Driver and Passenger Mutations in Cancer

Pon, Julia R.; Marra, Marco A.

doi:10.1146/annurev-pathol-012414-040312

Cited by 293 publications

(242 citation statements)

References 192 publications

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“…While passenger mutations are present in cancer genomes, they are not considered to contribute to cancer progression; instead, they are simply somatic mutations that arise during carcinogenesis and are carried along during clonal expansion. Driver mutations, on the other hand, are causal mutations that are directly implicated in carcinogenesis and the promotion of cancer growth (Stratton et al, 2009; Marx, 2014; Pon and Marra, 2015). To date, only a few studies have directly implicated TE insertions as cancer driver mutations.…”

Section: Introductionmentioning

confidence: 99%

Patterns of Transposable Element Expression and Insertion in Cancer

Clayton

Wang

Rishishwar

et al. 2016

Front. Mol. Biosci.

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Human transposable element (TE) activity in somatic tissues causes mutations that can contribute to tumorigenesis. Indeed, TE insertion mutations have been implicated in the etiology of a number of different cancer types. Nevertheless, the full extent of somatic TE activity, along with its relationship to tumorigenesis, have yet to be fully explored. Recent developments in bioinformatics software make it possible to analyze TE expression levels and TE insertional activity directly from transcriptome (RNA-seq) and whole genome (DNA-seq) next-generation sequence data. We applied these new sequence analysis techniques to matched normal and primary tumor patient samples from the Cancer Genome Atlas (TCGA) in order to analyze the patterns of TE expression and insertion for three cancer types: breast invasive carcinoma, head and neck squamous cell carcinoma, and lung adenocarcinoma. Our analysis focused on the three most abundant families of active human TEs: Alu, SVA, and L1. We found evidence for high levels of somatic TE activity for these three families in normal and cancer samples across diverse tissue types. Abundant transcripts for all three TE families were detected in both normal and cancer tissues along with an average of ~80 unique TE insertions per individual patient/tissue. We observed an increase in L1 transcript expression and L1 insertional activity in primary tumor samples for all three cancer types. Tumor-specific TE insertions are enriched for private mutations, consistent with a potentially causal role in tumorigenesis. We used genome feature analysis to investigate two specific cases of putative cancer-causing TE mutations in further detail. An Alu insertion in an upstream enhancer of the CBL tumor suppressor gene is associated with down-regulation of the gene in a single breast cancer patient, and an L1 insertion in the first exon of the BAALC gene also disrupts its expression in head and neck squamous cell carcinoma. Our results are consistent with widespread somatic activity of human TEs leading to numerous insertion mutations that can contribute to tumorigenesis in a variety of tissues.

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Section: Introductionmentioning

confidence: 99%

Patterns of Transposable Element Expression and Insertion in Cancer

Clayton

Wang

Rishishwar

et al. 2016

Front. Mol. Biosci.

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“…Therefore, more systematic screens of tumour and matched germline material using large patient cohorts will be needed. Since the screening for somatic mutations in cancer cells has been among the first fields to harness the power of MPS, and especially WGS [190], the methods used to identify driver mutations are better established than those to identify germline variants. Consequently, although missing driver variants have been reported, the identification of driver variants in (non-)coding regions [191] may lead to the discovery and improved prioritization of germline variants (Fig.…”

Section: Guidelines For Gene Discoverymentioning

confidence: 99%

The genetic heterogeneity of colorectal cancer predisposition - guidelines for gene discovery

et al. 2016

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BackgroundColorectal cancer (CRC) is a cumulative term applied to a clinically and genetically heterogeneous group of neoplasms that occur in the bowel. Based on twin studies, up to 45 % of the CRC cases may involve a heritable component. Yet, only in 5–10 % of these cases high-penetrant germline mutations are found (e.g. mutations in APC and DNA mismatch repair genes) that result in a familial aggregation and/or an early onset of the disease. Genome-wide association studies have revealed that another ~5 % of the CRC cases may be explained by a cumulative effect of low-penetrant risk factors. Recent attempts to identify novel genetic factors using whole exome and whole genome sequencing has proven to be difficult since the remaining, yet to be discovered, high penetrant CRC predisposing genes appear to be rare. In addition, most of the moderately penetrant candidate genes identified so far have not been confirmed in independent cohorts. Based on literature examples, we here discuss how careful patient and cohort selection, candidate gene and variant selection, and corroborative evidence may be employed to facilitate the discovery of novel CRC predisposing genes.ConclusionsThe picture emerges that the genetic predisposition to CRC is heterogeneous, involving complex interplays between common and rare (inter)genic variants with different penetrances. It is anticipated, however, that the use of large clinically well-defined patient and control datasets, together with improved functional and technical possibilities, will yield enough power to unravel this complex interplay and to generate accurate individualized estimates for the risk to develop CRC.

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“…However, the majority of mutations identified by high-throughput sequencing are passengers that do not provide a clonal advantage to cancer cells during tumor development [34]. Thus, it remains a major challenge to distinguish passenger mutations from driver mutations using this approach [35,36,37]. …”

Section: Identifying Cancer Genes By High-throughput Sequencing Ismentioning

confidence: 99%

Identifying Cancer Driver Genes Using Replication-Incompetent Retroviral Vectors

Bii

Trobridge

2016

Cancers

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Identifying novel genes that drive tumor metastasis and drug resistance has significant potential to improve patient outcomes. High-throughput sequencing approaches have identified cancer genes, but distinguishing driver genes from passengers remains challenging. Insertional mutagenesis screens using replication-incompetent retroviral vectors have emerged as a powerful tool to identify cancer genes. Unlike replicating retroviruses and transposons, replication-incompetent retroviral vectors lack additional mutagenesis events that can complicate the identification of driver mutations from passenger mutations. They can also be used for almost any human cancer due to the broad tropism of the vectors. Replication-incompetent retroviral vectors have the ability to dysregulate nearby cancer genes via several mechanisms including enhancer-mediated activation of gene promoters. The integrated provirus acts as a unique molecular tag for nearby candidate driver genes which can be rapidly identified using well established methods that utilize next generation sequencing and bioinformatics programs. Recently, retroviral vector screens have been used to efficiently identify candidate driver genes in prostate, breast, liver and pancreatic cancers. Validated driver genes can be potential therapeutic targets and biomarkers. In this review, we describe the emergence of retroviral insertional mutagenesis screens using replication-incompetent retroviral vectors as a novel tool to identify cancer driver genes in different cancer types.

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Driver and Passenger Mutations in Cancer

Cited by 293 publications

References 192 publications

Patterns of Transposable Element Expression and Insertion in Cancer

Patterns of Transposable Element Expression and Insertion in Cancer

The genetic heterogeneity of colorectal cancer predisposition - guidelines for gene discovery

Identifying Cancer Driver Genes Using Replication-Incompetent Retroviral Vectors

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