‘Latent drivers’ expand the cancer mutational landscape
Introduction
All cancer cells carry mutations in their genomes; some are inherited, others gained. Most mutations appear during normal cell growth [1••, 2••]. Pre-neoplastic mutations have been postulated to be ‘passengers’ as are most of those that emerge during cancer development. Driver mutations have been causally implicated in oncogenesis by conferring clonal selective advantage with the cell acquiring some of the hallmarks of cancer [3, 4, 5, 6]. Driver mutations also emerge in drug resistance. Cancer is an evolutionary process [7, 8], driven by somatic-cell mutational events with sequential, subclonal selection [9]. Mutation rates vary, and depend on the cancer type and its environment [10, 11, 12]. Applying the evolutionary clock model to tumor mutational data suggested that the vast majority of the mutations in metastatic lesions were already present in a large number of cells in the primary tumor [1••]. Similar to organ development [7], the long time period which is usually required for cancer symptoms to emerge reflects not only the evolutionary time, but the complexity of the mutational landscape. In contrast, drug resistance typically emerges on short timescales, begging the question of why.
The important question of why the development of the primary cancer can take a long period of time while drug resistance typically arises very rapidly is puzzling. Many resistance mechanisms may contribute. These include genomic rearrangements, deletions, as for example observed in Raf's deletion of the Ras binding domain, alternative signaling venues, for example other receptors taking over following EGFR's inhibition [13], or other mechanisms side-stepping regulatory controls [14, 15, 16]. Below we hypothesize that among these the many overlooked ‘latent driver’ mutations may bear on this conundrum. Our ‘latent driver’ hypothesis rests on a conformational view of protein molecules where mutations may incrementally shift the protein ensembles toward populating a constitutively active (or inactive for a repressor protein) state [17••]. While the extent of the shift by a pre-existing mutation may be small — which could be the reason why it escaped discovery — combinatorial emergence of a cooperative second may switch the protein and the cell to a constitutively active (or inactive) state bearing a cancer hallmark. Figure 1 presents a schematic diagram and its legend explains the differences between a driver mutation, a passenger mutation and a latent driver mutation, and how a latent mutation can work, summarizing the main concept of this paper.
Section snippets
The cancer mutational landscape
Cancers vary [9]. Most mutations are passengers and do not confer selective advantage; a few can be functionally relevant drivers. They can be point mutations, or other genetic aberrations, such as higher gene copy number, deletions, inversions, and translocations [18]. They can lead to over-expression or under-expression, or dysfunctional gene products. Most translocations appear to be passengers. There are ∼10 times fewer genes affected by chromosomal changes than by point mutations, and the
Driver and passenger mutations
A driver mutation confers growth advantage; a passenger mutation does not. Passenger mutations populate cancer genomes prior to the emergence of driver mutations [12]. Age-related statistics suggested 5–7 driver mutations in epithelial cancers such as breast, colorectal and prostate [19]; more recent analyses indicated that the number could be much higher [20].
Driver mutations can affect recruitment or catalysis. In recruitment, driver point mutations can be at the interface [21] and
The concept of ‘latent driver’ mutations
Currently, the classification is binary: a mutation is designated as either a driver or a passenger. This classification is important since it provides the genetic basis for cancer treatment decisions [17••]. Statistics is a primary factor in this classification [3, 4]. However, low statistics and lack of observable cancer hallmark effects do not necessarily imply that a passenger mutation does not harbor potential oncogenic effects. Here we suggest a modification of this assignment model.
Latent driver mutations can be understood through allosteric integration mechanisms
Signal transduction rarely reflects a single signaling source [34, 35]. Multiple signaling events act on a protein node, including binding and post-translational modifications, and the signal integration mechanisms govern the output response. In electronics, there are three types of logic gate mechanisms. We adopt these to describe a protein switching from an inactive to an active state (or vice versa): OR, AND or Graded. For the case of two allosteric events, in an OR gate one allosteric event
Approaches to differentiate between driver and passenger mutations
The catalog of somatic mutations establishes the record of mutations that accumulated in the cancer cell throughout the lifetime of the patient. Databases compiling these, such as COSMIC and TCGA have led to important discoveries [37••, 45, 46•, 47, 48, 49]; however, they are still predominantly unmined. Broadly, cancer genome analysis aims to identify cancer genes that carry driver mutations; thus, a key challenge is to distinguish oncogenic driver mutations from their neutral passenger
Conclusions
The number of observed driver mutations in solid tumors is smaller than that expected for tumor development and progression. Several explanations have been offered to explain the ‘missing mutations’, including technical issues, statistical problems, exclusion of the tumor stromal environment, accounting only for coding regions, and overlooking epigenetic effects [1••]. Latent drivers which are counted as passengers can be added to this list. Latent drivers’ actions are triggered by changes in
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under contract number HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was supported (in part) by the Intramural Research Program of the
References (64)
- et al.
The hallmarks of cancer
Cell
(2000) - et al.
Evaluation of candidate tumour suppressor genes on chromosome 18 in colorectal cancers
Nat Genet
(1996) - et al.
Allostery in disease and in drug discovery
Cell
(2013) - et al.
Cancer as an evolutionary and ecological process
Nat Rev Cancer
(2006) - et al.
Clonal evolution in cancer
Nature
(2012) - et al.
Antitumor activity of the selective Pan-RAF inhibitor TAK-632 in BRAF inhibitor-resistant melanoma
Cancer Res
(2013) - et al.
The structural pathway of interleukin 1 (IL-1) initiated signaling reveals mechanisms of oncogenic mutations and SNPs in inflammation and cancer
PLoS Comp Biol
(2014) - et al.
The molecular basis of targeting protein kinases in cancer therapeutics
Semin Cancer Biol
(2013) - et al.
Structures of lung cancer-derived EGFR mutants and inhibitor complexes: mechanism of activation and insights into differential inhibitor sensitivity
Cancer Cell
(2007) - et al.
Allosteric conformational barcodes direct signaling in the cell
Structure
(2013)