functional consequences remain understudied. Here we use genomic analyses of 106 human cell lines grown in two laboratories to show extensive clonal diversity. Further comprehensive genomic characterization of 27 strains of the common breast cancer cell line MCF7 uncovered rapid genetic diversification. Similar results were obtained with multiple strains of 13 additional cell lines. Notably, genetic changes were associated with differential activation of gene expression programs and marked differences in cell morphology and proliferation. Barcoding experiments showed that cell line evolution occurs as a result of positive clonal selection that is highly sensitive to culture conditions. Analyses of single-cell-derived clones demonstrated that continuous instability quickly translates into heterogeneity of the cell line. When the 27 MCF7 strains were tested against 321 anti-cancer compounds, we uncovered considerably different drug responses: at least 75% of compounds that strongly inhibited some strains were completely inactive in others. This study documents the extent, origins and consequences of genetic variation within cell lines, and provides a framework for researchers to measure such variation in efforts to support maximally reproducible cancer research.
Large cancer cell line collections broadly capture the genomic diversity of human cancers and pro... more Large cancer cell line collections broadly capture the genomic diversity of human cancers and provide valuable insight into anti-cancer drug response. Here, we show substantial agreement and biological consilience between drug sensitivity measurements and their associated genomic predictors from two publicly available large-scale pharmacogenomics resources: The Cancer Cell Line Encyclopedia and the Genomics of Drug Sensitivity in Cancer. In vitro pharmacologic sensitivity studies performed across panels of molecularly characterized cancer cell lines have proved useful in assessing the cellular activity of many compounds, assigning mechanisms of drug action, and determining genetic contexts for distinct cancer vulnerabilities1-6. A recent comparison study7 of the Cancer Cell Line
Recent treatment advances in metastatic BRAF mutant melanoma using targeted therapy have increase... more Recent treatment advances in metastatic BRAF mutant melanoma using targeted therapy have increased progression free survival by many months. However, resistance to these targeted agents is a common occurrence, with relapse occurring in almost every case. Many of the alterations that confer clinical resistance to RAF and MEK inhibitors in BRAF mutant melanoma reactivate the MAPK pathway, but remain sensitive to ERK inhibition in vitro. Prospectively determining mechanisms of resistance to MAPK pathway inhibitors, such as an ERK inhibitor, before clinical trials begin may inform which patients will respond to therapy, potential markers of resistance, or best therapy combinations. Previous studies have shown that in vitro random mutagenesis screens can select specific alleles seen in resistant patient populations. Since ERK inhibitors are entering clinical trials, we wanted to determine mutations in ERK1 and ERK2 that could confer resistance to ERK or RAF/MEK inhibition. Therefore, we ...
Abstract Compressed video processing is becoming increasingly important in many digital video app... more Abstract Compressed video processing is becoming increasingly important in many digital video applications. There are two main approaches for compressed video processing. The first approach is called re-encoding and the second is called compressed domain processing (CDP). Bit-rate reduction is a very common process in video processing applications. In our research, the bit-rate reduction process is implemented using an SNR-scaling scheme. We have implemented enhanced compressed domain processor ...
Dexamethasone (DEX) was previously shown (Jing et al., Biotechnol Bioeng. 2010;107:488-496) to pl... more Dexamethasone (DEX) was previously shown (Jing et al., Biotechnol Bioeng. 2010;107:488-496) to play a dual role in increasing sialylation of recombinant glycoproteins produced by Chinese Hamster Ovary (CHO) cells. DEX addition increased sialic acid levels of a recombinant fusion protein through increased expression of α2,3-sialyltransferase and β1,4-galactosyltransferase, but also decreased the sialidase-mediated, extracellular degradation of sialic acid through slowing cell death at the end of the culture period. This study examines the underlying mechanism for this cytoprotective action by studying the transcriptional response of the CHO cell genome upon DEX treatment using DNA microarrays and gene ontology term analysis. Many of those genes showing a significant transcriptional response were associated with the regulation of programmed cell death. The gene with the highest change in expression level, as validated by Quantitative PCR assays with TaqMan® probes and confirmed by Western Blot analysis, was the antiapoptotic gene Tsc22d3, also referred to as GILZ (glucocorticoid-induced leucine zipper). The pathway by which DEX suppressed cell death towards the end of the culture period was also confirmed by showing involvement of glucocorticoid receptors and GILZ through studies using the glucocorticoid antagonist mifepristone (RU-486). These findings advance the understanding of the mechanism by which DEX suppresses cell death in CHO cells and provide a rationale for the application of glucocorticoids in CHO cell culture processes.
Cancer genome sequencing efforts have revealed that ARID1A is frequently mutated in many types of... more Cancer genome sequencing efforts have revealed that ARID1A is frequently mutated in many types of cancer. Inactivating mutations occur in 45% of ovarian clear cell and endometrioid carcinomas, 19% of gastric cancers, 19% of bladder cancers, 14% of hepatocellular cancers, 12% of melanomas, and less frequently in colorectal, lung, breast and pancreatic cancers. ARID1A has also been validated as having bona fide tumor suppressor properties. Consequently, identification of specific vulnerabilities conferred by ARID1A mutation would have major relevance for human cancer. We therefore performed a systematic search for genetic vulnerabilities created by ARID1A mutation. Out of 9000+ genes screened, ARID1B, a related but mutually exclusive homolog of ARID1A in the SWI/SNF chromatin remodeling complex, was the number one gene preferentially required in ARID1A-mutant cancer cells. In validation studies, we find that knockdown of ARID1B indeed specifically impairs the proliferation of ARID1A-m...
In this paper, we study the generalized gapped k-mer filters and derive a closed form solution fo... more In this paper, we study the generalized gapped k-mer filters and derive a closed form solution for their coefficients. We consider nonnegative integers ℓ and k, with k ≤ ℓ, and an ℓ-tuple B = (b 1 ,. .. , b ℓ) of integers b i ≥ 2, i = 1,. .. , ℓ. We introduce and study an incidence matrix A = A ℓ,k;B. We develop a Möbius-like function ν B which helps us to obtain closed forms for a complete set of mutually orthogonal eigenvectors of A ⊤ A as well as a complete set of mutually orthogonal eigenvectors of AA ⊤ corresponding to nonzero eigenvalues. The reduced singular value decomposition of A and combinatorial interpretations for the nullity and rank of A, are among the consequences of this approach. We then combine the obtained formulas, some results from linear algebra, and combinatorial identities of elementary symmetric functions and ν B , to provide the entries of the Moore-Penrose pseudo-inverse matrix A + and the Gapped k-mer filter matrix A + A.
Iterative methods have led to better understanding and solving problems such as missing sampling,... more Iterative methods have led to better understanding and solving problems such as missing sampling, deconvolution, inverse systems, impulsive and Salt and Pepper noise removal problems. However, the challenges such as the speed of convergence and or the accuracy of the answer still remain. In order to improve the existing iterative algorithms, a non-linear method is discussed in this paper. The mentioned method is analyzed from different aspects, including its convergence and its ability to accelerate recursive algorithms.We show that this method is capable of improving Iterative Method (IM) as a non-uniform sampling reconstruction algorithm and some iterative sparse recovery algorithms such as Iterative Reweighted Least Squares (IRLS), Iterative Method with Adaptive Thresholding (IMAT), Smoothed 0 (SL0) and Alternating Direction Method of Multipliers (ADMM) for solving LASSO problems family (including Lasso itself, Lasso-LSQR and group-Lasso). It is also capable of both accelerating and stabilizing the well-known Chebyshev Acceleration (CA) method. Furthermore, the proposed algorithm can extend the stability range by reducing the sensitivity of iterative algorithms to the changes of adaptation rate.
Oligomers of length k, or k-mers, are convenient and widely used features for modeling the proper... more Oligomers of length k, or k-mers, are convenient and widely used features for modeling the properties and functions of DNA and protein sequences. However, k-mers suffer from the inherent limitation that if the parameter k is increased to resolve longer features, the probability of observing any specific k-mer becomes very small, and k-mer counts approach a binary variable, with most k-mers absent and a few present once. Thus, any statistical learning approach using k-mers as features becomes susceptible to noisy training set k-mer frequencies once k becomes large. To address this problem, we introduce alternative feature sets using gapped k-mers, a new classifier, gkm-SVM, and a general method for robust estimation of k-mer frequencies. To make the method applicable to large-scale genome wide applications, we develop an efficient tree data structure for computing the kernel matrix. We show that compared to our original kmer-SVM and alternative approaches, our gkm-SVM predicts functi...
Oligomers of fixed length, k, commonly known as k-mers, are often used as fundamental elements in... more Oligomers of fixed length, k, commonly known as k-mers, are often used as fundamental elements in the description of DNA sequence features of diverse biological function, or as intermediate elements in the constuction of more complex descriptors of sequence features such as position weight matrices. k-mers are very useful as general sequence features because they constitute a complete and unbiased feature set, and do not require parameterization based on incomplete knowledge of biological mechanisms. However, a fundamental limitation in the use of k-mers as sequence features is that as k is increased, larger spatial correlations in DNA sequence elements can be described, but the frequency of observing any specific k-mer becomes very small, and rapidly approaches a sparse matrix of binary counts. Thus any statistical learning approach using k-mers will be susceptible to noisy estimation of k-mer frequencies once k becomes large. Because all molecular DNA interactions have limited spatial extent, gapped k-mers often carry the relevant biological signal. Here we use gapped k-mer counts to more robustly estimate the ungapped k-mer frequencies, by deriving an equation for the minimum norm estimate of k-mer frequencies given an observed set of gapped k-mer frequencies. We demonstrate that this approach provides a more accurate estimate of the k-mer frequencies in real biological sequences using a sample of CTCF binding sites in the human genome.
MotivationGene fusions play a key role as driver oncogenes in tumors, and their reliable discover... more MotivationGene fusions play a key role as driver oncogenes in tumors, and their reliable discovery and detection are important for cancer research, diagnostics, prognostics and guiding personalized therapy. While discovering gene fusions from genome sequencing can be laborious and costly, the resulting “fusion transcripts” can be recovered from RNA-seq data of tumor and normal samples. However, alleged and putative fusion transcripts can also arise from multiple sources other than chromosomal rearrangements, including cis- or trans-splicing events, experimental artifacts during RNA-seq or computational errors of transcriptome reconstruction methods. Understanding how to discern, interpret, categorize, and verify predicted fusion transcripts is essential for consideration in clinical settings and prioritization for further research.SummaryHere, we present FusionInspector for in silico characterization and interpretation of candidate fusion transcripts from RNA-seq and exploration of ...
In cancer, telomere maintenance is critical for the development of replicative immortality. Using... more In cancer, telomere maintenance is critical for the development of replicative immortality. Using genome sequences from the Cancer Cell Line Encyclopedia and Genomics of Drug Sensitivity in Cancer Project, we calculated telomere content across 1299 cancer cell lines. We find that telomerase reverse transcriptase (TERT) expression correlates with telomere content in lung, central nervous system, and leukemia cell lines. Using CRISPR/Cas9 screening data, we show that lower telomeric content is associated with dependency of CST telomere maintenance genes. Increased dependencies of shelterin members are associated with wild-type TP53 status. Investigating the epigenetic regulation of TERT, we find widespread allele-specific expression in promoter-wildtype contexts. TERT promoter-mutant cell lines exhibit hypomethylation at PRC2-repressed regions, suggesting a cooperative global epigenetic state in the reactivation of telomerase. By incorporating telomere content with genomic features ac...
Myc transcription factors are well-established drivers of human cancers. However, despite being a... more Myc transcription factors are well-established drivers of human cancers. However, despite being amongst the most frequently mutated, translocated and overexpressed oncogenes, no therapy targeting the Myc family members directly has been developed to date. To sustain uncontrolled cell proliferation and tumor growth, Myc-driven cancers are known to be addicted to protein translation. This addiction creates a dependency on critical components of the translational machinery providing in turn a unique opportunity for therapeutic intervention. We hypothesized that targeting the translational termination factor GSPT1, a key regulator of protein synthesis, would constitute a vulnerability for Myc-driven tumors. GSPT1 contains a well-defined degron allowing for the recruitment of the E3 ligase cereblon (CRBN) and subsequent proteasomal degradation in the presence of molecular glue degraders. Herein we describe a novel orally bioavailable GSPT1-directed small molecule degrader MRT-2359, which...
SL-401 is a novel targeted therapy comprised of recombinant interleukin 3 (IL3) fused to a trunca... more SL-401 is a novel targeted therapy comprised of recombinant interleukin 3 (IL3) fused to a truncated diphtheria toxin (DT) payload. SL-401 delivers DT to cells expressing the IL3 receptor (CD123). After internalization, DT catalyzes ADP ribosylation of eukaryotic elongation factor 2 (eEF2), blocking protein synthesis and killing target cells. SL-401 is currently in clinical trials for CD123+ cancers, including acute myeloid leukemia (AML) and blastic plasmacytoid dendritic cell neoplasm (BPDCN). Other than CD123 expression, the determinants of response are largely unknown. Our goal was to study mechanisms of de novo and acquired resistance to inform combination strategies and enhance the efficacy of SL-401. In 16 AML and BPDCN patients enrolled in a phase 1-2 trial, we did not see decreased expression of CD123 by flow cytometry during or after SL-401. To study alternative resistance mechanisms, we generated 3-6 independent SL-401 resistant clones from each of 4 CD123+ AML (THP1, NOM...
The Myc family of transcription factors is a well-established driver of human cancers. However, d... more The Myc family of transcription factors is a well-established driver of human cancers. However, despite being amongst the most frequently mutated, translocated and overexpressed oncogenes, no therapy directly targeting the Myc family members has been developed to date. Abnormal activation of Myc results in uncontrolled cell growth that is associated with high translational output and ramp up of the protein translational machinery. This creates a dependency to protein translation and in turn represents a potential therapeutic vulnerability for Myc-driven tumors. Based on these considerations, we hypothesized that targeting the translational termination factor GSPT1, a key player of protein synthesis, may constitute a vulnerability for Myc-driven tumors. Using our proprietary Quantitative and Engineered Elimination of Neosubstrates (QuEENTM) platform we characterized and explored the known G-loop degron in GSPT1 that renders it amenable to cereblon-induced degradation by molecular glu...
Highlights d Topology of junction copy number reveals novel classes of complex structural variant... more Highlights d Topology of junction copy number reveals novel classes of complex structural variants d Rigma are deletion ''chasms'' at fragile sites arising early in GI tumor evolution d Pyrgo are superenhancer-associated duplication ''towers'' in breast and ovarian cancer d Tyfonas are ''typhoons'' of amplified fold-back inversions in acral melanoma
We recently demonstrated that genetic heterogeneity contributes to evolution and clinical outcome... more We recently demonstrated that genetic heterogeneity contributes to evolution and clinical outcome in chronic lymphocytic leukemia (CLL) (Landau et al., Cell 2013). As both genetic and epigenetic alterations contribute to the cellular phenotype and its fitness for selection, we hypothesized that heterogeneity in DNA methylation impacts leukemic evolution as well. We analyzed existing CLL methylation data (Kulis et al., Nat Gen 2012), and found higher heterogeneity in 450K arrays of 139 CLLs compared to 23 normal B cell samples, with a higher proportion of sites having intermediate levels of methylation (13.7% vs 10.7%, P<0.0001). Next, we re-analyzed whole genome bisulfite sequencing data from 2 CLL and 3 normal B cell samples to distinguish between 2 possible explanations for heterogeneity: 1) a mixture of cell subpopulations with ordered but differing methylation states, and 2) increased proportion of cells with ‘noisy’ or disordered methylation states. We found that the bulk of...
Human cancer cell lines are the workhorse of cancer research. Although cell lines are known to ev... more Human cancer cell lines are the workhorse of cancer research. Although cell lines are known to evolve in culture, the extent of the resultant genetic and transcriptional heterogeneity and its functional consequences remain understudied. Here we use genomic analyses of 106 human cell lines grown in two laboratories to show extensive clonal diversity. Further comprehensive genomic characterization of 27 strains of the common breast cancer cell line MCF7 uncovered rapid genetic diversification. Similar results were obtained with multiple strains of 13 additional cell lines. Notably, genetic changes were associated with differential activation of gene expression programs and marked differences in cell morphology and proliferation. Barcoding experiments showed that cell line evolution occurs as a result of positive clonal selection that is highly sensitive to culture conditions. Analyses of single-cell-derived clones demonstrated that continuous instability quickly translates into heterogeneity of the cell line. When the 27 MCF7 strains were tested against 321 anti-cancer compounds, we uncovered considerably different drug responses: at least 75% of compounds that strongly inhibited some strains were completely inactive in others. This study documents the extent, origins and consequences of genetic variation within cell lines, and provides a framework for researchers to measure such variation in efforts to support maximally reproducible cancer research.
Large cancer cell line collections broadly capture the genomic diversity of human cancers and pro... more Large cancer cell line collections broadly capture the genomic diversity of human cancers and provide valuable insight into anti-cancer drug response. Here, we show substantial agreement and biological consilience between drug sensitivity measurements and their associated genomic predictors from two publicly available large-scale pharmacogenomics resources: The Cancer Cell Line Encyclopedia and the Genomics of Drug Sensitivity in Cancer. In vitro pharmacologic sensitivity studies performed across panels of molecularly characterized cancer cell lines have proved useful in assessing the cellular activity of many compounds, assigning mechanisms of drug action, and determining genetic contexts for distinct cancer vulnerabilities1-6. A recent comparison study7 of the Cancer Cell Line
Recent treatment advances in metastatic BRAF mutant melanoma using targeted therapy have increase... more Recent treatment advances in metastatic BRAF mutant melanoma using targeted therapy have increased progression free survival by many months. However, resistance to these targeted agents is a common occurrence, with relapse occurring in almost every case. Many of the alterations that confer clinical resistance to RAF and MEK inhibitors in BRAF mutant melanoma reactivate the MAPK pathway, but remain sensitive to ERK inhibition in vitro. Prospectively determining mechanisms of resistance to MAPK pathway inhibitors, such as an ERK inhibitor, before clinical trials begin may inform which patients will respond to therapy, potential markers of resistance, or best therapy combinations. Previous studies have shown that in vitro random mutagenesis screens can select specific alleles seen in resistant patient populations. Since ERK inhibitors are entering clinical trials, we wanted to determine mutations in ERK1 and ERK2 that could confer resistance to ERK or RAF/MEK inhibition. Therefore, we ...
Abstract Compressed video processing is becoming increasingly important in many digital video app... more Abstract Compressed video processing is becoming increasingly important in many digital video applications. There are two main approaches for compressed video processing. The first approach is called re-encoding and the second is called compressed domain processing (CDP). Bit-rate reduction is a very common process in video processing applications. In our research, the bit-rate reduction process is implemented using an SNR-scaling scheme. We have implemented enhanced compressed domain processor ...
Dexamethasone (DEX) was previously shown (Jing et al., Biotechnol Bioeng. 2010;107:488-496) to pl... more Dexamethasone (DEX) was previously shown (Jing et al., Biotechnol Bioeng. 2010;107:488-496) to play a dual role in increasing sialylation of recombinant glycoproteins produced by Chinese Hamster Ovary (CHO) cells. DEX addition increased sialic acid levels of a recombinant fusion protein through increased expression of α2,3-sialyltransferase and β1,4-galactosyltransferase, but also decreased the sialidase-mediated, extracellular degradation of sialic acid through slowing cell death at the end of the culture period. This study examines the underlying mechanism for this cytoprotective action by studying the transcriptional response of the CHO cell genome upon DEX treatment using DNA microarrays and gene ontology term analysis. Many of those genes showing a significant transcriptional response were associated with the regulation of programmed cell death. The gene with the highest change in expression level, as validated by Quantitative PCR assays with TaqMan® probes and confirmed by Western Blot analysis, was the antiapoptotic gene Tsc22d3, also referred to as GILZ (glucocorticoid-induced leucine zipper). The pathway by which DEX suppressed cell death towards the end of the culture period was also confirmed by showing involvement of glucocorticoid receptors and GILZ through studies using the glucocorticoid antagonist mifepristone (RU-486). These findings advance the understanding of the mechanism by which DEX suppresses cell death in CHO cells and provide a rationale for the application of glucocorticoids in CHO cell culture processes.
Cancer genome sequencing efforts have revealed that ARID1A is frequently mutated in many types of... more Cancer genome sequencing efforts have revealed that ARID1A is frequently mutated in many types of cancer. Inactivating mutations occur in 45% of ovarian clear cell and endometrioid carcinomas, 19% of gastric cancers, 19% of bladder cancers, 14% of hepatocellular cancers, 12% of melanomas, and less frequently in colorectal, lung, breast and pancreatic cancers. ARID1A has also been validated as having bona fide tumor suppressor properties. Consequently, identification of specific vulnerabilities conferred by ARID1A mutation would have major relevance for human cancer. We therefore performed a systematic search for genetic vulnerabilities created by ARID1A mutation. Out of 9000+ genes screened, ARID1B, a related but mutually exclusive homolog of ARID1A in the SWI/SNF chromatin remodeling complex, was the number one gene preferentially required in ARID1A-mutant cancer cells. In validation studies, we find that knockdown of ARID1B indeed specifically impairs the proliferation of ARID1A-m...
In this paper, we study the generalized gapped k-mer filters and derive a closed form solution fo... more In this paper, we study the generalized gapped k-mer filters and derive a closed form solution for their coefficients. We consider nonnegative integers ℓ and k, with k ≤ ℓ, and an ℓ-tuple B = (b 1 ,. .. , b ℓ) of integers b i ≥ 2, i = 1,. .. , ℓ. We introduce and study an incidence matrix A = A ℓ,k;B. We develop a Möbius-like function ν B which helps us to obtain closed forms for a complete set of mutually orthogonal eigenvectors of A ⊤ A as well as a complete set of mutually orthogonal eigenvectors of AA ⊤ corresponding to nonzero eigenvalues. The reduced singular value decomposition of A and combinatorial interpretations for the nullity and rank of A, are among the consequences of this approach. We then combine the obtained formulas, some results from linear algebra, and combinatorial identities of elementary symmetric functions and ν B , to provide the entries of the Moore-Penrose pseudo-inverse matrix A + and the Gapped k-mer filter matrix A + A.
Iterative methods have led to better understanding and solving problems such as missing sampling,... more Iterative methods have led to better understanding and solving problems such as missing sampling, deconvolution, inverse systems, impulsive and Salt and Pepper noise removal problems. However, the challenges such as the speed of convergence and or the accuracy of the answer still remain. In order to improve the existing iterative algorithms, a non-linear method is discussed in this paper. The mentioned method is analyzed from different aspects, including its convergence and its ability to accelerate recursive algorithms.We show that this method is capable of improving Iterative Method (IM) as a non-uniform sampling reconstruction algorithm and some iterative sparse recovery algorithms such as Iterative Reweighted Least Squares (IRLS), Iterative Method with Adaptive Thresholding (IMAT), Smoothed 0 (SL0) and Alternating Direction Method of Multipliers (ADMM) for solving LASSO problems family (including Lasso itself, Lasso-LSQR and group-Lasso). It is also capable of both accelerating and stabilizing the well-known Chebyshev Acceleration (CA) method. Furthermore, the proposed algorithm can extend the stability range by reducing the sensitivity of iterative algorithms to the changes of adaptation rate.
Oligomers of length k, or k-mers, are convenient and widely used features for modeling the proper... more Oligomers of length k, or k-mers, are convenient and widely used features for modeling the properties and functions of DNA and protein sequences. However, k-mers suffer from the inherent limitation that if the parameter k is increased to resolve longer features, the probability of observing any specific k-mer becomes very small, and k-mer counts approach a binary variable, with most k-mers absent and a few present once. Thus, any statistical learning approach using k-mers as features becomes susceptible to noisy training set k-mer frequencies once k becomes large. To address this problem, we introduce alternative feature sets using gapped k-mers, a new classifier, gkm-SVM, and a general method for robust estimation of k-mer frequencies. To make the method applicable to large-scale genome wide applications, we develop an efficient tree data structure for computing the kernel matrix. We show that compared to our original kmer-SVM and alternative approaches, our gkm-SVM predicts functi...
Oligomers of fixed length, k, commonly known as k-mers, are often used as fundamental elements in... more Oligomers of fixed length, k, commonly known as k-mers, are often used as fundamental elements in the description of DNA sequence features of diverse biological function, or as intermediate elements in the constuction of more complex descriptors of sequence features such as position weight matrices. k-mers are very useful as general sequence features because they constitute a complete and unbiased feature set, and do not require parameterization based on incomplete knowledge of biological mechanisms. However, a fundamental limitation in the use of k-mers as sequence features is that as k is increased, larger spatial correlations in DNA sequence elements can be described, but the frequency of observing any specific k-mer becomes very small, and rapidly approaches a sparse matrix of binary counts. Thus any statistical learning approach using k-mers will be susceptible to noisy estimation of k-mer frequencies once k becomes large. Because all molecular DNA interactions have limited spatial extent, gapped k-mers often carry the relevant biological signal. Here we use gapped k-mer counts to more robustly estimate the ungapped k-mer frequencies, by deriving an equation for the minimum norm estimate of k-mer frequencies given an observed set of gapped k-mer frequencies. We demonstrate that this approach provides a more accurate estimate of the k-mer frequencies in real biological sequences using a sample of CTCF binding sites in the human genome.
MotivationGene fusions play a key role as driver oncogenes in tumors, and their reliable discover... more MotivationGene fusions play a key role as driver oncogenes in tumors, and their reliable discovery and detection are important for cancer research, diagnostics, prognostics and guiding personalized therapy. While discovering gene fusions from genome sequencing can be laborious and costly, the resulting “fusion transcripts” can be recovered from RNA-seq data of tumor and normal samples. However, alleged and putative fusion transcripts can also arise from multiple sources other than chromosomal rearrangements, including cis- or trans-splicing events, experimental artifacts during RNA-seq or computational errors of transcriptome reconstruction methods. Understanding how to discern, interpret, categorize, and verify predicted fusion transcripts is essential for consideration in clinical settings and prioritization for further research.SummaryHere, we present FusionInspector for in silico characterization and interpretation of candidate fusion transcripts from RNA-seq and exploration of ...
In cancer, telomere maintenance is critical for the development of replicative immortality. Using... more In cancer, telomere maintenance is critical for the development of replicative immortality. Using genome sequences from the Cancer Cell Line Encyclopedia and Genomics of Drug Sensitivity in Cancer Project, we calculated telomere content across 1299 cancer cell lines. We find that telomerase reverse transcriptase (TERT) expression correlates with telomere content in lung, central nervous system, and leukemia cell lines. Using CRISPR/Cas9 screening data, we show that lower telomeric content is associated with dependency of CST telomere maintenance genes. Increased dependencies of shelterin members are associated with wild-type TP53 status. Investigating the epigenetic regulation of TERT, we find widespread allele-specific expression in promoter-wildtype contexts. TERT promoter-mutant cell lines exhibit hypomethylation at PRC2-repressed regions, suggesting a cooperative global epigenetic state in the reactivation of telomerase. By incorporating telomere content with genomic features ac...
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Papers by Mahmoud Ghandi