Clinical and Experimental Pediatrics

The Korean Pediatric Society (대한소아청소년과학회)
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Clinical significance of loss of p16 protein by immunohistochemical staining in acute lymphoblastic leukemia

급성림프구성백혈병에서 면역조직화학염색에 의한 p16 단백질 소실의 의의

  • Jin, Hye Young (Department of Pediatrics, College of Medicine, Chungnam National University) ;
  • Kang, Kyoung In (Department of Pediatrics, College of Medicine, Chungnam National University) ;
  • Kim, Sun Young (Department of Pediatrics, College of Medicine, Chungnam National University) ;
  • Youn, You Sook (Department of Pediatrics, College of Medicine, Chungnam National University) ;
  • Kang, Joon Won (Department of Pediatrics, College of Medicine, Chungnam National University) ;
  • Jo, Deog Yeon (Department of Internal Medicine, College of Medicine, Chungnam National University) ;
  • Kwon, Kye Chul (Department of Clinical Laboratory Medicine, College of Medicine, Chungnam National University) ;
  • Park, Kyung Duk (Department of Pediatrics, Korea Cancer Center Hospital)
  • 진혜영 (충남대학교 의과대학 소아과학교실) ;
  • 강경인 (충남대학교 의과대학 소아과학교실) ;
  • 김선영 (충남대학교 의과대학 소아과학교실) ;
  • 윤유숙 (충남대학교 의과대학 소아과학교실) ;
  • 강준원 (충남대학교 의과대학 소아과학교실) ;
  • 조덕연 (충남대학교 의과대학 내과학교실) ;
  • 권계철 (충남대학교 의과대학 진단검사의학과교실) ;
  • 박경덕 (원자력병원 소아과)
  • Received : 2007.11.08
  • Accepted : 2007.12.23
  • Published : 2008.01.15
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Abstract

Purpose : p16 gene, mapped to the 9p21 chromosomal region, has emerged as a candidate tumor suppressor gene in human neoplasm. It is an inhibitor of cyclin-dependent kinase and inhibits Rb phosphorylation. In a variety of tumors including childhood acute lymphoblastic leukemia (ALL), deletion and/or mutation of the p16 gene has been found. Despite their high frequency, the prognostic importance of p16 alterations is still controversial in ALL and has been reported to be either unfavorable or similar to that of other patients. We studied the correlation between loss of p16 protein confirmed by immunohistochemical staining and clinical outcomes of patients diagnosed as ALL. Methods : We performed an immunohistochemical staining for p16 protein in 74 cases of bone marrow biopsy slide initially diagnosed as ALL between January 1998 and December 2006. We reviewed the clinical manifestations, laboratory findings, treatment outcomes retrospectively. Results : Of 74 slides, 12 were negative for p16 protein. Seven were males and 5 were females with a median age at diagnosis was 5.8 (1.3-18.8) years. Initial WBC were 17,225 $(500-403,300)/{\mu}L$. By immunologic surface marker analysis, 7 patients were early pre-B CALLA (+) and 5 patients were T-cell ALL. Two patients of intermediate risk group had relapsed and died. Three patients had family history of breast cancer. Four patients died and overall survival rates were $53.5{\pm}18.7%$. Conclusion : Loss of p16 protein is supposed to be an independent risk factor of childhood ALL associated with poor outcomes. In clinical setting, the clinician must take into account p16 status, not only at the genomic but also at the protein level. Further clinical experience on thoroughly investigated cases will help a better understanding between p16 status and clinical outcomes.

목 적 : p16 유전자는 염색체 9p21에 위치하는데 종양억제 유전자 중 하나로 cyclin-dependent kinase의 억제제로 작용하며 Rb 인산화를 억제한다. 다양한 종류의 종양에서 p16 유전자의 결실 또는 과메틸화가 발견되고 있는데 이는 급성림프구성백혈병에서도 흔히 발견되는 이상 소견으로 높은 빈도로 나타나고 있지만 급성림프구성백혈병의 예후와 p16 유전자의 연관성에 대해서는 아직 논란의 여지가 있다. 본 연구에서는 면역조직화학염색으로 확인한 p16 단백질의 소실과 급성림프구성백혈병 환아들의 임상 경과와의 연관성에 대하여 조사하고자 하였다. 방 법 : 1998년 1월부터 2006년 12월까지 급성림프구성백혈병으로 진단된 74명의 진단 시 골수 슬라이드에서 p16 단백질 면역조직화학염색을 하였다. 환아들의 임상 양상, 검사실 소견, 치료 후 경과에 대해서 후향적으로 조사하였다. 결 과 : 74명 중 12명에서 p16 단백질이 면역화학염색 결과 음성이었다. 이들 중 남아가 7명 여아가 5명이었으며 진단 시 연령의 중앙값은 5.8(1.3-18.8)세였다. 백혈구 수의 중앙값은 17,225 $(500-403,300)/{\mu}L$ 이었으며 면역표현형은 early pre-B CALLA (+)형이 7명, T 세포형은 5명이었다. 진단 시 예후 중간군이었던 두 명의 환아들에서 골수 재발 하였으며 3명의 환아들이 유방암의 가족력이 있었다. 4명이 사망하여 8년 생존율은 $53.5{\pm}18.7%$였다. 결 론 : p16 단백질의 소실은 소아 급성림프구성백혈병에서 불량한 예후와 연관된 인자로 추정되며 임상에서 진단 시 p16에 대한 유전자 검사뿐만 아니라 단백질에 대해서도 검사가 필요할 것으로 생각된다. 하지만 좀더 많은 환자들에 대한 분석이 더 정확한 연관성을 밝히는데 도움이 될 것으로 사료된다.

Keywords

Acknowledgement

Supported by : 충남대학교

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