Integrated analysis of recurrent properties of cancer genes to identify novel drivers
© D'Antonio and Ciccarelli.; licensee BioMed Central Ltd. 2013
Received: 19 December 2012
Accepted: 29 May 2013
Published: 29 May 2013
The heterogeneity of cancer genomes in terms of acquired mutations complicates the identification of genes whose modification may exert a driver role in tumorigenesis. In this study, we present a novel method that integrates expression profiles, mutation effects, and systemic properties of mutated genes to identify novel cancer drivers. We applied our method to ovarian cancer samples and were able to identify putative drivers in the majority of carcinomas without mutations in known cancer genes, thus suggesting that it can be used as a complementary approach to find rare driver mutations that cannot be detected using frequency-based approaches.
In recent years, the completion of dozens of high-throughput sequencing screenings of cancer genomes led to the identification of >10,000 genes that bear at least one non-synonymous mutation. The discovery of such a wealth of mutations that progressively accumulate in the cancer genome was to some extent surprising and substantiated the idea of tumours as evolutionary systems where most acquired variations are 'passenger' because they do not have any direct role in promoting cancer. These mutations are fixed in the cancer cell population owing to the presence in the same cells of 'driver' mutations that instead confer growth advantages . The identification of the (few) driver mutations among the (many) passenger variants is therefore key to pinpoint genes and pathways that play an active role in cancer development and may be used as therapeutic targets. Unfortunately, the distinction between driver and passenger mutations is not straightforward, because of the high heterogeneity of the mutational landscape among and within cancer types . One of the most widely used approaches to identify novel cancer genes (that is, genes that harbour driver mutations) measures the gene mutation frequency, relying on the assumption that genes that are important for the development of a certain cancer type are recurrently mutated in several tumours [2–17]. Frequency-based methods led to the detection of unexpectedly high mutation frequency of isocitrate dehydrogenases 1 and 2, eventually linking these enzymes to the onset of leukaemia and glioma [12, 18]. They also contributed to better understand the genetic heterogeneity of cancer, leading to the observation that only few genes are mutated in the vast majority of tumour types, while most cancer genes are mutated at high frequency in one or few cancer types . Also the analysis of pathways instead of genes contributed to reduce the heterogeneity of cancer mutational landscape, because often the de-regulation of cancer-associated pathways can occur through the mutations of different components . Pathway analysis for example identified significant enrichment of mutations in BRCA1 and ATM pathways in breast cancer, and WNT and TGFβ signalling pathways in colorectal cancer . Although these processes were already known to be involved in tumorigenesis , only a systematic approach led to assign a likely driver role to new pathway components. Following conceptually similar approaches, several groups have analysed the proteins encoded by cancer genes in the context of the human protein-protein interaction network and identified network modules that are significantly associated with mutations [22–24]. Network analysis showed that cancer genes encode proteins that are highly connected and central inside the network [25, 26]. This has been interpreted as a sign of fragility of cancer genes towards perturbations, because modifications of proteins at the crossroad of multiple biological processes are likely to have harmful consequences . In addition to encoding highly connected and central proteins, cancer genes share also other systems-level properties (that is, global properties that do not strictly depend on the individual gene function) that distinguish them from the rest of human genes. For example, they tend to maintain only one single copy in the genome, which suggests an intrinsic sensitivity of cancer genes towards gene dosage imbalance . Moreover, cancer genes mostly appeared at two time points in evolution: caretakers and tumour suppressors are ancient genes that have orthologs also in prokaryotes, while gatekeepers and oncogenes were acquired with metazoans . This suggests that tumorigenesis may arise from the impairment of either very basic or regulatory processes . The existence of properties that distinguish cancer genes from the rest of human genes may be used to discriminate between driver and passenger mutations because mutated genes that have properties similar to known cancer genes are, in principle, more likely to harbour driver mutations, particularly when the mutations alter the protein function. In the last years, several methods to predict damaging mutations have been developed taking into account the site conservation throughout evolution and the possible effects on protein structure, as well as on splice-sites and UTRs [30–34]. In this study we developed an integrative method that uses tumour, gene and mutation properties to eventually predict novel drivers. As a proof of principle we applied our selection procedure to a panel of >300 ovarian carcinoma patients and identified genes with a putative driver role in >70% of tumours with previously unknown genetic determinants.
The mutational landscape is cancer-specific and recurrently mutated genes are long
Dataset of known, candidates and mutated cancer genes
Known cancer genes
Candidate cancer genes
Rest of mutated genes
Next, we checked whether gene length might influence the recurrent mutations of the same gene in multiple tumours, since longer genes are likely to host a higher number of mutations. Indeed we found positive correlation between the tendency of a gene to be recurrently mutated and its length, particularly in the case of mutated genes with no evidence of cancer involvement, but surprisingly also for candidates (Figure 1C). In both groups the vast majority of genes that are mutated in >10 cancer types have a coding portion longer than 4,450 bp (top 5% of the longest human genes). As a comparison, only five known cancer genes that are mutated in >10 cancer types (NF1, EP300, BRCA2, MLL, ARID1A) are longer than 4,450 bp. Although a positive correlation between gene length and the number of mutations was expected for genes harbouring passenger mutations, the fact that it was observed also for candidates, but not for known cancer genes, show that current methods do not completely correct for this effect.
Our survey of cancer somatic mutations confirmed that most of them are cancer- and sample-specific. Furthermore, gene length influences the recurrence of mutations and it should be taken into account when selecting candidates only on the basis of gene mutation frequency.
The majority of mutated genes are tissue-selective and lowly expressed
We further investigated whether mutated genes are expressed in the same tissues where they are mutated. Unfortunately, such a direct comparison was possible only for three studies that had both mutation and expression data on the same samples, including the whole genomes of acute myeloid leukaemia  and primary lung tumour , and the mutational screenings of 722 protein-coding genes in 207 sarcoma samples . In all three studies we found a clear distinction between known cancer genes, which are expressed in higher fraction than the rest of human genes, and other mutated genes, which instead are expressed in lower fraction (Figure 2C, Additional file 2, Table S2, chi squared test). To confirm that this is a general trend in all 20 cancer types with available mutation data, we checked for the expression of mutated genes in the corresponding healthy counterparts (Additional file 2, Table S3). We found that in the normal tissues corresponding to 18 of the 20 cancer types, the fraction of expressed known cancer genes is higher than the rest of expressed human genes, and in 14 cases this difference is statistically significant (Figure 2D and Additional file 2, Table S4, chi squared test). The majority of both candidates and other mutated genes are instead not expressed in the tissues where they were found mutated (Figure 2D, Additional file 1, Figure S2A, chi-squared test). The only significant exception were candidate cancer genes in myeloma, which were expressed in higher fraction than the rest of human genes, probably also because of an overall low expression of human genes in blood and bone marrow (Additional file 2, Table S4). Interestingly, even when mutated genes are expressed, their expression levels are lower than the median expression of non-mutated genes in the same tissues, while known or candidate cancer genes are expressed at levels comparable with the overall tissue median (Figure 2E, Additional file 1, Figure S2B, and Additional file 2, Table S5, chi-squared test).
Altogether, these data showed that cancer genes with driver mutations tend to be expressed in the tissue where they are mutated, while genes likely harbouring passenger mutations are generally not expressed. Expression can be therefore used as a further filter to distinguish passenger from driver mutations. Although this might be expected, so far gene expression has not been thoroughly exploited for identifying driver mutations and only a small fraction of published re-sequencing screenings of cancer genomes takes it into account to directly discriminate between driver and passenger mutations [43, 60] or to assess the background mutation rate .
Identification of novel drivers in ovarian carcinomas
We applied our pipeline to 318 ovarian carcinomas with available sequencing and expression data that could be obtained from the Cancer Genome Atlas and used with no restrictions. Furthermore, all ovarian carcinomas underwent whole exome sequencing and matched expression profiling , therefore they constituted the ideal cases for our analysis. Before applying the pipeline for the selection of new drivers, we confirmed that also for this set of patients, similarly to other cancer types (Figure 2C), known cancer genes tend to be expressed in the tumour where they are mutated, while the rest of mutated genes are poorly expressed (Figure 3B and Additional file 1, Figure S3). The vast majority of the analysed ovarian carcinomas (286/318, 90% of the total) had at least one known cancer gene (mostly TP53) that was mutated and expressed and were therefore discarded from further analysis. After applying all other filters, we identified 58 putative driver mutations in 56 genes that were mutated and expressed in 23 of the 32 ovarian carcinomas with previously unknown genetics determinants (72%, Figure 3C).
To test the performance of our method in detecting known cancer drivers, we applied it to 130 of the 318 ovarian carcinomas that had mutations in 31 known tumour suppressor genes (Additional file 1, Figure S4). We correctly identified the mutated tumour suppressor genes as the cancer drivers in almost all tumours (123 out of 130 Additional file 2, Table S6). Furthermore, in the same samples we also identified additional putative drivers that are known to co-operate in tumour development. For example, in tumours where we found TP53 mutations, we also identified genes such as CDH1 and CDKN2C that often co-mutate with TP53 and are known to have synergic tumour-suppressor activity [63–66]. Therefore, in addition to pinpoint novel drivers, our method could also be applied to search for second hits or co-operating genes that help tumour development. In this respect one interesting putative co-driver is NUMB, a gene that encodes a negative regulator of NOTCH  and prevents TP53 ubiquitination and degradation . The functional impairment of this gene upon damaging mutation might thus enhance tumour development because of the activation of the NOTCH oncogene and the degradation of TP53 tumour suppressor.
Novel drivers of ovarian cancer resemble tumour suppressors and affect gene transcription, cell proliferation and survival
We had several indications that the mutated genes that we identified as putative drivers might indeed play an active role in ovarian carcinogenesis.
First, in addition to being all predicted as damaging by at least two out of three predictors (see Methods), 60% of the 58 mutations either modified protein functional domains or removed >50% of the protein sequence (Additional file 2, Table S7). Furthermore, the vast majority (77%) of the genomic sites where the mutation occurred are highly conserved among vertebrates (MultiZ score >0.95)  (Additional file 2, Table S7). Both these observations suggest a likely functional role of the mutations.
Putative novel drivers in ovarian cancer
Ovarian carcinoma sample
Ovarian cell lines with increased proliferation
Amino acid metabolism
Antigen receptor signalling
Finally, we investigated the association of the 56 putative driver genes with pathways known to be involved in ovarian cancer onset. We found that 13 of the 23 tumours (57% of the total) harboured mutations in 19 genes belonging to pathways that control cell proliferation and survival, including the RB and PI3K/RAS signalling pathways, which are altered in 67% and 45% of ovarian cancers, respectively  (Figure 4D). RNAi data were available for 14 out of these 19 genes and in all cases gene silencing led to increased proliferation in at least one ovarian cancer cell line and the block of eight genes (KDM5B, TIAM1, RAGEF2, PRKCQ, VAV1, PTPRG, RBL2 and MCM4) favoured cell growth in the majority of cell lines (Figure 4D). Although for the remaining 10 tumours no such a direct link with ovarian cancer could be drawn, six of them had alterations in gene transcription and in other two cases a general association with cancer could be made (Table 2). Therefore, overall >90% of tumours harboured genomic alterations in pathways associated with cancer.
The central tenet of our study was that cancer driver mutations occur in genes with peculiar properties and, therefore, such properties can be used to identify novel cancer genes. For example we showed that cancer genes with an established driver role are usually expressed in the tissue where they are mutated, thus suggesting that mutations in genes that are not expressed are neutral or passenger. In support to our results, the vast majority of cancer somatic mutations have been shown to occur in genomic regions associated with repressive chromatin marks . This indicates that indeed most cancer mutations are neutral and occur in transcription-silent regions of the genome.
In addition to expression profiles, we analysed the evolutionary, genomics and network properties of genes mutated in 32 ovarian cancer carcinomas with previously unknown genetics determinants. These tumours constitute only a small fraction of ovarian carcinomas (approximately 10% of the initial set) since the large majority of affected individuals bear mutations in known cancer genes, in particular in TP53. Although cancer is usually the outcome of the alteration of several genes and multiple drivers are required for cancer progression , we reasoned that focusing on tumours with no mutation in known cancer genes could increase the chances to find novel drivers. Furthermore, this would also help identifying a possible cause of cancer onset and development also in tumours that harbour rare mutations. With our approach we were indeed able to find 56 putative cancer genes in >70% of previously uncharacterized tumours, thus significantly reducing the fraction of patients with unknown cancer determinants. In the vast majority of cases, at least one of the putative drivers exerts a function in pathways that are altered in ovarian cancer. This confirms that the high heterogeneity of the cancer mutational landscape is reduced when considering biological processes rather than single genes .
As a comparison with our method, we investigated whether the 56 putative cancer genes had also been detected in the original study on the same set of ovarian carcinomas , which also identified possible cancer genes using a variety of approaches, from gene mutation frequency to pathway and network analysis . Our list of putative drivers showed very poor overlap with the genes identified in the original study, mainly because the latter were for the vast majority already known cancer genes or had no expression data, and were therefore discarded from our analysis. Interestingly, some overlap existed between our list of 56 drivers and the network modules that were significantly mutated in ovarian cancer . In particular, we identified five genes in common between the two lists. The silencing via RNA interference of three of these five genes (VAV1, TAF12 and GTF3) resulted in increased proliferation in at least 10 ovarian cancer cell lines. This strongly suggests a role of tumour suppression of these genes, and this is worth further experimental investigation.
Our analysis showed that the integration of several sources of information allows the identification of rare cancer genes. This may be of particular utility in tumours with no known driver mutations or where frequency-based methods cannot be applied. However, we also showed that an integrated analysis may be useful for the identification of mutated genes that may cooperate in promoting tumour development. The poor overlap with previous findings in the same set of tumour samples demonstrates that our approach is complementary to frequency-based methods. The integration of several methods based upon different theoretical assumptions may therefore result in a better and more complete characterization of the mutational landscape of cancer.
Gene sets used in the analysis
To derive a dataset of unique human genes (that is, genes with a unique locus in the genome), 33,398 protein sequences were retrieved from RefSeq v.51  and aligned to the human reference genome (hg19) using BLAT . In case of multiple isoforms aligning to the same locus, only the longest was retained . Only genes located on autosomal chromosomes and chromosome × were considered for further analysis, for a total of 19,009 unique human genes. Gene length was calculated as the coding portion of the longest isoform for each locus.
The dataset of 10,681 genes with at least one somatic non-synonymous mutation in cancer was collected from 39 mutational screenings of cancer tissues [2, 4–18, 35–57] (Table 1, Additional file 2, Table S1). Genes were grouped into three classes: (1) known cancer genes included all genes whose mutations or amplifications are known to be involved in tumorigenesis (Cancer Gene Census, frozen on 15 November 2011, and Census of Amplified Genes in Cancer) [58, 59]; (2) candidate cancer genes that were found recurrently mutated in different tumour samples and, therefore, likely to harbour driver mutations (candidates were extracted directly from the corresponding experiments, Additional file 2, Table S1); (3) genes with low frequency non-synonymous mutations. The rest of human genes used for comparison were defined as all human genes with either no mutations or only synonymous mutations (Table 1).
Expression of mutated genes in normal and cancer tissues
Expression data for 12,397 genes in 109 healthy tissues were derived from two microarray experiments on 36  and 73  normal human tissues, respectively, for a total of 109 unique tissues. The raw CEL files were downloaded from the corresponding series (GSE2361 and GSE1133) stored in the Gene Expression Omnibus (GEO) , normalised and analysed using the MAS5 algorithm included in the R affy package [79, 80] (Additional file 2, Table S10). Given that more than one probe could be associated with a single gene, a gene was labelled as 'expressed' if at least half of the corresponding probes had detection P values <0.05. Housekeeping genes were defined as genes expressed in at least 98% of the tissues (107/109), while tissue-specific genes were expressed in <25% of the tissues (27/109).
To test whether the fraction of housekeeping mutated genes (known, candidates and rest of genes with non-synonymous mutations) was different from the fraction of housekeeping genes among the rest of human genes, Fisher's exact test with one degree of freedom was used. Fisher's test was used because of the small number of genes that were compared (only 10 candidate genes were housekeeping). The same test was applied to assess the differences in the fraction of tissue-specific genes between mutated and non-mutated genes.
For three of the 39 mutational screenings [36, 43, 44], both expression and mutation data were available for each analysed tumour sample. The raw CEL files were downloaded from GEO and the data were processed as described for the normal tissues (Additional file 2, Table S10). Since the study by Barretina et al.  reported the mutational screen of 722 genes and only a small number of mutations were detected in each sample, tumours were clustered into four groups, on the basis of the tumour subtype (Additional file 2, Table S4). A pipeline similar to that described for the analysis of normal tissues was applied to determine whether higher fraction of cancer genes were expressed in the cancer tissues where they were also mutated. Briefly, the fractions of expressed mutated and non-mutated genes in each tumour sample were compared using chi-squared test with one degree of freedom, in each sample. As for the other analyses, the results were displayed as volcano plots where each log2ratios of the fractions of expressed genes between mutated genes and non-mutated genes were displayed in association with the corresponding P values of the chi-squared test.
Analysis of ovarian carcinoma samples
Genes mutated in ovarian carcinomas were derived from the Cancer Genome Atlas . In addition to all validated somatic mutations (data level 3), the raw CEL files of the expression data corresponding to the same tumour sample were also retrieved (platform HG_U133A, data level 1, Additional file 2, Table S10). Of the 323 tumours, five were removed because they did not undergo whole exome sequencing. The fraction of expressed and mutated genes was calculated for each carcinoma as described above, and compared with the corresponding fraction of expressed and non-mutated human genes using the chi-squared test (one degree of freedom). Starting from the list of all mutated genes, several filters were applied to identify putative driver mutations (Figure 3A). First, carcinomas with mutations in at least one known cancer gene from the Cancer Gene Census  and those with no expression data for any mutated gene were discarded. Second, three different predictors (SIFT , Polyphen  and MutationTaster ) were applied to infer the effect of mutations. Only frameshift, nonsense and splice-site mutations, as well as missense mutations predicted as damaging by two out the three predictors (SIFT score >0.95, Polyphen score >0.9, or labelled as 'disease causing' by MutationTaster ) were retained. Third, the gene length of the coding portion was taken into account and all genes in the bottom 95% of gene length were retained (coding length <4,450 bp). Genes longer than 4,450 bp were retained only if mutated in less than five different cancer types. This filter discarded genes that mutate at high frequency because of their length. Finally four systemic properties were investigated: protein connectivity and centrality in the protein-protein interaction network; interaction(s) with known cancer proteins; evolutionary origin; and duplicability. To measure protein connectivity and to determine the occurrence of direct interactions with known cancer proteins, data on 98,492 experimentally proven protein-protein interactions between 13,531 human proteins were integrated from five databases (HPRD , BioGRID , IntAct , MINT  and DIP ), as previously described . The IGRAPH module for R [89, 90] was used to measure degree, betweenness and direct interactions with known cancer proteins. Central hubs were defined as the 25% most connected (degree >14) and most central (betweenness >9,198) proteins of the network. Evolutionary origin and gene duplicability were defined as previously described . Briefly, gene origin was traced as the most ancient node of the tree of life where orthologs for a given human gene could be found. A gene was defined as duplicated if at least one human paralog was present in the corresponding cluster of orthologs, otherwise it was considered as singleton. All scripts used to run this pipeline are available as Additional file 3.
Effect of gene silencing on cell proliferation using RNA interference
Where m and n are the number of replicates in the considered cell line h and in the reference DNA pool, respectively. Having a median of five probes associated with a single gene, only the top-scoring shRNA value among all probes was considered as the representative effect of that gene on cell proliferation in order to minimise the false positives . The ratio was preferred to the difference between cell lines and DNA pool (as in the original paper ) in order to better appreciate the modifications in the cell proliferation caused by gene silencing. To measure the overall effect on gene proliferation of the silencing of known cancer genes, the log2ratio shRNA distributions between 395 genes (95 tumour suppressors and 300 oncogenes) from the Cancer Gene Census with at least one shRNA probe and the rest of 10,546 non-mutated genes in all 102 cancer cell lines were compared (Figure 4A). Shapiro-Wilk test was applied to control for the shape of the distributions. Since the distribution could not be considered as normal (P value <10-50, Additional file 1, Figure S5), Wilcoxon test was used to assess the differences between them. For the analysis on ovarian cancer, only the 25 ovarian cancer cell lines and 15 known cancer genes (seven tumour suppressors and eight oncogenes) that were associated with ovarian cancer in the original annotation of the Cancer Gene Census were considered (Figure 4B).
We thank the members of the Ciccarelli lab for useful discussion. This work was supported by the Italian Association for Cancer Research (AIRC-IG 12742) and by the 'Giovani Ricercatori' Grant of the Italian Ministry of Health to FDC.
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