Human cancers express mutator phenotypes: origin, consequences and targeting

Loeb, Lawrence A.

doi:10.1038/nrc3063

Cited by 358 publications

(308 citation statements)

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“…This is illustrated, for example, by exomic sequencing of separate, histologically distinct regions micro‐dissected from individual human pancreatic ductal carcinomas (PDACs): each showed a specific mutational repertoire indicative of multiple subclonal populations within the same primary tumor (Yachida et al., 2010). Consistent with these findings, recent whole‐genome deep (or high‐throughput) sequencing analysis of individual tumors has revealed that a particular tumor specimen may contain up to 50,000 different non‐synonymous mutations affecting several hundred genes, with mutation rates of 0.5–20 per megabase (Loeb, 2011; Sellers, 2011). As opposed to exomic sequencing, unbiased whole‐genome deep sequencing should in principle be able to detect complex genetic rearrangements, insertions and deletions, which may enact pivotal gain‐ and loss‐of‐function driver events not manifested by point mutations, as shown recently in prostate cancer (Berger et al., 2011).…”

Section: Addressing Tumor Heterogeneity and Complexitymentioning

confidence: 69%

“…As opposed to exomic sequencing, unbiased whole‐genome deep sequencing should in principle be able to detect complex genetic rearrangements, insertions and deletions, which may enact pivotal gain‐ and loss‐of‐function driver events not manifested by point mutations, as shown recently in prostate cancer (Berger et al., 2011). The remarkable number of mutations found in cancer genomes supports the notion that cancers express a “mutator phenotype” that is an enabling characteristic for acquisition of hallmark capabilities, caused for example by loss‐of‐function mutations in genes that maintain genomic integrity (Hanahan and Weinberg, 2011; Loeb, 2011). …”

Section: Addressing Tumor Heterogeneity and Complexitymentioning

confidence: 81%

“…This figure is suspected to be an underestimation of the mutational landscape of individual tumors, as the analytic techniques that have been used most frequently, such as PCR‐based sequencing of DNA extracted from total tumor lysates, may not detect mutations occurring in subclonal tumor cell populations (Loeb, 2011; Sellers, 2011). This is illustrated, for example, by exomic sequencing of separate, histologically distinct regions micro‐dissected from individual human pancreatic ductal carcinomas (PDACs): each showed a specific mutational repertoire indicative of multiple subclonal populations within the same primary tumor (Yachida et al., 2010).…”

Section: Addressing Tumor Heterogeneity and Complexitymentioning

confidence: 99%

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The biology of personalized cancer medicine: Facing individual complexities underlying hallmark capabilities

2012

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It is a time of great promise and expectation for the applications of knowledge about mechanisms of cancer toward more effective and enduring therapies for human disease. Conceptualizations such as the hallmarks of cancer are providing an organizing principle with which to distill and rationalize the abject complexities of cancer phenotypes and genotypes across the spectrum of the human disease. A countervailing reality, however, involves the variable and often transitory responses to most mechanism‐based targeted therapies, returning full circle to the complexity, arguing that the unique biology and genetics of a patient's tumor will in the future necessarily need to be incorporated into the decisions about optimal treatment strategies, the frontier of personalized cancer medicine. This perspective highlights considerations, metrics, and methods that may prove instrumental in charting the landscape of evaluating individual tumors so to better inform diagnosis, prognosis, and therapy. Integral to the consideration is remarkable heterogeneity and variability, evidently embedded in cancer cells, but likely also in the cell types composing the supportive and interactive stroma of the tumor microenvironment (e.g., leukocytes and fibroblasts), whose diversity in form, regulation, function, and abundance may prove to rival that of the cancer cells themselves. By comprehensively interrogating both parenchyma and stroma of patients' cancers with a suite of parametric tools, the promise of mechanism‐based therapy may truly be realized.

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Section: Addressing Tumor Heterogeneity and Complexitymentioning

confidence: 69%

Section: Addressing Tumor Heterogeneity and Complexitymentioning

confidence: 81%

Section: Addressing Tumor Heterogeneity and Complexitymentioning

confidence: 99%

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The biology of personalized cancer medicine: Facing individual complexities underlying hallmark capabilities

2012

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“…Arising from a single cell, with its own spectrum of unique somatic mutations that accumulated over the more than 50 rounds of cell division since fertilization of the egg, a million or more cells arise that share the same set of clonally amplified somatic mutations (both drivers and passengers). In parallel, many low-abundance mutations arise as a consequence of what has been termed a mutator phenotype, resulting from mutations in genes involved in genome maintenance[106]. This creates a large degree of mutational heterogeneity within the tumor.…”

Section: Mps Applications In Mutation Analysismentioning

confidence: 99%

Direct mutation analysis by high-throughput sequencing: From germline to low-abundant, somatic variants

Gundry

Vijg

2012

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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DNA mutations are the source of genetic variation within populations. The majority of mutations with observable effects are deleterious. In humans mutations in the germ line can cause genetic disease. In somatic cells multiple rounds of mutations and selection lead to cancer. The study of genetic variation has progressed rapidly since the completion of the draft sequence of the human genome. Recent advances in sequencing technology, most importantly the introduction of massively parallel sequencing (MPS), have resulted in more than a hundred-fold reduction in the time and cost required for sequencing nucleic acids. These improvements have greatly expanded the use of sequencing as a practical tool for mutation analysis. While in the past the high cost of sequencing limited mutation analysis to selectable markers or small forward mutation targets assumed to be representative for the genome overall, current platforms allow whole genome sequencing for less than $5,000. This has already given rise to direct estimates of germline mutation rates in multiple organisms including humans by comparing whole genome sequences between parents and offspring. Here we present a brief history of the field of mutation research, with a focus on classical tools for the measurement of mutation rates. We then review MPS, how it is currently applied and the new insight into human and animal mutation frequencies and spectra that has been obtained from whole genome sequencing. While great progress has been made, we note that the single most important limitation of current MPS approaches for mutation analysis is the inability to address low-abundance mutations that turn somatic tissues into mosaics of cells. Such mutations are at the basis of intra-tumor heterogeneity, with important implications for clinical diagnosis, and could also contribute to somatic diseases other than cancer, including aging. Some possible approaches to gain access to low-abundance mutations are discussed, with a brief overview of new sequencing platforms that are currently waiting in the wings to advance this exploding field even further.

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“…In addition to the polymerase activity, Pol d and Pol e possess 3 0 to 5 0 exonuclease activity, which enables them to proofread errors that may have occurred during DNA replication [Thomas et al, 1991;Uitto et al, 1992;McCulloch et al, 2008]. The exonuclease proofreading activity increases the fidelity of DNA synthesis thereby suppressing mutagenesis and preventing diseases such as cancer [Loeb, 2011].…”

Section: Dna Replicationmentioning

confidence: 99%

Mouse models of DNA polymerases

Menezes¹,

Sweasy²

2012

Environ and Mol Mutagen

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In 1956, Arthur Kornberg discovered the mechanism of the biological synthesis of DNA and was awarded the Nobel Prize in Physiology or Medicine in 1959 for this contribution, which included the isolation and characterization of Escherichia coli DNA polymerase I. Now there are 15 known DNA polymerases in mammalian cells that belong to four different families. These DNA polymerases function in many different cellular processes including DNA replication, DNA repair, and damage tolerance. Several biochemical and cell biological studies have provoked a further investigation of DNA polymerase function using mouse models in which polymerase genes have been altered using gene-targeting techniques. The phenotypes of mice harboring mutant alleles reveal the prominent role of DNA polymerases in embryogenesis, prevention of premature aging, and cancer suppression. Environ. Mol. Mutagen. 53:645-665, 2012. V V C 2012 Wiley Periodicals, Inc.

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Human cancers express mutator phenotypes: origin, consequences and targeting

Cited by 358 publications

References 109 publications

The biology of personalized cancer medicine: Facing individual complexities underlying hallmark capabilities

The biology of personalized cancer medicine: Facing individual complexities underlying hallmark capabilities

Direct mutation analysis by high-throughput sequencing: From germline to low-abundant, somatic variants

Mouse models of DNA polymerases

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