Cancer Letters

Cancer Letters

Volume 268, Issue 2, 18 September 2008, Pages 177-186
Cancer Letters

CpG island methylator phenotype (CIMP) in cancer: Causes and implications

https://doi.org/10.1016/j.canlet.2008.03.022Get rights and content

Abstract

Strong evidence exists for a subgroup of tumours, from a variety of tissue types, exhibiting concordant tumour specific DNA methylation: the “CpG island methylator phenotype” (CIMP). Occurrence of CIMP is associated with a range of genetic and environmental factors, although the molecular causes are not well-understood. Both increased expression and aberrant targeting of DNA methyltransferases (DNMTs) could contribute to the occurrence of CIMP. One under-explored area is the possibility that DNA damage may induce or select for CIMP during carcinogenesis or treatment of tumours with chemotherapy. DNA damaging agents can induce DNA damage at guanine rich regions throughout the genome, including CpG islands. This DNA damage can result in stalled DNA synthesis, which will lead to localised increased DNMT1 concentration and therefore potentially increased DNA methylation at these sites. Chemotherapy can select for cells which have increased tolerance to DNA damage due to increased lesion bypass, in some cases by mechanisms which involve inactivation of genes by CpG island methylation. CIMP has been associated with worse patient prognosis, probably due to increased epigenetic plasticity. Therefore, further clinical testing of the diagnostic and prognostic value of the current CIMP markers, as well as increasing our understanding of the molecular causes underlying CIMP are required.

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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