Chao Dennis L, Sanchez Carissa A, Galipeau Patricia C, Blount Patricia L, Paulson Thomas G, Cowan David S, Ayub Kamran, Odze Robert D, Rabinovitch Peter S, Reid Brian J
Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
Clin Cancer Res. 2008 Nov 1;14(21):6988-95. doi: 10.1158/1078-0432.CCR-07-5063.
Elevated cellular proliferation and cell cycle abnormalities, which have been associated with premalignant lesions, may be caused by inactivation of tumor suppressor genes. We measured proliferative and cell cycle fractions of biopsies from a cohort of patients with Barrett's esophagus to better understand the role of proliferation in early neoplastic progression and the association between cell cycle dysregulation and tumor suppressor gene inactivation.
Cell proliferative fractions (determined by Ki67/DNA multiparameter flow cytometry) and cell cycle fractions (DNA content flow cytometry) were measured in 853 diploid biopsies from 362 patients with Barrett's esophagus. The inactivation status of CDKN2A and TP53 was assessed in a subset of these biopsies in a cross-sectional study. A prospective study followed 276 of the patients without detectable aneuploidy for an average of 6.3 years with esophageal adenocarcinoma as an end point.
Diploid S and 4N (G(2)/tetraploid) fractions were significantly higher in biopsies with TP53 mutation and loss of heterozygosity. CDKN2A inactivation was not associated with higher Ki67-positive, diploid S, G(1), or 4N fractions. High Ki67-positive and G(1)-phase fractions were not associated with the future development of esophageal adenocarcinoma (P=0.13 and P=0.15, respectively), whereas high diploid S-phase and 4N fractions were (P=0.03 and P<0.0001, respectively).
High Ki67-positive proliferative fractions were not associated with inactivation of CDKN2A and TP53 or future development of cancer in our cohort of patients with Barrett's esophagus. Biallelic inactivation of TP53 was associated with elevated 4N fractions, which have been associated with the future development of esophageal adenocarcinoma.
细胞增殖增加和细胞周期异常与癌前病变相关，可能由肿瘤抑制基因失活引起。我们测量了一组巴雷特食管患者活检组织的增殖和细胞周期分数，以更好地了解增殖在早期肿瘤进展中的作用以及细胞周期失调与肿瘤抑制基因失活之间的关联。
在362例巴雷特食管患者的853份二倍体活检组织中测量细胞增殖分数（通过Ki67/DNA多参数流式细胞术测定）和细胞周期分数（DNA含量流式细胞术）。在一项横断面研究中，对这些活检组织的一个亚组评估了CDKN2A和TP53的失活状态。一项前瞻性研究对276例无可检测非整倍体的患者进行了平均6.3年的随访，以食管腺癌为终点。
在有TP53突变和杂合性缺失的活检组织中，二倍体S期和4N（G2/四倍体）分数显著更高。CDKN2A失活与较高的Ki67阳性、二倍体S期、G1期或4N分数无关。高Ki67阳性和G1期分数与食管腺癌的未来发生无关（分别为P = 0.13和P = 0.15），而高二倍体S期和4N分数则有关（分别为P = 0.03和P < 0.0001）。
在我们的巴雷特食管患者队列中，高Ki67阳性增殖分数与CDKN2A和TP53失活或癌症未来发生无关。TP53双等位基因失活与升高的4N分数相关，而4N分数与食管腺癌的未来发生有关。
