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The vast amount of available sequencing data allows the scientific community to explore different genetic alterations that may drive cancer or favor cancer progression. Software developers have proposed a myriad of predictive tools, allowing researchers and clinicians to compare and prioritize driver genes and mutations and their relative pathogenicity. However, there is little consensus on the computational approach or a golden standard for comparison. Hence, benchmarking the different tools depends highly on the input data, indicating that overfitting is still a massive problem. One of the solutions is to limit the scope and usage of specific tools. However, such limitations force researchers to walk on a tightrope between creating and using high-quality tools for a specific purpose and describing the complex alterations driving cancer. While the knowledge of cancer development increases daily, many bioinformatic pipelines rely on single nucleotide variants or alterations in a vacuum without accounting for cellular compartments, mutational burden or disease progression. Even within bioinformatics and computational cancer biology, the research fields work in silos, risking overlooking potential synergies or breakthroughs. Here, we provide an overview of databases and datasets for building or testing predictive cancer driver tools. Furthermore, we introduce predictive tools for driver genes, driver mutations, and the impact of these based on structural analysis. Additionally, we suggest and recommend directions in the field to avoid silo-research, moving towards integrative frameworks.

In eukaryotes, cellular differentiation is often orchestrated by programmed arrays of activation and repression of genes underlying the specific phenotypes of cell-types. To complete its life cycle, the single-celled Apicomplexan parasite Plasmodium falciparum, the most deadly of the human malaria parasites, must repeatedly differentiate and convert into unique cell types that can exploit niches within their human and mosquito hosts. One of these key developmental transitions occurs in the human host and includes sexual-stage commitment, followed by gametocyte development, which results in male and female gametocytes that can infect the female anopheline mosquito once taken up during the blood meal. The following gamete stage undergoes fusion and meiosis, followed by morphological changes as they invade the midgut wall to form the oocyst. The sexual stages are responsible for malaria transmission and the spread of antimalarial resistance, making it an important target for malaria eradication. Previous studies have established the understanding of a few mechanisms involved in sexual differentiation; the transcription factor, AP2-G, is a master regulator of sexual commitment. Uncovering genes and regulators underlying P. falciparum sexual stage development, including host-parasite interactions are the subjects of this thesis. In paper I, we describe the temporal landscape of differential transcriptional programs underlying the P. falciparum male and female gametocyte development and highlight a bifurcation point for the onset of differential male and female transcriptional programs. Furthermore, we predict novel candidate driver genes underlying sexual cell fate determination in P. falciparum. Finally, we traced the potential sex-specific regulatory mechanisms among the ApiAP2 family of transcription factors including prediction of target genes based on co-expression and the presence of upstream binding sites, rendering a motif-driven gene regulatory network. In

In eukaryotes, cellular differentiation is often orchestrated by programmed arrays of activation and repression of genes underlying the specific phenotypes of cell-types. To complete its life cycle, the single-celled Apicomplexan parasite Plasmodium falciparum, the most deadly of the human malaria parasites, must repeatedly differentiate and convert into unique cell types that can exploit niches within their human and mosquito hosts. One of these key developmental transitions occurs in the human host and includes sexual-stage commitment, followed by gametocyte development, which results in male and female gametocytes that can infect the female anopheline mosquito once taken up during the blood meal. The following gamete stage undergoes fusion and meiosis, followed by morphological changes as they invade the midgut wall to form the oocyst. The sexual stages are responsible for malaria transmission and the spread of antimalarial resistance, making it an important target for malaria eradication. Previous studies have established the understanding of a few mechanisms involved in sexual differentiation; the transcription factor, AP2-G, is a master regulator of sexual commitment. Uncovering genes and regulators underlying P. falciparum sexual stage development, including host-parasite interactions are the subjects of this thesis. In paper I, we describe the temporal landscape of differential transcriptional programs underlying the P. falciparum male and female gametocyte development and highlight a bifurcation point for the onset of differential male and female transcriptional programs. Furthermore, we predict novel candidate driver genes underlying sexual cell fate determination in P. falciparum. Finally, we traced the potential sex-specific regulatory mechanisms among the ApiAP2 family of transcription factors including prediction of target genes based on co-expression and the presence of upstream binding sites, rendering a motif-driven gene regulatory network. In

In eukaryotes, cellular differentiation is often orchestrated by programmed arrays of activation and repression of genes underlying the specific phenotypes of cell-types. To complete its life cycle, the single-celled Apicomplexan parasite Plasmodium falciparum, the most deadly of the human malaria parasites, must repeatedly differentiate and convert into unique cell types that can exploit niches within their human and mosquito hosts. One of these key developmental transitions occurs in the human host and includes sexual-stage commitment, followed by gametocyte development, which results in male and female gametocytes that can infect the female anopheline mosquito once taken up during the blood meal. The following gamete stage undergoes fusion and meiosis, followed by morphological changes as they invade the midgut wall to form the oocyst. The sexual stages are responsible for malaria transmission and the spread of antimalarial resistance, making it an important target for malaria eradication. Previous studies have established the understanding of a few mechanisms involved in sexual differentiation; the transcription factor, AP2-G, is a master regulator of sexual commitment. Uncovering genes and regulators underlying P. falciparum sexual stage development, including host-parasite interactions are the subjects of this thesis. In paper I, we describe the temporal landscape of differential transcriptional programs underlying the P. falciparum male and female gametocyte development and highlight a bifurcation point for the onset of differential male and female transcriptional programs. Furthermore, we predict novel candidate driver genes underlying sexual cell fate determination in P. falciparum. Finally, we traced the potential sex-specific regulatory mechanisms among the ApiAP2 family of transcription factors including prediction of target genes based on co-expression and the presence of upstream binding sites, rendering a motif-driven gene regulatory network. In

In eukaryotes, cellular differentiation is often orchestrated by programmed arrays of activation and repression of genes underlying the specific phenotypes of cell-types. To complete its life cycle, the single-celled Apicomplexan parasite Plasmodium falciparum, the most deadly of the human malaria parasites, must repeatedly differentiate and convert into unique cell types that can exploit niches within their human and mosquito hosts. One of these key developmental transitions occurs in the human host and includes sexual-stage commitment, followed by gametocyte development, which results in male and female gametocytes that can infect the female anopheline mosquito once taken up during the blood meal. The following gamete stage undergoes fusion and meiosis, followed by morphological changes as they invade the midgut wall to form the oocyst. The sexual stages are responsible for malaria transmission and the spread of antimalarial resistance, making it an important target for malaria eradication. Previous studies have established the understanding of a few mechanisms involved in sexual differentiation; the transcription factor, AP2-G, is a master regulator of sexual commitment. Uncovering genes and regulators underlying P. falciparum sexual stage development, including host-parasite interactions are the subjects of this thesis. In paper I, we describe the temporal landscape of differential transcriptional programs underlying the P. falciparum male and female gametocyte development and highlight a bifurcation point for the onset of differential male and female transcriptional programs. Furthermore, we predict novel candidate driver genes underlying sexual cell fate determination in P. falciparum. Finally, we traced the potential sex-specific regulatory mechanisms among the ApiAP2 family of transcription factors including prediction of target genes based on co-expression and the presence of upstream binding sites, rendering a motif-driven gene regulatory network. In

Development of primary mediastinal B-cell lymphoma (PMBL) is driven by cumulative genomic aberrations. We discovered a unique copy-neutral loss of heterozygosity (CN-LOH) landscape of PMBL which distinguishes this tumor from other B-cell malignancies, including the biologically related diffuse large B-cell lymphoma. Using single nucleotide polymorphism array analysis we identified large-scale CN-LOH lesions in 91% (30/33) of diagnostic PMBLs and both investigated PMBL-derived cell lines. Altogether, the cohort showed 157 extra-large (25.3-248.4 Mb) CN-LOH lesions affecting up to 14 chromosomes per case (mean of 4.4) and resulting in a reduction of heterozygosity an average of 9.9% (range 1.3-51%) of the genome. Predominant involvement of terminal chromosomal segments suggests the implication of B-cell specific crossover events in the pathogenesis of PMBL. Notably, CN-LOH stretches non-randomly clustered on 6p (60%), 15 (37.2%), and 17q (40%), and frequently co-occurred with homozygous mutations in the MHC I (6p21), B2M (15q15), and GNA13 (17q23) genes, respectively, as shown by preliminary whole-exome/genome sequencing data. Altogether, our findings implicate CN-LOH as a novel and distinct mutational process contributing to the molecular pathogenesis of PMBL. The aberration acting as "second hit" in the Knudson hypothesis, ranks as the major mechanism converting to homozygosity the PMBL-related driver genes. Screening of the cohort of 199 B cell leukemia/lymphoma whole-genomes revealed significant differences in the CN-LOH landscape of PMBL and other B-cell malignancies, including the biologically related diffuse large B-cell lymphoma.

Development of primary mediastinal B-cell lymphoma (PMBL) is driven by cumulative genomic aberrations. We discovered a unique copy-neutral loss of heterozygosity (CN-LOH) landscape of PMBL which distinguishes this tumor from other B-cell malignancies, including the biologically related diffuse large B-cell lymphoma. Using single nucleotide polymorphism array analysis we identified large-scale CN-LOH lesions in 91% (30/33) of diagnostic PMBLs and both investigated PMBL-derived cell lines. Altogether, the cohort showed 157 extra-large (25.3–248.4 Mb) CN-LOH lesions affecting up to 14 chromosomes per case (mean of 4.4) and resulting in a reduction of heterozygosity an average of 9.9% (range 1.3–51%) of the genome. Predominant involvement of terminal chromosomal segments suggests the implication of B-cell specific crossover events in the pathogenesis of PMBL. Notably, CN-LOH stretches non-randomly clustered on 6p (60%), 15 (37.2%), and 17q (40%), and frequently co-occurred with homozygous mutations in the MHC I (6p21), B2M (15q15), and GNA13 (17q23) genes, respectively, as shown by preliminary whole-exome/genome sequencing data. Altogether, our findings implicate CN-LOH as a novel and distinct mutational process contributing to the molecular pathogenesis of PMBL. The aberration acting as “second hit” in the Knudson hypothesis, ranks as the major mechanism converting to homozygosity the PMBL-related driver genes. Screening of the cohort of 199 B cell leukemia/lymphoma whole-genomes revealed significant differences in the CN-LOH landscape of PMBL and other B-cell malignancies, including the biologically related diffuse large B-cell lymphoma., SCOPUS: ar.j, DecretOANoAutActif, info:eu-repo/semantics/published

Background: Driver mutations are the genetic components responsible for tumor initiation and progression. These variants, which may be inherited, influence cancer risk and therefore underlie many familial cancers. The present study examines the potential association between SNPs in driver genes SF3B1 (rs4685), TBX3 (rs12366395, rs8853, and rs1061651) and MAP3K1 (rs72758040) and BC in BRCA1/2-negative Chilean families. Methods: The SNPs were genotyped in 486 BC cases and 1258 controls by TaqMan Assay. Results: Our data do not support an association between rs4685:C > T, rs8853:T > C, or rs1061651:T > C and BC risk. However, the rs12366395-G allele (A/G + G/G) was associated with risk in families with a strong history of BC (OR = 1.2 [95% CI 1.0–1.6] p = 0.02 and OR = 1.5 [95% CI 1.0–2.2] p = 0.02, respectively). Moreover, rs72758040-C was associated with increased risk in cases with a moderate-to-strong family history of BC (OR = 1.3 [95% CI 1.0–1.7] p = 0.02 and OR = 1.3 [95% CI 1.0–1.8] p = 0.03 respectively). Finally, risk was significantly higher in homozygous C/C cases from families with a moderate-to-strong BC history (OR = 1.8 [95% CI 1.0–3.1] p = 0.03 and OR = 1.9 [95% CI 1.1–3.4] p = 0.01, respectively). We also evaluated the combined impact of rs12366395-G and rs72758040-C. Familial BC risk increased in a dose-dependent manner with risk allele count, reflecting an additive effect (p-trend = 0.0002). Conclusions: Our study suggests that germline variants in driver genes TBX3 (rs12366395) and MAP3K1 (rs72758040) may influence BC risk in BRCA1/2-negative Chilean families. Moreover, the presence of rs12366395-G and rs72758040-C could increase BC risk in a Chilean population.

Cancer is a complex disease in which cells progressively accumulate mutations disrupting their cellular processes. A fraction of these mutations drive tumourigenesis by affecting oncogenes or tumour suppressor genes, but many mutations are passengers with no clear contribution to tumour development. The advancement of DNA and RNA sequencing technologies has enabled in-depth analysis of thousands of human tumours from various tissues to perform systematic characterization of their (epi)genomes and transcriptomes in order to identify (epi)genetic changes associated with cancer. Combined with considerable progress in algorithmic development, this expansion in scale has resulted in the identification of many cancer-associated mutations, genes and pathways that are considered to be potential drivers of tumour development. However, it remains challenging to systematically identify drivers affected by complex genomic rearrangements and drivers residing in non-coding regions of the genome or in complex amplicons or deletions of copy-number driven tumours. Furthermore, functional characterization is challenging in the human context due to the lack of genetically tractable experimental model systems in which the effects of mutations can be studied in the context of their tumour microenvironment. In this respect, mouse models of human cancer provide unique opportunities for pinpointing novel driver genes and their detailed characterization. In this review, we provide an overview of approaches for complementing human studies with data from mouse models. We also discuss state-of-the-art technological developments for cancer gene discovery and validation in mice., Pattern Recognition and Bioinformatics

Cancer is a complex disease in which cells progressively accumulate mutations disrupting their cellular processes. A fraction of these mutations drive tumourigenesis by affecting oncogenes or tumour suppressor genes, but many mutations are passengers with no clear contribution to tumour development. The advancement of DNA and RNA sequencing technologies has enabled in-depth analysis of thousands of human tumours from various tissues to perform systematic characterization of their (epi)genomes and transcriptomes in order to identify (epi)genetic changes associated with cancer. Combined with considerable progress in algorithmic development, this expansion in scale has resulted in the identification of many cancer-associated mutations, genes and pathways that are considered to be potential drivers of tumour development. However, it remains challenging to systematically identify drivers affected by complex genomic rearrangements and drivers residing in non-coding regions of the genome or in complex amplicons or deletions of copy-number driven tumours. Furthermore, functional characterization is challenging in the human context due to the lack of genetically tractable experimental model systems in which the effects of mutations can be studied in the context of their tumour microenvironment. In this respect, mouse models of human cancer provide unique opportunities for pinpointing novel driver genes and their detailed characterization. In this review, we provide an overview of approaches for complementing human studies with data from mouse models. We also discuss state-of-the-art technological developments for cancer gene discovery and validation in mice., Pattern Recognition and Bioinformatics

Purpose Germline mutations in tumour suppressor genes cause various cancers. These genes are also somatically mutated in sporadic tumours. We hypothesized that there may also be cancer-related germline variants in the genes commonly mutated in sporadic breast tumours. Methods After excluding the well-characterized breast cancer (BC) genes, we screened 15 novel genes consistently classified as BC driver genes in next-generation sequencing approaches for single nucleotide polymorphisms (SNPs). Altogether 40 SNPs located in the core promoter, 5'- and 3'-UTR or which were nonsynonymous SNPs were genotyped in 782 Swedish incident BC cases and 1,559 matched controls. After statistical analyses, further evaluations related to functional prediction and signatures of selection were performed. Results TBX3 was associated with BC risk (rs2242442: OR = 0.76, 95% CI 0.64-0.92, dominant model) and with less aggressive tumour characteristics. An association with BC survival and aggressive tumour characteristics was detected for the genes ATR (rs2227928: HR = 1.63; 95% CI 1.00-2.64, dominant model), RUNX1 (rs17227210: HR = 3.50, 95% CI 1.42-8.61, recessive model) and TTN (rs2303838: HR = 2.36; 95% CI 1.04-5.39; rs2042996: HR = 2.28; 95% CI 1.19-4.37, recessive model). According to the experimental ENCODE data all these SNPs themselves or SNPs in high linkage disequilibrium with them (r (2) ae 0.80) were located in regulatory regions. RUNX1 and TTN showed also several signatures of positive selection. Conclusion The study gave evidence that germline variants in BC driver genes may have impact on BC risk and/or survival. Future studies could discover further germline variants in known or so far unknown driver genes which contribute to cancer development.

Background Gain of chromosome 20q is an important factor in the progression from colorectal adenomas to carcinomas. Genes that drive 20q gain are expected to show correlation of mRNA and protein expression levels with 20q DNA copy number status while functionally influencing cancer processes. CSE1L, DIDO1 and RBM39 are located on the 20q amplicon and affect processes such as cell viability and anchorage-independent growth in colorectal cancer. This study aimed to investigate whether CSE1L, DIDO1 and RBM39 may drive 20q amplification. Methods Protein expression levels were examined by immunohistochemical evaluation of tissue microarrays containing a series of colorectal adenoma and carcinoma samples, which were characterized by genome-wide (microarray-based) DNA and mRNA profiling. Results CSE1L, DIDO1 and RBM39 mRNA expression levels correlated with chromosome 20q DNA copy number status. CSE1L protein expression was not associated with 20q gain, although its expression was increased in carcinomas compared to adenomas. DIDO1 and RBM39 protein expression was quite strong in the majority of tumors irrespective of 20q DNA copy number status. Conclusion The lack of correlation between protein expression levels and 20q DNA copy number status implies that CSE1L, DIDO1 and RBM39 are merely passengers rather than drivers of chromosome 20q gain in colorectal adenoma-to-carcinoma progression.