Brosens Lodewijk A A, Iacobuzio-Donahue Christine A, Keller Josbert J, Hustinx Steven R, Carvalho Ralph, Morsink Folkert H, Hylind Linda M, Offerhaus G Johan, Giardiello Francis M, Goggins Michael
Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Clin Cancer Res. 2005 Jun 1;11(11):4090-6. doi: 10.1158/1078-0432.CCR-04-2379.
Colorectal cancers arising in patients with familial adenomatous polyposis (FAP) can be largely prevented by polyp surveillance and prophylactic colectomy. As a result, duodenal adenocarcinoma has become a leading cause of death in patients with FAP. Cyclooxygenase 2 (COX-2) inhibition is effective against colorectal polyposis in FAP, but is less effective in treating duodenal polyps. We compared the expression of COX-2 in duodenal and colorectal adenomas from patients with FAP and from patients with sporadic neoplasms and correlated expression to a COX-2 promoter polymorphism (-765G/-->C) that is reported to influence COX-2 expression.
The study population included 36 FAP patients with colonic adenomas, 22 FAP patients with duodenal adenomas, 22 patients with sporadic duodenal adenomas, and 17 patients with sporadic duodenal adenocarcinoma. Neoplastic and corresponding normal tissue COX-2 expressions were determined using immunohistochemistry on tissue microarrays. The prevalence and ethnic distribution of a polymorphism in the COX-2 promoter that influences COX-2 expression (-765G --> C) were determined in DNA from 274 individuals by real-time quantitative PCR.
Among patients with FAP, histologically normal duodenal mucosa showed higher COX-2 expression than normal colonic mucosa (P < 0.02), and duodenal adenomas had higher COX-2 expression than colonic adenomas (P </= 0.01). In addition, the normal duodenum of patients with FAP showed higher COX-2 expression than the normal duodenal mucosa of patients with sporadic adenomas (P < 0.05). COX-2 expression was significantly higher in the normal-appearing (P < 0.01) mucosa of patients with FAP carrying the -765GG genotype compared with those carrying the -765GC or -765CC genotypes. The -765C genotype was more common in African Americans than in Caucasians (52% versus 33%, P < 0.01).
High COX-2 expression in the normal and adenomatous duodenal mucosa of patients with FAP may explain the poorer response of these neoplasms to chemoprevention with COX-2 inhibitors.
家族性腺瘤性息肉病（FAP）患者发生的结直肠癌可通过息肉监测和预防性结肠切除术在很大程度上得到预防。因此，十二指肠腺癌已成为FAP患者的主要死亡原因。环氧合酶2（COX-2）抑制对FAP患者的结直肠息肉病有效，但对十二指肠息肉的治疗效果较差。我们比较了FAP患者和散发性肿瘤患者十二指肠和结肠腺瘤中COX-2的表达，并将其表达与据报道影响COX-2表达的COX-2启动子多态性（-765G/-->C）相关联。
研究人群包括36例患有结肠腺瘤的FAP患者、22例患有十二指肠腺瘤的FAP患者、22例散发性十二指肠腺瘤患者和1例散发性十二指肠腺癌患者。使用组织微阵列上的免疫组织化学法测定肿瘤组织和相应正常组织中COX-2的表达。通过实时定量PCR测定274名个体DNA中影响COX-2表达的COX-2启动子多态性（-765G --> C）的患病率和种族分布。
在FAP患者中，组织学正常的十二指肠黏膜COX-2表达高于正常结肠黏膜（P < 0.02），十二指肠腺瘤的COX-2表达高于结肠腺瘤（P </= 0.01）。此外，FAP患者的正常十二指肠COX-2表达高于散发性腺瘤患者的正常十二指肠黏膜（P < 0.05）。与携带-765GC或-765CC基因型的FAP患者相比，携带-765GG基因型的FAP患者外观正常（P < 0.01）的黏膜中COX-2表达明显更高。-765C基因型在非裔美国人中比在白种人中更常见（52%对33%，P < 0.01）。
FAP患者正常和腺瘤性十二指肠黏膜中COX-2的高表达可能解释了这些肿瘤对COX-2抑制剂化学预防反应较差的原因。
