Tuberculosis and Respiratory Diseases

The Korean Academy of Tuberculosis and Respiratory Diseases (대한결핵및호흡기학회)
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Promoter Polymorphism of RRM1 Gene in Korean Lung Cancer Population

한국인 폐암 환자에서 RRM1 유전자 Promoter의 다형성

  • Ko, Kyung Haeng (Department of Internal Medicine, Chonnam National University Medical School, H.Lee Moffitt Cancer Center) ;
  • Kim, Eun Joung (Department of Internal Medicine, Chonnam National University Medical School, H.Lee Moffitt Cancer Center) ;
  • Oh, In Jae (Department of Internal Medicine, Chonnam National University Medical School, H.Lee Moffitt Cancer Center) ;
  • Kim, Soo Ock (Department of Internal Medicine, Chonnam National University Medical School, H.Lee Moffitt Cancer Center) ;
  • Son, Jun Gwang (Department of Internal Medicine, Chonnam National University Medical School, H.Lee Moffitt Cancer Center) ;
  • Jung, Jong Pil (Department of Internal Medicine, Chonnam National University Medical School, H.Lee Moffitt Cancer Center) ;
  • Cho, Gye Jung (Department of Internal Medicine, Chonnam National University Medical School, H.Lee Moffitt Cancer Center) ;
  • Ju, Jin Young (Department of Internal Medicine, Chonnam National University Medical School, H.Lee Moffitt Cancer Center) ;
  • Kim, Kyu Sik (Department of Internal Medicine, Chonnam National University Medical School, H.Lee Moffitt Cancer Center) ;
  • Kim, Yu Il (Department of Internal Medicine, Chonnam National University Medical School, H.Lee Moffitt Cancer Center) ;
  • Lim, Sung Chul (Department of Internal Medicine, Chonnam National University Medical School, H.Lee Moffitt Cancer Center) ;
  • Kim, Young Chul (Department of Internal Medicine, Chonnam National University Medical School, H.Lee Moffitt Cancer Center) ;
  • Bepler, Gerold (Department of Internal Medicine, Chonnam National University Medical School, H.Lee Moffitt Cancer Center)
  • 고경행 (전남대학교 의과대학 내과학교실, H.Lee Moffitt Cancer Center) ;
  • 김은정 (전남대학교 의과대학 내과학교실, H.Lee Moffitt Cancer Center) ;
  • 오인재 (전남대학교 의과대학 내과학교실, H.Lee Moffitt Cancer Center) ;
  • 김수옥 (전남대학교 의과대학 내과학교실, H.Lee Moffitt Cancer Center) ;
  • 손준광 (전남대학교 의과대학 내과학교실, H.Lee Moffitt Cancer Center) ;
  • 정종필 (전남대학교 의과대학 내과학교실, H.Lee Moffitt Cancer Center) ;
  • 조계중 (전남대학교 의과대학 내과학교실, H.Lee Moffitt Cancer Center) ;
  • 주진영 (전남대학교 의과대학 내과학교실, H.Lee Moffitt Cancer Center) ;
  • 김규식 (전남대학교 의과대학 내과학교실, H.Lee Moffitt Cancer Center) ;
  • 김유일 (전남대학교 의과대학 내과학교실, H.Lee Moffitt Cancer Center) ;
  • 임성철 (전남대학교 의과대학 내과학교실, H.Lee Moffitt Cancer Center) ;
  • 김영철 (전남대학교 의과대학 내과학교실, H.Lee Moffitt Cancer Center) ;
  • Received : 2006.07.24
  • Accepted : 2006.08.31
  • Published : 2006.09.30
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Abstract

Background: LOH11A is a region with frequent allele loss (>75%) in lung cancer that is located on the centromeric part of chromosome 11p15.5. Clinical and cell biological studies suggest that this region contains a gene associated with metastatic tumor spread. RRM1 encoding the M1 subunit of ribonucleotide reductase, which is an enzyme that catalyses the rate-limiting step in deoxyribonucleotide synthesis, is located in the LOH11A region. Methods: Polymorphisms were found at nucleotide position (-)37 (C/A) and (-)524 (C/T) from the beginning of exon 1 of the RRM1 gene that might regulate the expression of RRM1. We studied the polymorphisms in 127 Korean individuals (66 lung cancer and 61 normal controls) and compared with those of 140 American patients with lung cancer. Results: CC, AC and AA were found at the (-)37 position in 64(50.4%), 55(43.3%), and 8(6.3%) out of 127 Korean individuals (66 cancer, 61 non-cancer patients), respectively. There was a similar frequency of allele A at (-)37 in the American(27.9%) and Korean population(28.0%). CC, CT and TT was found at the (-)524 position in 24(18.9%), 44(34.6%), and 59(46.5%) out of the 127 Korean individuals, respectively. There was a similar frequency of allele C at (-)524 in the American(34.6%) and Korean population(36.2%). There was no difference in the frequency of the (-)37 and (-)524 genotypes between the cancer and non-cancer group. However there was a significant correlation of the genotypes between (-)37 and (-)524 (p<0.001), which suggests the possible coordination of these polymorphisms in the regulation of the promoter activity of the RRM1 gene. Conclusion: RRM1 promoter polymorphisms were not found to be significant risk factors for lung cancer. However, a further study of the promoter activity and expression of the RRM1 gene according to the pattern of the polymorphism will be needed.

연구배경: 약 75% 의 비소세포 폐암에서 loss of heterozygosity (LOH)를 보이는 11p15.5 에 위치한 ribonucleotide reductase M1 subunit gene(RRM1) 유전자는 ras transformed fibroblast를 이용한 실험에서 암세포의 전이능력을 감소시키는 것으로 보고되어 있어서 암억제 유전자로서의 가능성이 높다. RRM1의 promoter 부위인 exon 1 시작에서 (-)37과 (-)524번째 염기에 A/C 그리고 C/T 다형성이 발견되었는데 이 다형성의 양상에 따라 RRM1 유전자의 발현 정도가 조절될 수 있어서 폐암 발생의 위험도가 다를 수 있다. 대상 및 방법: 전남대학교 병원에 내원한 폐암환자들과 비폐암 대조군 환자 127예와 미국인 폐암 환자 140예의 말초혈액 백혈구로부터 얻은 DNA를 이용하여 미국인과 한국인에서의 유전자 다형성의 분포 및 임상적 의의를 조사하였다. 결 과: RRM1 유전자의 Exon 1 으로 부터 (-)37 염기에서 A/C 유전자 다형성은 127예 중 CC가 64예(50.4%), AC는 55예(43.3%), 그리고 AA는 8예(6.3%)에서 발견되었다. Allele A의 빈도는 미국인들의 27.9%에 비하여 한국인에서 28.0%로 차이가 없었고, 폐암군과 비폐암군 간에도 유의한 차이는 관찰되지 않았다. RRM1 유전자의 (-)524 염기에서 C 또는 T 유전자 다형성의 양상은 CC가 24예(18.9%), CT는 44예(34.6%), 그리고 TT는 59예(46.5%)에서 발견되었다. Allele C의 빈도는 36.2%로써 미국인의 34.6%와 차이가 없었고, 폐암군과 비폐암군 간에도 차이는 관찰되지 않았다. RRM1 유전자의 (-)37 염기는 인종에 관계없이 70% 이상에서 C 이었고, (-)524 염기는 65% 정도에서 T를 보이고 있었다. 또한 (-)37과 (-)524 염기는 서로 밀접한 상관관계를 보이고 있었다. 즉 (-)37염기가 모두 C 인 경우 (-)524 염기도 모두 T인 빈도가 높았고, (-)37 염기가 한 개라도 A를 가지고 있는 경우 (-)524 염기도 C를 가지고 있는 빈도가 높았다 (p<0.001). 결 론: RRM1 유전자의 발현을 조절하는 promoter 부위의 두 개의 유전자 다형성의 빈도는 인종 간에 그리고 폐암군과 비폐암군 간에 차이가 없어서 폐암 발생의 위험인자는 아니었다. 그러나 두 유전자 다형성이 서로 특정 조합을 보임으로 그 조합 양상에 따른 promoter 활성도에 대한 연구가 뒤따라야 할 것이다.

Keywords

References

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