The role of SMAD4 in early-onset colorectal cancer.
The role of SMAD4 in early-onset colorectal cancer.
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DOI：
10.1111/j.1463-1318.2009.01779.x
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发表时间：
2010-03
期刊：
影响因子：
--
通讯作者：
Southey MC
中科院分区：
文献类型：
--
作者：
Royce SG;Alsop K;Haydon A;Mead L;Smith LD;Tesoriero AA;Giles GG;Jenkins MA;Hopper JL;Southey MC
据报道，18 q区域内的染色体丢失和SMAD 4表达丢失是结直肠癌肿瘤进展期间常见的体细胞事件;然而，其与发病年龄的相关性尚未得到广泛研究。我们分析了一项基于人群的病例家族研究中的109例肿瘤，该研究基于45岁之前诊断的结直肠癌。这些早发性结直肠癌患者先前已筛查生殖系错配修复基因突变、微卫星不稳定性（包括TGFβRII中的单核苷酸重复）和体细胞k-ras突变。我们使用免疫组织化学方法测量了SMAD 4蛋白表达，并使用定量实时PCR方法测量了SMAD 4拷贝数。SMAD 4蛋白表达的缺失在27/109（25%）的测试癌症中观察到，并且当与结肠中产生的肿瘤（11/66，17%）相比时，在直肠肿瘤（15/41，36%）中更常见（P = 0.04）。SMAD 4蛋白表达与TGFβR11突变状态、SMAD 4拷贝数、家族史、MSI状态、肿瘤分期或分级无关。SMAD 4表达缺失是早发性结直肠肿瘤的常见特征，因为它在其他年龄组诊断的结直肠癌中也是如此。总的来说，目前已知的与早发性结直肠癌有关的分子途径（遗传和表观遗传）只能解释一小部分疾病，需要进一步探索。
Chromosomal loss within the region of 18q and loss of SMAD4 expression have been reported to be frequent somatic events during colorectal cancer tumour progression; however, their associations with age at onset have not been widely studied. We analysed 109 tumours from a population-based case-family study based on colorectal cancers diagnosed before the age of 45 years. These patients with early-onset colorectal cancer had been previously screened for germ-line mismatch repair gene mutations, microsatellite instability (that included the mononucleotide repeat in TGFβRII) and somatic k-ras mutations. We measured SMAD4 protein expression using immunohistochemistry and SMAD4 copy number using quantitative real-time PCR. Loss of SMAD4 protein expression was observed in 27/109 (25%) of cancers tested and was more commonly observed in rectal tumours (15/41, 36%) when compared with tumours arising in the colon (11/66, 17%) (P = 0.04). There was no association between SMAD4 protein expression and TGFβR11 mutation status, SMAD4 copy number, family history, MSI status, tumour stage or grade. Loss of SMAD4 expression is a common feature of early-onset colorectal tumours as it is in colorectal cancers diagnosed in other age-groups. Taken together, the molecular pathways (genetic and epigenetic) now known to be involved in early-onset colorectal cancer only explain a small proportion of the disease and require further exploration.
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