Methylation of INK4 and CIP/KIP families of cyclin-dependent kinase inhibitor in chronic lymphocytic leukaemia in Chinese patients

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BlankMethylation of INK4 and CIP/KIP families of cyclin-dependent kinase

inhibitor in chronic lymphocytic leukaemia in Chinese patients

C S Chim1, T K Fung1, K F Wong2, J S Lau3, M Law4 and R Liang1

1 Department of Medicine, Queen Hospital, Hong Kong

2 Department of Pathology, Queen Hospital

3 Department of Medicine, Queen Hospital

4 University Department of Medicine and Clinical Oncology, Queen Hospital

Correspondence to:

C S Chim

University Department of Medicine, Queen Hospital, University of Hong Kong,

Pokfulam Road, Hong Kong; jcschim@...

Background: INK4 (p15, p16, p18 and p19) and CIP/KIP (p21, p27 and p57) are two

families of cyclin-dependent kinase inhibitors (CKI) targeting CDK4/6 and CDK2,

respectively.

Aim: To study the role of methylation in the inactivation of CKI in chronic

lymphocytic leukaemia (CLL).

Materials and methods: Methylation-specific polymerase chain reaction was

carried out on DNA obtained from the bone marrow of 56 newly diagnosed patients

with CLL.

Results: Similar demographic features and clinical outcome were observed in our

patients when compared with Caucasian patients, including an indolent clinical

course (10-year overall survival 51%) and advanced Rai stage (p = 0.006), and a

high-risk karyotype such as trisomy 12 and complex aberrations (p = 0.03). In

the INK4 family, methylation in p15 and p16 occurred in 20 (35.7%) and 8 (14.3%)

patients, respectively. In all, 5 (8.9%) CLL samples harboured concurrent

methylation of both p15 and p16. Apart from an association of p16 methylation

with higher presenting leucocyte count (64.5x109/l in methylated p16 and

16.0x109/l in unmethylated p16 patients; p = 0.016), there was no association

between p15 and p16 methylation and age, sex and Rai stage. No difference was

observed in the overall survival for patients with and without p15 and p16

methylation. By contrast, p18 and Rb were unmethylated in all samples. In the

CIP/KIP family, apart from infrequent methylation of p57 in 4 (7.1%) patients,

methylation of p21 and p27 was uniformly absent.

Conclusion: p15 and, less frequently, p16 of the INK4 family of CKI, instead of

the CIP or KIP family, were targeted by methylation in CLL. p16 methylation was

associated with a higher lymphocyte count at presentation. This is the first

comprehensive study of the epigenetic dysregulation of the INK4 and CIP/KIP

families of CKI in Chinese patients with CLL.

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Abbreviations: CDK4/6, cyclin-dependent kinases 4 and 6; CKI, cyclin-dependent

kinase inhibitors; CLL, chronic lymphocytic leukaemia; MSP, methylation-specific

polymerase chain reaction; M-MSP, methylated MSP; U-MSP, unmethylated MSP; PCR,

polymerase chain reaction