Oncogenomics
Cancer is a genetic disease caused by accumulation of DNA mutations and epigenetic alterations leading to unrestrained cell proliferation and neoplasm formation.
The completion of the Human Genome Project facilitated the field of oncogenomics and increased the abilities of researchers to find oncogenes.
A number of recently devised methods can assess the DNA methylation status in cancers versus normal tissues.
[4] Some methods assess methylation of CpGs located in different classes of loci, including CpG islands, shores, and shelves as well as promoters, gene bodies, and intergenic regions.
The remaining 8 were new mutations and all were single base changes: Four were in families that are strongly associated with cancer pathogenesis (PTPRT, CDH24, PCLKC and SLC15A1).
[9] In 2011, the genome of an exceptional bladder cancer patient whose tumor had been eliminated by the drug everolimus was sequenced, revealing mutations in two genes, TSC1 and NF2.
The initiative allows such exceptional patients (who have responded positively for at least six months to a cancer drug that usually fails) to have their genomes sequenced to identify the relevant mutations.
[10] In 2014 the Center for Molecular Oncology rolled out the MSK-IMPACT test, a screening tool that looks for mutations in 341 cancer-associated genes.
Potential functions include their transformational capabilities relating to tumour formation and specific roles at each stage of cancer development.
[22] Operomics aims to integrate genomics, transcriptomics and proteomics to understand the molecular mechanisms that underlie the cancer development.
These models are generated by methods including retroviral insertion mutagenesis or graft transplantation of cancerous cells.
The machinery of replication and genome maintenance can be damaged by mutations, or altered by physiological conditions and differential levels of expression in cancer (see references in[25]).
As pointed out by Gao et al.,[26] the stability and integrity of the human genome are maintained by the DNA-damage response (DDR) system.
The first implementation of Non-negative Matrix Factorization (NMF) method is available in Sanger Institute Mutational Signature Framework in the form of a MATLAB package.
[39] Thus, the identification of collaterally deleted redundant genes carrying out an essential cellular function may be the untapped reservoir for then pursuing a synthetic lethality approach.
[41] ENO2, which encodes enolase 2, is mostly expressed in neural tissues, leading to the postulation that in ENO1-deleted GBM, ENO2 may be the ideal target as the redundant homologue of ENO1.
[44] Dey et al. show that ME2 genomic deletion in pancreatic ductal adenocarcinoma cells results in high endogenous reactive oxygen species, consistent with KRAS-driven pancreatic cancer, and essentially primes ME2-null cells for synthetic lethality by depletion of redundant NAD(P)+-dependent isoform ME3.
The effects of ME3 depletion were found to be mediated by inhibition of de novo nucleotide synthesis resulting from AMPK activation and mitochondrial ROS-mediated apoptosis.
[45][44] Meanwhile, Oike et al. demonstrated the generalizability of the concept by targeting redundant essential-genes in process other than metabolism, namely the SMARCA4 and SMARCA2 subunits in the chromatin-remodeling SWI/SNF complex.
Treatments based on the principle of synthetic lethality have prolonged the survival of cancer patients, and show promise for future advances in reversal of carcinogenesis.
A major type of synthetic lethality operates on the DNA repair defect that often initiates a cancer, and is still present in the tumor cells.
A human Phase II clinical trial, with 41 patients, evaluated one synthetic lethal approach for tumors with or without MMR defects.
ARID1A, a chromatin modifier, is required for non-homologous end joining, a major pathway that repairs double-strand breaks in DNA,[52] and also has transcription regulatory roles.
[56] Pre-clinical studies in cells and in mice show that synthetic lethality for ARID1A deficiency occurs by either inhibition of the methyltransferase activity of EZH2,[57][58] or with addition of the kinase inhibitor dasatinib.
The project systematically sequences the exons and flanking splice junctions of the genomes of primary tumors and cancerous cell lines.
Phosphatidylinositold 3-kinases (PIK3CA) gene encodes for lipid kinases that commonly contain mutations in colorectal, breast, gastric, lung and various other cancers.
MtDNA content alterations found in blood samples might be able to serve as a screening marker for predicting future cancer susceptibility as well as tracking malignant tumor progression.
Along with these potential helpful characteristics of mtDNA, it is not under the control of the cell cycle and is important for maintaining ATP generation and mitochondrial homeostasis.
They can range from single-nucleotide polymorphisms (SNPs), chromosomal aberrations, changes in DNA copy number, microsatellite instability, promoter region methylation, or even high or low protein levels.
[90] Between 2013 and 2019 only 6.8% of people with cancer in 2 US states underwent genetic testing, suggesting broad under-utilization of information that could improve treatment decisions and patient outcomes.
