Hardingham J E, Butler W J, Roder D, Dobrovic A, Dymock R B, Sage R E, Roberts-Thomson I C
Department of Haematology-Oncology, Queen Elizabeth Hospital, Australia.
Gut. 1998 May;42(5):669-72. doi: 10.1136/gut.42.5.669.
Somatic mutations in K-ras and TP53 may be associated with both acetylator status and prognosis in colorectal cancer.
To determine whether cancers with somatic mutations are more frequent in fast acetylators and whether mutations or acetylator status influence prognosis after colorectal surgery.
One hundred consecutive subjects undergoing elective surgery for colorectal cancer.
Acetylator status was determined by polymerase chain reaction (PCR) genotyping for polymorphism in the N-acetyltransferase 2 (NAT2) gene. Mutations in K-ras (codon 12) and TP53 were determined by PCR analysis using restriction enzyme digestion and single strand conformation polymorphism respectively. Survival from colorectal cancer for up to five years after diagnosis was analysed using the Kaplan-Meier product limit estimator. Cox proportional hazards regression was used to compare survival rates after adjusting for tumour stage.
Mutations in K-ras and TP53 were independent of acetylator status. By log rank test, survival was significantly reduced in subjects with TP53 mutations (p = 0.003) but was not significantly related to acetylator status or the presence of K-ras mutations. After adjustment for tumour stage, subjects with both TP53 and K-ras mutations had a 4.2-fold case fatality (95% confidence interval 1.5 to 11.6) when compared with that of a TP53 negative reference group.
The presence of both TP53 and K-ras mutations in colorectal tumours is an adverse prognostic marker which is independent of tumour stage.
K-ras和TP53的体细胞突变可能与结直肠癌的乙酰化状态及预后相关。
确定快速乙酰化者中发生体细胞突变的癌症是否更常见，以及突变或乙酰化状态是否影响结直肠手术后的预后。
100例连续接受择期结直肠癌手术的患者。
通过聚合酶链反应（PCR）基因分型检测N-乙酰转移酶2（NAT2）基因多态性来确定乙酰化状态。分别使用限制性内切酶消化和单链构象多态性的PCR分析来检测K-ras（密码子12）和TP53的突变。使用Kaplan-Meier乘积限估计法分析诊断后长达五年的结直肠癌生存率。采用Cox比例风险回归在调整肿瘤分期后比较生存率。
K-ras和TP53的突变与乙酰化状态无关。通过对数秩检验，TP53突变患者的生存率显著降低（p = 0.003），但与乙酰化状态或K-ras突变的存在无显著相关性。在调整肿瘤分期后，与TP53阴性参照组相比，同时具有TP53和K-ras突变的患者病死率高4.2倍（95%置信区间1.5至11.6）。
结直肠肿瘤中同时存在TP53和K-ras突变是一种不良预后标志物，且独立于肿瘤分期。
