Papers by Raju Kucherlapati
Journal of Clinical Oncology
Cell reports, Jan 10, 2018
A systematic cataloging of genes affected by genomic rearrangement, using multiple patient cohort... more A systematic cataloging of genes affected by genomic rearrangement, using multiple patient cohorts and cancer types, can provide insight into cancer-relevant alterations outside of exomes. By integrative analysis of whole-genome sequencing (predominantly low pass) and gene expression data from 1,448 cancers involving 18 histopathological types in The Cancer Genome Atlas, we identified hundreds of genes for which the nearby presence (within 100 kb) of a somatic structural variant (SV) breakpoint is associated with altered expression. While genomic rearrangements are associated with widespread copy-number alteration (CNA) patterns, approximately 1,100 genes-including overexpressed cancer driver genes (e.g., TERT, ERBB2, CDK12, CDK4) and underexpressed tumor suppressors (e.g., TP53, RB1, PTEN, STK11)-show SV-associated deregulation independent of CNA. SVs associated with the disruption of topologically associated domains, enhancer hijacking, or fusion transcripts are implicated in gene...
Progress in Pediatric Cardiology
Oncotarget, Jan 10, 2017
Homologous recombination (HR) enables precise DNA repair after DNA double strand breaks (DSBs) us... more Homologous recombination (HR) enables precise DNA repair after DNA double strand breaks (DSBs) using identical sequence templates, whereas homeologous recombination (HeR) uses only partially homologous sequences. Homeologous recombination introduces mutations through gene conversion and genomic deletions through single-strand annealing (SSA). DNA mismatch repair (MMR) inhibits HeR, but the roles of mammalian MMR MutL homologues (MLH1, PMS2 and MLH3) proteins in HeR suppression are poorly characterized. Here, we demonstrate that mouse embryonic fibroblasts (MEFs) carrying Mlh1, Pms2, and Mlh3 mutations have higher HeR rates, by using 7,863 uniquely mapping paired direct repeat sequences (DRs) in the mouse genome as endogenous gene conversion and SSA reporters. Additionally, when DSBs are induced by gamma-radiation, Mlh1, Pms2 and Mlh3 mutant MEFs have higher DR copy number alterations (CNAs), including DR CNA hotspots previously identified in mouse MMR-deficient colorectal cancer (dM...
Cancer cell, Jun 8, 2017
Molecular alterations involving the PI3K/AKT/mTOR pathway (including mutation, copy number, prote... more Molecular alterations involving the PI3K/AKT/mTOR pathway (including mutation, copy number, protein, or RNA) were examined across 11,219 human cancers representing 32 major types. Within specific mutated genes, frequency, mutation hotspot residues, in silico predictions, and functional assays were all informative in distinguishing the subset of genetic variants more likely to have functional relevance. Multiple oncogenic pathways including PI3K/AKT/mTOR converged on similar sets of downstream transcriptional targets. In addition to mutation, structural variations and partial copy losses involving PTEN and STK11 showed evidence for having functional relevance. A substantial fraction of cancers showed high mTOR pathway activity without an associated canonical genetic or genomic alteration, including cancers harboring IDH1 or VHL mutations, suggesting multiple mechanisms for pathway activation.
Cancer research, Jul 16, 2017
Oncogenic gene fusions drive many human cancers, but tools to more quickly unravel their function... more Oncogenic gene fusions drive many human cancers, but tools to more quickly unravel their functional contributions are needed. Here we describe methodology permitting fusion gene construction for functional evaluation. Using this strategy, we engineered the known fusion oncogenes, BCR-ABL1, EML4-ALK, and ETV6-NTRK3, as well as 20 previously uncharacterized fusion genes identified in TCGA datasets. In addition to confirming oncogenic activity of the known fusion oncogenes engineered by our construction strategy, we validated five novel fusion genes involving MET, NTRK2, and BRAF kinases that exhibited potent transforming activity and conferred sensitivity to FDA-approved kinase inhibitors. Our fusion construction strategy also enabled domain-function studies of BRAF fusion genes. Our results confirmed other reports that the transforming activity of BRAF fusions results from truncation-mediated loss of inhibitory domains within the N-terminus of the BRAF protein. BRAF mutations residin...
Cancer Cell, 2017
Highlights d Uterine carcinosarcomas (UCSs) have frequent TP53 mutations d UCSs demonstrate a str... more Highlights d Uterine carcinosarcomas (UCSs) have frequent TP53 mutations d UCSs demonstrate a strong and varied degree of epithelialmesenchymal transition d MicroRNA expression in UCSs is under epigenetic control d Multiple alterations are present in UCSs in genes that are therapeutic targets
The Journal of pathology, Jan 14, 2016
The gene encoding Migration and Invasion Inhibitory Protein (MIIP), located on 1p36.22, is a pote... more The gene encoding Migration and Invasion Inhibitory Protein (MIIP), located on 1p36.22, is a potential tumour suppressor gene in glioma. In this study, we aimed to explore the role and mechanism of action of MIIP in colorectal cancer (CRC). MIIP protein expression gradually decreased along the colorectal adenoma-carcinoma sequence and was negatively correlated with lymph node and distant metastasis in 526 colorectal tissue samples (P<0.05 for all). Analysis of The Cancer Genome Atlas (TCGA) data showed that decreased MIIP expression was significantly associated with MIIP hemizygous deletion (P=0.0005) that was detected in 27.7% (52/188) of CRC cases, and associated with lymph node and distant metastasis (P<0.05 for both). We deleted one copy of the MIIP gene in HCT-116 CRC cells using zinc finger nuclease technology and demonstrated that MIIP haploinsufficiency resulted in increased colony formation and cell migration and invasion, which was consistent with the results from si...
The ability of autonomously replicating plasmids to recombine in mamma- lian cells was investigat... more The ability of autonomously replicating plasmids to recombine in mamma- lian cells was investigated. Two deletion plasmids of the eukaryotic-prokaryotic shuttle vector pSV2neo were cotransfected into transformed monkey COS cells. Examination of the low molecular weight DNA isolated after 48 hr of incubation revealed that recombination between the plasmids had occurred. The DNA was also used to transform recA- E.
Cytogenet Genome Res, 1976
Cancer Research, Sep 15, 1997
tlth Apc mutation may actually lead to decreased immune, inflammatory, and gastric hyperplastic r... more tlth Apc mutation may actually lead to decreased immune, inflammatory, and gastric hyperplastic responses to Helicobacterinfection, suggesting the possibility of a novel role for this tumor suppressor gene in the immune and local tissue responses to gastric bacterial infection.
ABSTRACT In May 2007, Amgen Inc. (Amgen) received disappointing news from the European Medicines ... more ABSTRACT In May 2007, Amgen Inc. (Amgen) received disappointing news from the European Medicines Agency (EMEA) that its drug Vectibix, developed to fight metastatic colorectal cancer, had been rejected. This was especially surprising news given that a similar rival drug had received approval several years prior. Moreover, Vectibix had also received Food and Drug Administration approval in 2006. During additional trials, Amgen has learned that the Vectibix is only effective with the 60% of the population that has a specific gene marker. Given this development, what should Amgen&#39;s strategy around Vectibix be both in Europe and the United States?Learning Objective: To help conference participants understand how advances in the field of personalized medicine impact drug management and strategy.
Birth Defects Original Article Series, Feb 1, 1975
Progress in Nucleic Acid Research and Molecular Biology, Feb 1, 1989
Nat Struct Mol Biol, 2005
A mistake was introduced during production in the next-to-last sentence in the legend of Figure 3... more A mistake was introduced during production in the next-to-last sentence in the legend of Figure 3 (page 649) of the manuscript. The correct legend for Figure 3 is printed here. We apologize for any inconvenience this may have caused. "Figure 3 Functions of the KH and RRM domains. (a) The KH domain binds single-stranded nucleic acid; only the type I fold is shown 113. (b) An RRM domain can interact with a target RNA (i) or protein (ii) via its β-sheet surface. An RRM can also interact with a protein via its α-helical surface on the opposite side (iii). In U2AF65, an extra helix (α3) at the C terminus interacts with the β-sheet surface of RRM3 (iv), which would occlude RNA binding. However, the α3 helix swings away upon RNA binding, facilitating protein dimerization and RNA binding, in U1A RRM, or unfolds upon RNA binding in CstF64 RRM 114 (v). Protein names denote examples of each type of interaction."
Uploads
Papers by Raju Kucherlapati