Genetic alterations
Cancer is fundamentally a disease of tissue growth regulation failure. In order for a normal cell to transform into a cancer cell, the genes which regulate cell growth and differentiation must be altered.[48]The affected genes are divided into two broad categories. Oncogenes are genes which promote cell growth and reproduction. Tumor suppressor genes are genes which inhibit cell division and survival. Malignant transformation can occur through the formation of novel oncogenes, the inappropriate over-expression of normal oncogenes, or by the under-expression or disabling of tumor suppressor genes. Typically, changes in many genes are required to transform a normal cell into a cancer cell.[49]
Genetic changes can occur at different levels and by different mechanisms. The gain or loss of an entire chromosome can occur through errors in mitosis. More common are mutations, which are changes in the nucleotide sequence of genomic DNA.
Large-scale mutations involve the deletion or gain of a portion of a chromosome. Genomic amplification occurs when a cell gains many copies (often 20 or more) of a small chromosomal locus, usually containing one or more oncogenes and adjacent genetic material. Translocation occurs when two separate chromosomal regions become abnormally fused, often at a characteristic location. A well-known example of this is the Philadelphia chromosome, or translocation of chromosomes 9 and 22, which occurs in chronic myelogenous leukemia, and results in production of the BCR-abl fusion protein, an oncogenic tyrosine kinase.
Small-scale mutations include point mutations, deletions, and insertions, which may occur in the promoter region of a gene and affect its expression, or may occur in the gene's coding sequence and alter the function or stability of its protein product. Disruption of a single gene may also result from integration of genomic material from a DNA virus or retrovirus, and resulting in the expression of viral oncogenes in the affected cell and its descendants.
Replication of the enormous amount of data contained within the DNA of living cells will probabilistically result in some errors (mutations). Complex error correction and prevention is built into the process, and safeguards the cell against cancer. If significant error occurs, the damaged cell can "self-destruct" through programmed cell death, termed apoptosis. If the error control processes fail, then the mutations will survive and be passed along to daughter cells.
Some environments make errors more likely to arise and propagate. Such environments can include the presence of disruptive substances called carcinogens, repeated physical injury, heat, ionising radiation, or hypoxia.[50]
The errors which cause cancer are self-amplifying and compounding, for example:
- A mutation in the error-correcting machinery of a cell might cause that cell and its children to accumulate errors more rapidly.
- A further mutation in an oncogene might cause the cell to reproduce more rapidly and more frequently than its normal counterparts.
- A further mutation may cause loss of a tumour suppressor gene, disrupting the apoptosis signalling pathway and resulting in the cell becoming immortal.
- A further mutation in signaling machinery of the cell might send error-causing signals to nearby cells.
Classically, cancer has been viewed as a set of diseases that are driven by progressive genetic abnormalities that include mutations in tumour-suppressor genes and oncogenes, and chromosomal abnormalities. However, it has become apparent that cancer is also driven by epigenetic alterations.[52]
Epigenetic alterations refer to functionally relevant modifications to the genome that do not involve a change in the nucleotide sequence. Examples of such modifications are changes in DNA methylation (hypermethylation and hypomethylation) and histone modification [53] and changes in chromosomal architecture (caused by inappropriate expression of proteins such as HMGA2 or HMGA1).[54] Each of these epigenetic alterations serves to regulate gene expression without altering the underlying DNA sequence. These changes may remain through cell divisions, last for multiple generations, and can be considered to be epimutations (equivalent to mutations).
Epigenetic alterations occur frequently in cancers. As an example, Schnekenburger and Diederich[55] listed protein coding genes that were frequently altered in their methylation in association with colon cancer. These included 147 hypermethylated and 27 hypomethylated genes. Of the hypermethylated genes, 10 were hypermethylated in 100% of colon cancers, and many others were hypermethylated in more than 50% of colon cancers.
While large numbers of epigenetic alterations are found in cancers, the epigenetic alterations in DNA repair genes, causing reduced expression of DNA repair proteins, may be of particular importance. Such alterations are thought to occur early in progression to cancer and to be a likely cause of the genetic instability characteristic of cancers.[56][57][58][59]
Reduced expression of DNA repair genes causes deficient DNA repair. This is shown in the figure at the 4th level from the top. (In the figure, red wording indicates the central role of DNA damage and defects in DNA repair in progression to cancer.) When DNA repair is deficient DNA damages remain in cells at a higher than usual level (5th level from the top in figure), and these excess damages cause increased frequencies of mutation and/or epimutation (6th level from top of figure). Mutation rates increase substantially in cells defective in DNA mismatch repair[60][61] or in homologous recombinational repair (HRR).[62] Chromosomal rearrangements and aneuploidy also increase in HRR defective cells.[63]
Higher levels of DNA damage not only cause increased mutation (right side of figure), but also cause increased epimutation. During repair of DNA double strand breaks, or repair of other DNA damages, incompletely cleared sites of repair can cause epigenetic gene silencing.[64][65]
Deficient expression of DNA repair proteins due to an inherited mutation can cause increased risk of cancer. Individuals with an inherited impairment in any of 34 DNA repair genes (see article DNA repair-deficiency disorder) have an increased risk of cancer, with some defects causing up to a 100% lifetime chance of cancer (e.g. p53 mutations).[66] Germ line DNA repair mutations are noted in a box on the left side of the figure, with an arrow indicating their contribution to DNA repair deficiency. However, such germline mutations (which cause highly penetrant cancer syndromes) are the cause of only about 1 percent of cancers.[67]
In sporadic cancers, deficiencies in DNA repair are occasionally caused by a mutation in a DNA repair gene, but are much more frequently caused by epigenetic alterations that reduce or silence expression of DNA repair genes. This is indicated in the figure at the 3rd level from the top. For example, when 113 colorectal cancers were examined in sequence, only four had a missense mutation in the DNA repair gene MGMT, while the majority had reduced MGMT expression due to methylation of the MGMT promoter region (an epigenetic alteration).[68] Five different studies found that between 40% and 90% of colorectal cancers have reduced MGMT expression due to methylation of the MGMT promoter region.[69][70][71][72][73]
Similarly, out of 119 cases of mismatch repair-deficient colorectal cancers that lacked DNA repair gene PMS2 expression, PMS2 was deficient in 6 due to mutations in the PMS2 gene, while in 103 cases PMS2 expression was deficient because its pairing partner MLH1 was repressed due to promoter methylation (PMS2 protein is unstable in the absence of MLH1).[74] In the other 10 cases, loss of PMS2 expression was likely due to epigenetic overexpression of the microRNA, miR-155, which down-regulates MLH1.[75]
In further examples, tabulated in the article Epigenetics, epigenetic defects were found at frequencies of between 13%-100% for the DNA repair genes BRCA1, WRN, FANCB, FANCF, MGMT, MLH1, MSH2, MSH4, ERCC1, XPF, NEIL1 and ATM in cancers including those in breast, ovarian, colorectal, and head and neck. In particular, two or more epigenetic deficiencies in expression of ERCC1, XPF and/or PMS2 occurred simultaneously in the majority of the 49 colon cancers evaluated by Facista et al.[76]
Many studies of heavy metal-induced carcinogenesis show that such heavy metals cause reduction in expression of DNA repair enzymes, some through epigenetic mechanisms. In some cases, DNA repair inhibition is proposed to be a predominant mechanism in heavy metal-induced carcinogenicity. For example, one group of studies shows that arsenic inhibits the DNA repair genes PARP, XRCC1, Ligase III, Ligase IV, DNA POLB, XRCC4, DNA PKCS, TOPO2B, OGG1, ERCC1, XPF, XPB, XPC, XPE and P53.[77][78][79][80][81][82] Another group of studies shows that cadmium inhibits the DNA repair genes MSH2, ERCC1, XRCC1, OGG1, MSH6, DNA-PK, XPD and XPC.[83][84][85][86][87]
Cancers usually arise from an assemblage of mutations and epimutations that confer a selective advantage leading to clonal expansion (see Field defects in progression to cancer). Mutations, however, may not be as frequent in cancers as epigenetic alterations. An average cancer of the breast or colon can have about 60 to 70 protein-altering mutations, of which about 3 or 4 may be “driver” mutations, and the remaining ones may be “passenger” mutations.[88] Colon cancers were also found to have an average of 17 duplicated segments of chromosomes, 28 deleted segments of chromosomes and up to 10 translocations.[89] However, by comparison, epigenetic alterations appear to be more frequent in colon cancers. There are large numbers of hypermethylated genes in colon cancer, as discussed above.[55]
In addition, there are frequent epigenetic alterations of the DNA sequences coding for small RNAs called microRNAs (or miRNAs). MiRNAs do not code for proteins, but can “target” protein-coding genes and reduce their expression. For instance, epigenetic increase in CpG island methylation of the DNA sequence encoding miR-137 reduces its expression and is a frequent early epigenetic event in colorectal carcinogenesis, occurring in 81% of colon cancers and in 14% of the normal appearing colonic mucosa adjacent to the cancers. Silencing of miR-137 can affect expression of over 400 genes, the targets of this miRNA.[90] Changes in the level of miR-137 expression cause altered mRNA expression of the target genes by 2 to 20-fold and corresponding, though often smaller, changes in expression of the protein products of the genes. Other microRNAs, with likely comparable numbers of target genes, are even more frequently epigenetically altered in colonic field defects and in the colon cancers that arise from them. These include miR-124a, miR-34b/c and miR-342 which are silenced by CpG island methylation of their encoding DNA sequences in primary tumors at rates of 99%, 93% and 86%, respectively, and in the adjacent normal appearing mucosa at rates of 59%, 26% and 56%, respectively.[91][92] Thus, epigenetic alterations are a major source of changes in gene expression, important in cancer.
As pointed out above under genetic alterations, cancer is caused by failure to regulate tissue growth, when the genes which regulate cell growth and differentiation are altered. It has become clear that these alterations are caused by both DNA sequence mutation in oncogenes and tumor suppressor genes as well as by epigenetic alterations. The epigenetic deficiencies in expression of DNA repair genes, in particular, likely cause an increased frequency of mutations, some of which then occur in oncogenes and tumor suppressor genes.
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