Predicting cancer drivers: are we there yet?
© BioMed Central Ltd. 2012
Published: 26 November 2012
Genomic variants with a key role in causing cancer or affecting the response to cancertherapeutics need to be identified so that they can be targeted for therapy. The transFIC tool aimsto identify somatic point mutations that drive cancer in sequencing projects. This package isavailable as a web service, a stand-alone program and a website. It improves the functionalprediction scores generated by popular established prediction tools and will be useful to cancerresearchers.
See research article: http://genomemedicine.com/content/4/11/89
The functional impact of cancer-associated mutations
Mutations give rise to cancerous cells by affecting genes. For example, 'gain of function'mutations in oncogenes such as EGFR and KRAS promote tumor progression, and 'lossof function' mutations in the tumor-suppressor gene TP53 promote cancer by dysregulatingthe cell cycle. Mutations that provide a selective growth advantage to the cancer cell are called'driver' mutations. 'Passenger' mutations, by contrast, are present in cancer genomes but do notgive such a growth advantage.
Identifying driver genes is important for clinical applications. If certain mutations are presentin specific cancer-associated genes, then the cancer drugs that target these genes and theirrespective pathways might behave differently, thus affecting the treatment outcome. For example, theBRAF gene encodes a serine/threonine kinase and is known to contain activating somaticmutations in melanomas, colorectal cancer and other cancers . In a metastatic colorectal cancer study, it was reported that none of the patients withBRAF mutations responded to treatment with the drugs panitumumab or cetuximab . Thus, activating somatic mutations can affect drug sensitivities.
Identifying driver and passenger mutations
When sequencing a cancer genome, somatic single base substitutions can number in the tens ofthousands . Sifting through these somatic single nucleotide variants (SNVs) to pin down the fewdriver mutations implicated in cancer is a challenge. Most researchers concentrate on the somaticmutations that cause missense changes in gene products. This focus helps to reduce the number ofmutations for further investigation.
To achieve the ultimate goal of distinguishing driver mutations from passenger mutations, oneapproach is to sequence many cancer samples and then identify the highly mutated genes and/or therecurrent mutations across all of the samples. The disadvantage of this approach is that many cancersamples need to be sequenced, and it is not straightforward to prioritize genes with a small numberof somatic mutations. To supplement this approach, one could look at the severity of the mutationsin the gene and assess whether they change the gene's function. It may be possible to detect drivergenes in addition to the frequently mutated genes by using this supplementary approach. In this way,some of the genes with a smaller number of mutations would gain stronger support as cancer-causinggenes as opposed to background noise .
Available cancer missense mutation prediction tools
Stand-alone software, website
Genomic coordinates in space
Tab-delimited format. RefSeq, CCDS or Ensembl identifiers, together with the respective aminoacid change
Passenger mutation rate information is available for specific types of cancer
Protein sequence and a list of amino acid changes
A list of RefSeq accession identifiers with amino acid changes
Users can simultaneously analyze various combinations of mutations in a single proteinsequence
Batch submission is available only with protein RefSeq identifiers
SIFT score and alignment
Pfam domain and GO analysis
Web service, stand-alone, website
Users can upload up to 300 mutations at a time and run up to 20 jobs (on the website)
Transformed prediction scores from SIFT, PolyPhen-2, MutationAssessor and CHASM
COSMIC and/or dbSNP annotations
Website, Web API
Users can analyze a list of mutations (on the website)
Batch submission is available
Functional Impact score
Link to three-dimensional protein structure
UniProt and RefSeq identifiers
Cancer Gene Census and COSMIC annotations
Gene and protein domain annotations
Mapped reads from a set of tumor and normal sample pairs in BAM format
Predicted or validated SNVs and indels from the cohort in MAF format
Regions of interest to users (such as exon-intron boundaries) in BED format
Any available clinical information
Users can analyze whole genomes and/or exomes
Significantly mutated genes and/or pathways
Annotations for known databases
Links mutations to user-provided clinical information
In this issue of Genome Medicine, Abel Gonzalez-Perez, Jordi Deu-Pons and NuriaLopez-Bigas  have developed a computational method called transFIC (TRANSformed Functional Impact forCancer) to predict somatic mutations that are putative drivers of tumorigenesis. The authors madethe initial observation that cancer-associated genes are less likely to have deleterious germlinevariation than genes that are not involved in cancer. Based on this observation, transFIC firstlooks at the scores generated by a missense prediction tool such as SIFT, PolyPhen-2,MutationAssessor  or CHASM. It then normalizes the initial prediction scores by taking into account agene's tolerance to deleterious germline variation. The transformed scores are used to rank thesomatic mutations that have functional effects, and mutations with higher transFIC scores areconsidered candidate cancer drivers. This process improves the performance of the original scoresfrom pre-existing tools, by approximately a twofold to sevenfold increase in the Matthew'scorrelation coefficient, on various datasets.
In summary, the transFIC prediction tool reported by Gonzalez-Perez et al. has manyuser-friendly features to discriminate cancer driver mutations from mutations that are neutral.TransFIC could be of great use to the cancer research community because it improves the functionalimpact scores of four well-known tools and uses these transformed scores to prioritize mutations.This tool also has the potential to be useful in cancer resequencing projects to predict thefunctional impact of somatic cancer mutations.
Beyond driver mutations
The validation of driver mutations will be easier in the future because lower sequencing costswill allow the deep sequencing of tumor samples. Because driver mutations are expected to occurearly in the development of cancer cells, these mutations will tend to be present at higherfrequencies in a cancer sample than passenger mutations, which occur later. Deep sequencing providesbetter estimates of mutation frequencies compared to sequencing at medium coverage and thereforedeep sequencing helps distinguish driver and passenger mutations.
After distinguishing these two types of mutations, it is crucial to pinpoint the keycancer-causing genes and pathways. Software packages such as MuSiC  and MutSig  aid in this step by prioritizing genes that are significantly mutated. These packagesidentify frequently mutated genes, pathways and gene families across a group of patients for variouscancer types, and they also highlight clinically relevant mutations. This entire process could allowbetter treatment. For example, the My Cancer Genome website  captures cancer variation and the reported drug responses for various cancers. Thisinformation can then make doctors aware of the outcome of a patient's drug response based on thepatient's genotype. Discovery and distribution of this knowledge will lead to improved personalizedcancer treatment.
List of abbreviations used
Application Programming Interface
Browser Extensible Data
Consensus CoDing Sequence Project
Cancer-specific High-throughput Annotation of SomaticMutations
Catalogue of Somatic Mutations in Cancer
Single Nucleotide Polymorphismdatabase
Mutation Annotation Format
Mutational Significance in Cancer
Sorting Intolerant From Tolerant
TRANSformed Functional Impact for Cancer
Uniform Resource Locator.
We thank Dr Francesca Menghi and Dr Joyce Suling Lin for proof-reading. We apologize if we haveneglected to cite cancer tools or references because of space limitations.
- Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, et al: Mutations of the BRAF gene in human cancer. Nature. 2002, 417: 949-954. 10.1038/nature00766.View ArticlePubMedGoogle Scholar
- Di Nicolantonio F, Martini M, Molinari F, Sartore-Bianchi A, Arena S, Saletti P, De Dosso S, Mazzucchelli L, Frattini M, Siena S, Bardelli A: Wild-type BRAF is required for response to panitumumab or cetuximab in metastaticcolorectal cancer. J Clin Oncol. 2008, 26: 5705-5712. 10.1200/JCO.2008.18.0786.View ArticlePubMedGoogle Scholar
- Pleasance ED, Cheetham RK, Stephens PJ, McBride DJ, Humphray SJ, Greenman CD, Varela I, Lin ML, Ordóñez GR, Bignell GR, Ye K, Alipaz J, Bauer MJ, Beare D, Butler A, Carter RJ, Chen L, Cox AJ, Edkins S, Kokko-Gonzales PI, Gormley NA, Grocock RJ, Haudenschild CD, Hims MM, James T, Jia M, Kingsbury Z, Leroy C, Marshall J, Menzies A, et al: A comprehensive catalogue of somatic mutations from a human cancer genome. Nature. 2010, 463: 191-196. 10.1038/nature08658.View ArticlePubMed CentralPubMedGoogle Scholar
- Carter H, Chen S, Isik L, Tyekucheva S, Velculescu VE, Kinzler KW, Vogelstein B, Karchin R: Cancer-specific high-throughput annotation of somatic mutations: computational prediction ofdriver missense mutations. Cancer Res. 2009, 69: 6660-6667. 10.1158/0008-5472.CAN-09-1133.View ArticlePubMed CentralPubMedGoogle Scholar
- Kaminker JS, Zhang Y, Watanabe C, Zhang Z: CanPredict: a computational tool for predicting cancer-associated missense mutations. Nucleic Acids Res. 2007, 35: W595-W598. 10.1093/nar/gkm405.View ArticlePubMed CentralPubMedGoogle Scholar
- Gonzalez-Perez A, Deu-Pons J, Lopez-Bigas N: Improving the prediction of the functional impact of cancer mutations by baseline tolerancetransformation. Genome Med. 2012, 4: 89-10.1186/gm390.View ArticlePubMed CentralPubMedGoogle Scholar
- Reva B, Antipin Y, Sander C: Predicting the functional impact of protein mutations: application to cancer genomics. Nucleic Acids Res. 2011, 39: e118-10.1093/nar/gkr407.View ArticlePubMed CentralPubMedGoogle Scholar
- Dees ND, Zhang Q, Kandoth C, Wendl MC, Schierding W, Koboldt DC, Mooney TB, Callaway MB, Dooling D, Mardis ER, Wilson RK, Ding L: MuSiC: identifying mutational significance in cancer genomes. Genome Res. 2012, 22: 1589-1598. 10.1101/gr.134635.111.View ArticlePubMed CentralPubMedGoogle Scholar
- Cancer Genome Analysis Tool. [https://confluence.broadinstitute.org/display/CGATools/MutSig]
- Personalized Cancer Medicine Resource. [http://www.mycancergenome.org/]