A census of amplified and overexpressed human cancer genes

2010 ◽  
Vol 10 (1) ◽  
pp. 59-64 ◽  
Author(s):  
Thomas Santarius ◽  
Janet Shipley ◽  
Daniel Brewer ◽  
Michael R. Stratton ◽  
Colin S. Cooper
Keyword(s):  
Human Cancer ◽  
Cancer Genes

scholarly journals Genome-Based Identification of Cancer Genes by Proviral Tagging in Mouse Retrovirus-Induced T-Cell Lymphomas

2003 ◽  
Vol 77 (3) ◽  
pp. 2056-2062 ◽  
Author(s):  
Rachel Kim ◽  
Alla Trubetskoy ◽  
Takeshi Suzuki ◽  
Nancy A. Jenkins ◽  
Neal G. Copeland ◽  
...  
Keyword(s):  
T Cell ◽  
Molecular Mechanisms ◽  
Mouse Genome ◽  
Human Cancer ◽  
Inverse Pcr ◽  
Ras Signaling ◽  
Cancer Genes ◽  
Altered Expression ◽  
New Genes ◽  
T Cell Lymphomas

ABSTRACT The identification of tumor-inducing genes is a driving force for elucidating the molecular mechanisms underlying cancer. Many retroviruses induce tumors by insertion of viral DNA adjacent to cellular oncogenes, resulting in altered expression and/or structure of the encoded proteins. The availability of the mouse genome sequence now allows analysis of retroviral common integration sites in murine tumors to be used as a genetic screen for identification of large numbers of candidate cancer genes. By positioning the sequences of inverse PCR-amplified, virus-host junction fragments within the mouse genome, 19 target genes were identified in T-cell lymphomas induced by the retrovirus SL3-3. The candidate cancer genes included transcription factors (Fos, Gfi1, Lef1, Myb, Myc, Runx3, and Sox3), all three D cyclins, Ras signaling pathway components (Rras2/TC21 and Rasgrp1), and Cmkbr7/CCR7. The most frequent target was Rras2. Insertions as far as 57 kb away from the transcribed portion were associated with substantially increased transcription of Rras2, and no coding sequence mutations, including those typically involved in Ras activation, were detected. These studies demonstrate the power of genome-based analysis of retroviral insertion sites for cancer gene discovery, identify several new genes worth examining for a role in human cancer, and implicate the pathways in which those genes act in lymphomagenesis. They also provide strong genetic evidence that overexpression of unmutated Rras2 contributes to tumorigenesis, thus suggesting that it may also do so if it is inappropriately expressed in human tumors.

Cytogenetic approaches to human cancer genes 1

1994 ◽  
Vol 8 (6) ◽  
pp. 408-413 ◽  
Author(s):  
Peter C. Nowell
Keyword(s):  
Human Cancer ◽  
Cancer Genes

A Dual Proto-Oncogenic and Tumor Suppressive Role of LRF/POKEMON In Hemopoietic Malignancies through Control of Cell Fate Decision

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. SCI-14-SCI-14
Author(s):  
Pier Paolo Pandolfi
Keyword(s):  
Cell Fate ◽  
Cellular Differentiation ◽  
Conflicts Of Interest ◽  
Human Cancer ◽  
Cellular Transformation ◽  
Related Factor ◽  
Cancer Genes ◽  
Cell Fate Decisions

Abstract Abstract SCI-14 LRF (Leukemia/lymphoma-related factor, also known as POKEMON) is a member of the POZ and Kruppel (POK) family of transcription factors. LRF has been shown to play an essential role in embryonic development and to act as a master regulator of cellular differentiation in virtually any tissue where it is found expressed, including the hemopoietic compartment. As we will discuss, LRF inactivation in the mouse blocks cellular differentiation in both myeloid/erythroid and lymphoid compartments. On the other hand, LRF has been shown to possess a potent proto-oncogenic activity both in vitro and in vivo. In fact, LRF itself can transform primary cells in combination with known oncogenes and is also essential for cellular transformation of mouse embryonic fibroblasts. In addition, overexpression of LRF in immature B and T progenitor cells in vivo in the mouse lead to lethal precursor T-cell lymphoblastic lymphoma/leukemia. In agreement with this notion, LRF is aberrantly expressed in a variety of human cancers, including diffuse large B cell and follicular lymphomas, but also ovarian and breast cancers. Further, the LRF gene is found amplified in a subset of non-small cell lung cancers (NSCLCs), illustrating a direct role in human cancer. However, we speculated that due to the key role of LRF in cell fate decisions, LRF/POKEMON loss could also contribute to tumorigenesis by blocking cellular differentiation. We will discuss provocative in vivo data in support of the notion that LRF/POKEMON can indeed act as a bona fide tumor suppressor representing a compelling example of two-faced cancer genes. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Selective pressures on human cancer genes along the evolution of mammals

2018 ◽  
Author(s):  
Alberto Vicens ◽  
David Posada
Keyword(s):  
Positive Selection ◽  
Hereditary Cancer ◽  
Clonal Selection ◽  
Human Cancer ◽  
Cancer Genes ◽  
Pathogenic Variants ◽  
Potential Association ◽  
Show Evidence ◽  
Mammalian Genomes ◽  
Evolution Of Mammals

AbstractCancer is a disease of the genome caused by somatic mutation and subsequent clonal selection. Several genes associated to cancer in humans, hereafter cancer genes, also show evidence of (germline) positive selection among species. Taking advantage of a large collection of mammalian genomes, we systematically looked for statistically significant signatures of positive selection using dN/dS models in a list of 430 cancer genes. Among these, we identified 63 genes under putative positive selection in mammals, which are significantly enriched in processes like crosslinking DNA repair. We also found evidence of a higher incidence of positive selection in cancer genes bearing germline mutations, like BRCA2, where positively selected residues are physically linked with known pathogenic variants, suggesting a potential association between germline positive selection and risk of hereditary cancer. Overall, our results suggest that genes associated with hereditary cancer have less selective constraints than genes related to sporadic cancer. Also, that the adaptive evolution of human cancer genes in mammals has been most likely driven by adaptive changes in important traits not directly related to cancer.

scholarly journals Selective Pressures on Human Cancer Genes along the Evolution of Mammals

Genes ◽  
2018 ◽  
Vol 9 (12) ◽  
pp. 582 ◽  
Author(s):  
Alberto Vicens ◽  
David Posada
Keyword(s):  
Positive Selection ◽  
Cancer Susceptibility ◽  
Human Cancer ◽  
Synonymous Site ◽  
Fanconi Anaemia ◽  
Cancer Genes ◽  
Synonymous Substitutions ◽  
Recessive Mutations ◽  
Show Evidence ◽  
Positively Selected Sites

Cancer is a disease driven by both somatic mutations that increase survival and proliferation of cell lineages and the evolution of genes associated with cancer risk in populations. Several genes associated with cancer in humans, hereafter cancer genes, show evidence of germline positive selection among species. Taking advantage of a large collection of mammalian genomes, we systematically looked for signatures of germline positive selection in 430 cancer genes available in COSMIC. We identified 40 cancer genes with a robust signal of positive selection in mammals. We found evidence for fewer selective constraints—higher number of non-synonymous substitutions per non-synonymous site to the number of synonymous substitutions per synonymous site (dN/dS)—and higher incidence of positive selection—more positively selected sites—in cancer genes bearing germline and recessive mutations that predispose to cancer. This finding suggests a potential association between relaxed selection, positive selection, and risk of hereditary cancer. On the other hand, we did not find significant differences in terms of tissue or gene type. Human cancer genes under germline positive selection in mammals are significantly enriched in the processes of DNA repair, with high presence of Fanconi anaemia/Breast Cancer A (FA/BRCA) pathway components and T cell proliferation genes. We also show that the inferred positively selected sites in the two genes with the strongest signal of positive selection, i.e., BRCA2 and PTPRC, are in regions of functional relevance, which could be relevant to cancer susceptibility.

Taking Human Cancer Genes to the Fish: A Transgenic Model of Melanoma in Zebrafish

Zebrafish ◽  
2005 ◽  
Vol 1 (4) ◽  
pp. 363-368 ◽  
Author(s):  
E. Elizabeth Patton ◽  
Leonard I. Zon
Keyword(s):  
Human Cancer ◽  
Cancer Genes ◽  
Transgenic Model

dbCID: a manually curated resource for exploring the driver indels in human cancer

2019 ◽  
Vol 20 (5) ◽  
pp. 1925-1933 ◽  
Author(s):  
Zhenyu Yue ◽  
Le Zhao ◽  
Na Cheng ◽  
Hua Yan ◽  
Junfeng Xia
Keyword(s):  
Dna Sequences ◽  
Human Cancer ◽  
Computational Method ◽  
Genomic Research ◽  
Cancer Genes ◽  
Cancer Driver ◽  
Sequencing Technologies ◽  
Four Levels ◽  
External Test ◽  
Frameshift Indels

Abstract While recent advances in next-generation sequencing technologies have enabled the creation of a multitude of databases in cancer genomic research, there is no comprehensive database focusing on the annotation of driver indels (insertions and deletions) yet. Therefore, we have developed the database of Cancer driver InDels (dbCID), which is a collection of known coding indels that likely to be engaged in cancer development, progression or therapy. dbCID contains experimentally supported and putative driver indels derived from manual curation of literature and is freely available online at http://bioinfo.ahu.edu.cn:8080/dbCID. Using the data deposited in dbCID, we summarized features of driver indels in four levels (gene, DNA, transcript and protein) through comparing with putative neutral indels. We found that most of the genes containing driver indels in dbCID are known cancer genes playing a role in tumorigenesis. Contrary to the expectation, the sequences affected by driver frameshift indels are not larger than those by neutral ones. In addition, the frameshift and inframe driver indels prefer to disrupt high-conservative regions both in DNA sequences and protein domains. Finally, we developed a computational method for discriminating cancer driver from neutral frameshift indels based on the deposited data in dbCID. The proposed method outperformed other widely used non-cancer-specific predictors on an external test set, which demonstrated the usefulness of the data deposited in dbCID. We hope dbCID will be a benchmark for improving and evaluating prediction algorithms, and the characteristics summarized here may assist with investigating the mechanism of indel–cancer association.

scholarly journals Important role of indels in somatic mutations of human cancer genes

2010 ◽  
Vol 11 (1) ◽  
Author(s):  
Haiwang Yang ◽  
Yan Zhong ◽  
Cheng Peng ◽  
Jian-Qun Chen ◽  
Dacheng Tian
Keyword(s):  
Somatic Mutations ◽  
Human Cancer ◽  
Cancer Genes

scholarly journals Comprehensive analysis of clustered mutations in cancer reveals recurrent APOBEC3 mutagenesis of ecDNA

2021 ◽  
Author(s):  
Erik N Bergstrom ◽  
Jens-Christian Luebeck ◽  
Mia Petljak ◽  
Vineet Bafna ◽  
Paul S. Mischel ◽  
...  
Keyword(s):  
Somatic Mutations ◽  
Human Cancer ◽  
Cancer Genes ◽  
Base Substitutions ◽  
Cancer Genomes ◽  
Cancer Types ◽  
Mutational Processes ◽  
Comprehensive Characterization

Clustered somatic mutations are common in cancer genomes with prior analyses revealing several types of clustered single-base substitutions, including doublet- and multi-base substitutions, diffuse hypermutation termed omikli, and longer strand-coordinated events termed kataegis. Here, we provide a comprehensive characterization of clustered substitutions and clustered small insertions and deletions (indels) across 2,583 whole-genome sequenced cancers from 30 cancer types. While only 3.7% of substitutions and 0.9% of indels were found to be clustered, they contributed 8.4% and 6.9% of substitution and indel drivers, respectively. Multiple distinct mutational processes gave rise to clustered indels including signatures enriched in tobacco smokers and homologous-recombination deficient cancers. Doublet-base substitutions were caused by at least 12 mutational processes, while the majority of multi-base substitutions were generated by either tobacco smoking or exposure to ultraviolet light. Omikli events, previously attributed to the activity of APOBEC3 deaminases, accounted for a large proportion of clustered substitutions. However, only 16.2% of omikli matched APOBEC3 patterns with experimental validation confirming additional mutational processes giving rise to omikli. Kataegis was generated by multiple mutational processes with 76.1% of all kataegic events exhibiting AID/APOBEC3-associated mutational patterns. Co-occurrence of APOBEC3 kataegis and extrachromosomal-DNA (ecDNA) was observed in 31% of samples with ecDNA. Multiple distinct APOBEC3 kataegic events were observed on most mutated ecDNA. ecDNA containing known cancer genes exhibited both positive selection and kataegic hypermutation. Our results reveal the diversity of clustered mutational processes in human cancer and the role of APOBEC3 in recurrently mutating and fueling the evolution of ecDNA.

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