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Concurrent p16 methylation pattern as an adverse prognostic factor in multiple myeloma: a methylation-specific polymerase chain reaction study using two different primer sets

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Abstract

Disruption of cell cycle control genes, including p16, is known to contribute to the cancerogenesis of multiple myeloma (MM). We investigated the methylation status of p16 and its association with common cytogenetic changes, clinicolaboratory findings, and survival in MM. Methylation-specific polymerase chain reaction was performed in 99 newly diagnosed MM patients using two different sets of primers (p16M1 and p16M2). Four patterns of p16 promoter methylation were observed: (1) concurrent methylation of p16M1 and p16M2 (P1P2), 27.3%; (2) methylation of p16M1 alone (P1N2), 7.1%; (3) methylation of p16M2 alone (N1P2), 26.3%; and (4) no methylation (N1N2), 39.4%. Patients with p16P1P1 showed shorter survivals than those with the other methylation patterns (P1N2, N1P2, or N1N2; median survival, 12 vs. 43 months; P < 0.001), regardless of the treatment protocol. In a multivariate analysis, p16P1P2 was an independent prognostic factor of adverse outcome in MM. According to International Staging System (ISS), the study population could be divided into 21.2% (20/94) for stage I, 22.3% (21/94) for stage II, and 56.4% (53/94) for stage III (P = 0.003). ISS can divide patients into prognostic groups. Of note, in patients older than 60 years, ISS was not reflective of disease stage (P = 0.114). If p16P1P2 sets up as stage 4 of ISS, modified ISS could be a more reliable staging system irrespective of age in Korean MM patients (P = 0.003 and P = 0.004 in patients younger than 60 years and in patients older than 60 years, respectively). Our study suggests the potential use of p16 methylation status in predicting the outcome of MM patients and the applicability of demethylating agents in MM.

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Acknowledgement

This work was supported in part by (1) the National R&D Program for Cancer Control, Ministry of Health, Welfare and Family Affairs, Republic of Korea (0720440), and (2) the Korea Science and Engineering Foundation (KOSEF) funded by the Ministry of Education, Science, and Technology (20100020584). Tae Young Kim and Bora Oh are grateful for being awarded a BK21 fellowship.

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Authors and Affiliations

  1. Department of Laboratory Medicine, Chosun University College of Medicine, Gwangju, South Korea

    Geon Park

  2. Green Cross Reference Laboratory, Yong-In, Gyeonggi-do, South Korea

    Seong Ho Kang

  3. Department of Internal Medicine, Cachon University Gil Hospital, Incheon, Gyeonggi-do, South Korea

    Jae Hoon Lee

  4. Department of Internal Medicine, Asan Medical Center, Seoul, South Korea

    Cheolwon Suh

  5. Department of Laboratory Medicine, Seoul National University Hospital, Seoul National University College of Medicine, 28 Yeongundong, Chongrogu, Seoul, 110-744, South Korea

    Miyoung Kim, Seung Man Park, Han Ik Cho & Dong Soon Lee

  6. Department of Molecular and Clinical Oncology, Seoul National University College of Medicine, Seoul, South Korea

    Tae Young Kim, Bora Oh & Dong Soon Lee

  7. Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea

    Tae Young Kim, Bora Oh & Dong Soon Lee

  8. Dow Biomedica Inc., Seoul, South Korea

    Hyun Jung Min

  9. Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea

    Sung Soo Yoon

  10. Center for Bioanalysis, Korea Research Institute of Standards and Science, Daejeon, South Korea

    In Chul Yang

  11. Korean Association of Healthy Promotion, Seoul, South Korea

    Han Ik Cho

  12. Department of Tumor Biology, Seoul National University College of Medicine, Seoul, South Korea

    Dong Soon Lee

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  1. Geon Park
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The Korean Multiple Myeloma Working Party (KMMWP)

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Correspondence to Dong Soon Lee.

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Geon Park and Seong Ho Kang contributed equally as first authors.

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Park, G., Kang, S.H., Lee, J.H. et al. Concurrent p16 methylation pattern as an adverse prognostic factor in multiple myeloma: a methylation-specific polymerase chain reaction study using two different primer sets. Ann Hematol 90, 73–79 (2011). https://doi.org/10.1007/s00277-010-1043-9

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  • DOI: https://doi.org/10.1007/s00277-010-1043-9

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