한국인의 편평세포암과 기저세포암에서 Methylenetetrahydrofolate reductase(MTHFR)와 Thymidylate synthase(TS) 유전자 돌연변이

Abstract

[한글]피부암의 발생에 복구 유전자의 돌연변이, 엽산 합성과정의 손상, 유전자 합성과정의 변성등 유전적 불안정을 초래하는 여러 가지의 원인들이 보고되었다. Methylentetrahydrofolate reductase(MTHFR)와 Thymidylate synthase(TS)는 엽산 대사과정과 유전자 합성과정에 중요한 효소로 최근 들어 다른 질병과의 관련성이 밝혀지면서 관심이 높아지고 있다. 본 연구는 MTHFR과 TS의 돌연변이형과 관련하여, 한국인의 기저세포암과 편평세포암 발생위험도를 조사하였다.

연세대학교 원주의과대학과 포천중문의과대학 성형외과에서 피부암으로 수술 받고 병리학적 진단을 받은 기저세포암 환자 100명, 편평세포암 환자 100명과 포천중문의과대학 임상의학 연구소의 유전자 표본 중 암 병력을 갖지 않은 207명을 대조군으로 MTHFR과 TS의 돌연변이형을 Polymerase Chain Reaction(PCR)/ Restriction Fragment Length Polymorphism(RFLP)을 시행하여 분석하였다.

MTHFR 677C>T, MTHFR 1298A>C 돌연변이는 기저세포암과 편평세포암 환자에서 모두 대조군과 의미 있는 차이를 나타내지 않았다. TS 3'UTR 1494 6bp 돌연변이는 기저세포암 발생 위험도가 통계학적으로 유의 있게 높았다. 즉, 이형접합 변이형(-6bp/+6bp)에서 2.8배(AOR=2.821), 동형접합 변이형(+6bp/ +6bp)에서 7배(AOR=7.539), 그리고 이형접합 변이형이거나 동형접합변이형인 경우에 암발생 위험도는 3배(AOR=3.079)이상 높았다. 그러나 TS 3'UTR 1494 6bp 돌연변이는 편평세포암에서 대조군과 비교하여 유의한 차이를 보이지 않았다.

이상의 결과로 TS 3'UTR 1494 6bp deletion/insertion은 한국인에서 기저세포암 발생위험도를 높이는 인자임 강력히 시사한다.

[영문]Methylentetrahydrofolate reductase(MTHFR) and Thymidylate synthase (TS) are important enzymes in folic acid metabolism and DNA synthesis. Despite intense evidences of MTHFR and TS in relation with oncogenesis, direct linkage of these genes with skin cancer was poorly documented. Moreover, whether these gene would be plausible risk factor of skin cancer is veiled. To adress these issues, we analyzed the risk-factor relationship between a variety of MTHFR and TS polymorphism with the basal cell carcinoma and squamous cell carcinoma of Korean people.

The study population was composed of 200 patients with skin cancer(n=100 squamous cell carcinoma, n=100 basal cell carcinoma) and 207 control subjects. Patients with skin cancer were enrolled and recruited form January 1998 to March 2006 in the Department of Plastic and Reconstructive Surgery at Yonsei Wonju Christian Hospital and the Department of Plastic and Reconstructive Surgery at Bundang CHA General Hospital. The controls(n=207) were healthy individuals without any history of premalignant skin lesions or other malignant disorders. Blood and tissue samples from both groups were analyzed for the presence of MTHFR C677T, MTHFR A1298C polymorphism and 3'UTR 1494 6bp deletion/insertion using the RCP/RELP method.

We found that MTHFR A1298C is a factor that contributes to the development of squamous cell carcinoma among people 55 years or older by almost 3 times(OR=3.351) the normal rate. However, in patients of basal cell carcinoma and squamous cell carcinoma, MTHFR C677T and MTHFR A1298C mutations did not show a meaningful difference to the control. In basal cell carcinoma, TS 3'UTR 1494 6bp deletion/insertion significantly increases the statistical risk of basal cell carcinoma. The risk of cancer is increased 2.8 times(AOR=2.821) in heterozygous type variables(-6bp/+6bp), 7 times(AOR=7.53 9) in homozygous type variables(+6bp/ +6bp), and by 3 times (AOR=3.079) in the case where heterozygous type variables(-6bp/+6bp) and homozygous variables(+6bp/ +6bp) are combined. However, in squamous cell carcinoma, TS 3'UTR 1494 6bp deletion/insertion does not result in any meaningful differences with a control. In addition, when AA/6bp(+) is compared with AA/6bp(-) in combination with MTHFR A1298C/TS 3'UTR 1494 6bp deletion/insertion, there is a correlation between AA/6bp(+) and AA/6bp(-) that shows the risk of basal cell carcinoma is increased by 3 times (AOR=3.288).

The data indicates that TS 3'UTR 1494 6bp deletion/insertion significantly produces a higher risk of basal cell carcinoma.