Location in the large bowel influences the APC mutations observed in FAP adenomas
Location in the large bowel influences the APC mutations observed in FAP adenomas
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大肠的位置影响 FAP 腺瘤中观察到的 APC 突变
DOI：
10.1007/s10689-010-9332-y
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发表时间：
2010
期刊：
影响因子：
2.2
通讯作者：
Ian Tomlinson
中科院分区：
文献类型：
--
作者：
O. Will;S. Leedham;George Elia;R. Phillips;Susan K Clark;Ian Tomlinson;Ian Tomlinson
右结肠在胚胎起源、腔环境和功能上与左结肠不同。在散发性结直肠癌和家族性腺瘤性息肉病(FAP)中，息肉密度和癌症易感性因结肠部位而有显著差异。FAP中的腺瘤在小肠和结肠有不同的突变谱。本研究旨在探讨结肠位置是否也影响FAP的APC突变谱。对5例1309密码子突变患者的127例1~2 mm轻度异型增生腺瘤和3例1265密码子突变患者的41例患者进行了杂合性丢失(LOH)频率的分析。我们选择了来自结肠不同位置的息肉。采用免疫组织化学方法检测Wnt通路的激活、凋亡和增殖情况。在1309突变患者的息肉中，杂合性缺失的频率显示出从直肠(最高)到盲肠/升结肠(最低)的梯度，但在近端胚系APC突变的患者中不存在这种情况。逐个隐窝的分析证实了整个息肉的LOH发现。β-catenin和caspase-3在肿瘤和正常组织中的表达无明显差异，但Ki-67在肿瘤和正常组织中的表达从升结肠到直肠呈递减趋势。结肠部位改变了APC的突变谱，改变了隐窝细胞的增殖。1309密码子突变患者的直肠息肉中较高的LOH频率可能有助于解释与具有其他种系APC突变的患者相比，他们在该位置的息肉负担增加。
The right colon differs from the left, in embryological origin, luminal environment, and function. In both sporadic colorectal cancer and Familial Adenomatous Polyposis (FAP), polyp density and cancer susceptibility vary markedly by colonic site. Adenomas in FAP have a different mutational spectrum in small intestine versus colon. This study aimed to investigate whether colonic location also influences the APC mutation spectrum in FAP. 127 1–2 mm mildly dysplastic adenomas from 5 patients with a codon 1309 germline mutation, and 41 from 3 patients with mutations proximal to codon 1265, were analysed to assess the frequency of loss of heterozygosity (LOH). We chose polyps from different locations in the colon. Immunohistochemistry for beta-catenin, caspase-3 and Ki-67 was performed to assess Wnt pathway activation, apoptosis and proliferation. In polyps from patients with a 1309 mutation, the frequency of LOH showed a gradient from rectum (highest) to caecum/ascending colon (lowest), but this was not present in patients with proximal germline APC mutations. Crypt-by-crypt analysis confirmed the LOH findings from whole polyps. Beta-catenin and caspase-3 expression showed no significant variation by colonic region, but Ki-67 expression decreased from ascending colon to rectum in tumours and normal tissue. Colonic site alters the mutational spectrum of APC, and crypt cell proliferation. The higher frequency of LOH in rectal polyps from patients with codon 1309 mutations may help to explain their increased polyp burden at this site compared with patients who have other germline APC mutations.