CpG island methylator phenotype (CIMP) in cancer: Causes and implications
Section snippets
Does concordant DNA methylation occur during tumour development?
Aberrant CpG island (CGI) hypermethylation is a hallmark of cancer and is characterised by tumour-specific hypermethylation of several hundreds of CGIs [1]. If aberrant methylation occurs randomly during tumour development, then one would expect a normal distribution of the methylation index1 with one tumour type specific average value. However, in 1999, two distinct subgroups of
Mechanisms underlying increased methylation rates?
Increased DNA methylation activity could be one possible reason for the frequent aberrant methylation of CGIs in CIMP tumours. Increased expression of DNA methyltransferases (DNMTs) has been reported in several cancers [11], [32], [33], [34], [35], [36], [37], [38], [39]. Association of DNMT1 overexpression with CIMP+ seems to be more frequently reported in studies detecting DNMT1 overexpression by immunohistochemistry (IHC) [11], [34], [36] than in studies detecting DNMT1 overexpression by
Does concordant methylation occur during chemotherapy?
A range of genetic and environmental factors are associated with the occurrence of CIMP [3], [30], [45], [50], [61]. Chemotherapy is a key part of a patient’s cancer treatment. This raises the question whether chemotherapy itself can represent an “environmental” factor that can favour the occurrence of CIMP in surviving tumour cells. Agents used in cancer chemotherapy such as 6-thioguanine [62] or cisplatin [63] induce DNA damage. For example, cisplatin can crosslink neighbouring guanine
Targeting of aberrant methylation
What determines which specific DNA sequences become methylated during tumourigenesis? Two major mechanisms can be envisioned: Aberrant de novo methylation events (methylation-independent) or aberrant expansion of existing methylation (methylation-dependent). In the methylation-independent model, aberrant DNA methylation should occur independently of existing DNA methylation. This could happen at sites of DNA repair or stalled replication forks, similar to the situation described above for
Implication as prognostic or predictive signature?
It has been proposed that tumours need to acquire certain traits such as evasion of apoptosis, limitless replicative potential, self-sufficiency in growth signals and others during their development [81]. In fact, many genes involved in these properties can become methylated in tumours ([71] and references therein). CIMP+ tumours represent a subgroup of tumours with elevated epimutation rates. Elevated epimutation rates and the resulting increased epigenetic plasticity should enable CIMP+
Implications for therapy
Do CIMP+ tumours possess an Achilles’ heel that can be exploited? Firstly, if commitment to a CIMP+ phenotype occurs early during tumour development, the increased methylation of normally unmethylated DNA sequences could be used for improved early diagnosis. DNA methylation has been detected in several body fluids including blood plasma ([97] and references therein) which could therefore serve as easily accessible surrogate sources for routine screening for abnormal DNA methylation. In theory,
Conclusion and outlook
The concept of CIMP has received some scepticism since it was proposed in 1999 but is now well-accepted in response to recent studies. Several studies show that CIMP+ tumours have worse prognosis probably due to their increased epigenetic plasticity. Therefore it will be important to identify the molecular cause of CIMP but also to test the current set of methylation markers for detection of CIMP. However, CIMP+ tumours may be easier to diagnose at an early stage since aberrant DNA methylation
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