Cancer Genome Landscapes

Abstract

Over the past decade, comprehensive sequencing efforts have revealed the genomic landscapes of common forms of human cancer. For most cancer types, this landscape consists of a small number of “mountains” (genes altered in a high percentage of tumors) and a much larger number of “hills” (genes altered infrequently). To date, these studies have revealed ~140 genes that, when altered by intragenic mutations, can promote or “drive” tumorigenesis. A typical tumor contains two to eight of these “driver gene” mutations; the remaining mutations are passengers that confer no selective growth advantage. Driver genes can be classified into 12 signaling pathways that regulate three core cellular processes: cell fate, cell survival, and genome maintenance. A better understanding of these pathways is one of the most pressing needs in basic cancer research. Even now, however, our knowledge of cancer genomes is sufficient to guide the development of more effective approaches for reducing cancer morbidity and mortality.

Emerging therapeutic targets in myeloproliferative neoplasms and peripheral T-cell leukemia and lymphomas

“…Approximately 4 million coding mutations have been identified, defining 500 genes that act as functional cancer drivers [5,6], many of which participate in core cancer pathways [7]. The ability to define hyperactivated signaling pathways that are commonly deregulated allows for development of new therapies.…”

“…Although infrequent in MPN, more than 10% of AML cases harbor activating RAS mutations. RAS-RAF signaling can be triggered by normal cytokine, growth factor, or hyperactive JAK action and it constitutes a core cancer pathway [7]. RAS-RAF is upstream of MAPK-ERK signaling and it can further activate RHO and RAC GTPase proteins, which were reported to be essential for nuclear shuttling of STAT5A [42].…”

Long-peptide vaccination with driver gene mutations in p53 and Kras induces cancer mutation-specific effector as well as regulatory T cell responses

“…8 Mutations in genes which are essential for oncogenesis are known as driver mutations. 9 Passenger mutations are expendable to sustain a malignant phenotype, which can result in Ag-loss variants of the tumor once a Darwinian selection pressure is imposed by therapeutic intervention. 10,11 Therefore, targeting driver mutations in a TSA-specific therapy is indicative.…”

“…10,11 Therefore, targeting driver mutations in a TSA-specific therapy is indicative. Important driver genes in colorectal 9,12 and pancreatic 13 tumorigenesis are mutated alleles of the oncogene KRAS and the tumor suppressor gene/oncogene TP53 . Indeed, mutated Kras and p53 proteins can comprise TSAs, as mutated Kras epitopes around the hot-spot mutation site G12 14-18 and also mutated p53 epitopes comprising hot-spot variants have previously been described.…”

Adaptive dynamics of unstable cancer populations: The canonical equation

“…However, certain points can be made if we give values within realistic parameter ranges to our function. The number of both oncogenes and house‐keeping genes have been widely assessed, and we take them to be about $N_R\approx 140$ (Vogelstein et al., 2013) and $N_{\mathrm{normalHK}}\approx 3804$ (Eisenberg & Levanon, 2013), respectively. Interestingly enough, considering small replication effects for ${\mathrm{\delta }}_R$, such experimental values produce an adaptive landscape (Figure 2) that has a positive gradient within the region of $\mathrm{\mu }\in [{10}^{-9},{10}^{-4}]$, so that our evolutionary trajectories will be bounded within a region of instability levels in accordance with those experimentally measured for tumour cells (Tomlinson, Novelli, & Bodmer, 1996).…”