Arg462Gln sequence variation in the prostate-cancer-susceptibility gene RNASEL and age of onset of hereditary non-polyposis colorectal cancer:: a case-control study
Arg462Gln sequence variation in the prostate-cancer-susceptibility gene RNASEL and age of onset of hereditary non-polyposis colorectal cancer:: a case-control study
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DOI：
10.1016/s1470-2045(05)70253-9
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发表时间：
2005-08-01
期刊：
影响因子：
51.1
通讯作者：
Schackert, HK
中科院分区：
文献类型：
--
作者：
Krüger, S;Silber, AS;Schackert, HK
背景：RNASE L被认为是遗传性前列腺癌的易感基因，编码核糖核酸酶L，参与细胞凋亡，是一种候选的肿瘤抑制蛋白。RNASEL的一种常见的序列变异Arg462Gln与遗传性和散发性前列腺癌有关，而Gln变体在体外约有三倍的RNase活性降低。鉴于遗传性非息肉病的发病年龄与结直肠之间的关系。本研究旨在探讨RNASL基因Arg462Gln变异对遗传性非息肉病性结直肠癌发病年龄的影响。方法对251例遗传性非息肉病性结直肠癌患者进行MSH2(n=141)或MLH1(n=110)致病胚系突变，以结直肠癌为首发肿瘤，检测RNASL基因第462位密码子变异，并与439例健康对照进行比较。结果发现，遗传性非息肉病性结直肠癌患者的发病年龄中位数为40岁(17~75岁)。Arg/Gln基因携带者年龄为37岁(13-69岁)，Gln/Gln基因携带者为34岁(20-49岁)(p=0.0198)。只有RNASE-L基因对发病年龄有显著影响(p=0.0062)，为加性遗传方式。两组基因型之间的配对比较显示，两个纯合子组(即Arg/Arg和Gln/Gln)在发病年龄上存在显著差异(平均年龄相差4.8岁[SD1.7]，p=0.0044)。RNASEL密码子462的基因型别与遗传性非息肉病性结直肠癌的发病年龄呈剂量依赖关系，并可能在该病的预防策略中发挥作用。
Background RNASEL is thought to be a susceptibility gene for hereditary prostate cancer and encodes the endoribonuclease RNase L, which has a role in apoptosis and is a candidate tumour-suppressor protein. A common sequence variation in RNASEL, Arg462Gln, has been associated with hereditary and sporadic prostate cancer, and the Gln variant has about three-fold reduced RNase activity in vitro. In view of the association between the age of onset of hereditary non-polyposis colorectal. cancer and functionally different variants of P53, which play a key part in the apoptotic pathway, we aimed to assess whether the Arg462Gln variation of RNASEL affects the age of onset of hereditary non-polyposis colorectal cancer.Methods We screened 251 patients with hereditary non-polyposis colorectal cancer who were unrelated, had pathogenic germline mutations in MSH2 (n=141) or MLH1 (n=110), and had colorectal carcinoma as the first tumour, for variation at codon 462 of RNASEL and compared them with 439 healthy controls.Findings The median age of onset was 40 years (range 17-75) for patients with an Arg/Arg genotype at codon 462, 37 years (13-69) for patients with an Arg/Gln genotype, and 34 years (20-49) for those with a Gln/Gln genotype (p=0.0198). Only the RNASEL genotype had a significant effect on age of onset (p=0.0062) in an additive mode of inheritance. Pair-wise comparisons between genotype groups showed that the two homozygous groups (ie, Arg/Arg vs Gln/Gln) differed significantly in age of disease onset (mean age difference 4.8 years [SD 1.7], p=0.0044).Interpretation A sequence variation in the prostate-cancer-susceptibility gene RNASEL has a role in a different, unassociated malignant disease. Genotypes at RNASEL codon 462 are associated with age of onset of hereditary non-polyposis colorectal cancer in a dose-dependent way, and might have a role in preventive strategies for this disease.