驱动突变与融合基因

2021-02-05 本文已影响0人 evolisgreat

驱动突变与乘客突变^[1]

All cancers arise as a result of somatically acquired changes in the DNA of cancer cells. That does not mean, however, that all the somatic abnormalities present in a cancer genome have been involved in development of the cancer. Indeed, it is likely that some have made no contribution at all. To embody this concept, the terms ‘driver’ and ‘passenger’ mutation have been coined.

A driver mutation is causally implicated in oncogenesis. It has conferred growth advantage on the cancer cell and has been positively selected in the microenvironment of the tissue in which the cancer arises. A driver mutation need not be required for maintenance of the final cancer (although it often is) but it must have been selected at some point along the lineage of cancer development shown in Fig. 1.

A passenger mutation has not been selected, has not conferred clonal growth advantage and has therefore not contributed to cancer development. Passenger mutations are found within cancer genomes because somatic mutations without functional consequences often occur during cell division.

figure 1.PNG

驱动基因

What is a driver gene
A driver gene is one that contains driver gene mutations^[2]. But driver genes may also contain passenger gene mutations. For example, APC is a large driver gene, but only those mutations that truncate the encoded protein within its N-terminal 1600 amino acids are driver gene mutations. Missense mutations throughout the gene, as well as protein-truncating mutations in the C-terminal 1200 amino acids, are passenger gene mutations.

Oncogenes are defined as driver genes in which driver mutations are activating or result in new functions. Tumor suppressors are driver genes in which driver mutations are inactivating^[3].

How Many Mut-Driver Genes Exist?^[2]

Though all 20,000 protein-coding genes have been evaluated in the genome-wide sequencing studies of 3284 tumors, with a total of 294,881 mutations reported, only 125 Mut-driver genes, as defined by the 20/20 rule, have been discovered to date (table S2A). Of these, 71 are tumor suppressor genes and 54 are oncogenes.

Epigenome and cancer^[3]

Epigenetic Changes as Drivers of Oncogenesis
Epigenetic changes affect more than just miRNA. Many of the missing driver genes may not have been recognized as drivers because they are affected not by mutations but rather by epigenetic changes, such as changes in DNA methylation, histone modification, nucleosome composition, or nucleosome placement (see the sidebar, Chromatin Structure).

Epigenetics is the study of changes in gene expression that are not mediated by changes in DNA sequence. Traditionally only heritable changes were considered epigenetic, but some authors now expand the definition to include transient changes . However, only heritable changes can be selected for on the basis of a growth advantage, and thus only heritable changes can be drivers. Epigenetic changes that can be inherited across cell division may thus act as drivers. Mutations are changes in DNA sequence and thus do not include epigenetic changes.

Epigenome Modifiers as Driver Genes

Driver epigenetic changes may result from mutations in genes involved in chromatin structure and DNA modification. The scope of mutations in epigenome modifiers has only recently become appreciated. Across cancers from 13 sites, the proportion of samples with protein-altering mutations in candidate driver chromatin regulatory factors ranged from less than 10% to more than 80%. In rhabdoid cancers, mutations in a subunit of the SWI/SNF nucleosome-remodeling complex are present in almost all samples.

融合基因

A fusion gene is defined as two genes that are joined so that they are transcribed and translated as a single unit. Gene fusion is one of the hallmarks of cancer genome via chromosomal rearrangement initiated by DNA double-strand breakage. To date, many fusion genes (FGs) have been established as important biomarkers and therapeutic targets in multiple cancer types.

The causative molecular event in chronic myeloid leukaemia (CML) is the formation of a BCR–ABL fusion gene, leading to expression of a constitutively active BCR–ABL tyrosine kinase^[4]. The ABL1 proto-oncogene originally encodes tyrosine kinase signalling protein whose activity is highly regulated during cell division. When fusion between two gene segment occurred, the fusion of BCL results in upregulation of the ABL1 gene (converts proto-oncogene into oncogene). The uncontrolled expression of oncogene results in the activation of tyrosine kinase protein. This abnormal functional protein causes uncontrolled and uninterrupted cell division (especially in the bone marrow and blood cell) results in chronic myeloid leukemia.
In addition to their direct role in the activation of an oncogene, the BCR-ABL1 fusion gene segment also affects some other signalling pathways which are required in the cell proliferation, cell signalling and apoptosis. Some of the affected pathways are:

JAK/STAT pathway
IKAROS gene and DNA binding protein
Ras/MAPK pathway
MAPK/ERK/Ras pathway

In most cases, the BCR–ABL fusion gene results from the translocation t(9;22), which creates a shortened chromosome 22 known as the Philadelphia (Ph) chromosome. The translocation led to a chimeric BCR-ABL1 transcript, which encoded a continuously activated form of the ABL kinase, resulting in inhibited apoptosis and promoted proliferation. Clinically, CML is characterised by three phases: chronic, accelerated and blastic phase.

Philadephia-chromosome.jpeg