Chao Dennis L, Maley Carlo C, Wu Xifeng, Farrow Diana C, Galipeau Patricia C, Sanchez Carissa A, Paulson Thomas G, Rabinovitch Peter S, Reid Brian J, Spitz Margaret R, Vaughan Thomas L
Division of Human Biology, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, C1-157, Seattle, WA 98109, USA.
Cancer Epidemiol Biomarkers Prev. 2006 Oct;15(10):1935-40. doi: 10.1158/1055-9965.EPI-06-0492.
Defects in DNA damage recognition and repair have been associated with a wide variety of cancers. We conducted a prospective study to determine whether mutagen sensitivity, as determined by an in vitro assay, was associated with the future development of cancer in patients with Barrett's esophagus, which is associated with increased risk of progression to esophageal adenocarcinoma.
We measured sensitivity to bleomycin in peripheral blood lymphocytes in a cohort of 220 patients with Barrett's esophagus. We followed these patients for 1,230 person-years (range, 3 months to 10.1 years; median, 6.4 years), using development of cancer and aneuploidy as end points. A subset of these patients was evaluated for inactivation of tumor-suppressor genes CDKN2A/p16 and TP53 [by mutation and loss of heterozygosity (LOH)] in their Barrett's segments at the time of, or before, the bleomycin test, and the patients were stratified by CDKN2A/p16 and TP53 status in an analysis of mutagen sensitivity and progression.
Bleomycin-sensitive patients were found to be at significantly greater risk of developing aneuploidy (adjusted hazard ratio, 3.71; 95% confidence interval, 1.44-9.53) and nonsignificantly greater risk of cancer (adjusted hazard ratio, 1.63; 95% confidence interval, 0.71-3.75). Among patients with detectable LOH at the TP53 locus (on chromosome 17p), increasing bleomycin sensitivity was associated with increased risk of developing cancer (P(trend) < 0.001) and aneuploidy (P(trend) = 0.005).
This study supports the hypothesis that sensitivity to mutagens increases the risk of neoplastic progression in persons with Barrett's esophagus, particularly those with 17p LOH including TP53.
DNA损伤识别和修复缺陷与多种癌症相关。我们开展了一项前瞻性研究，以确定通过体外检测确定的诱变敏感性是否与巴雷特食管患者未来患癌风险相关，巴雷特食管与进展为食管腺癌的风险增加有关。
我们在一组220例巴雷特食管患者中测量了外周血淋巴细胞对博来霉素的敏感性。我们以患癌和非整倍体的发生为终点，对这些患者进行了1230人年的随访（范围为3个月至10.1年；中位数为6.4年）。在博来霉素检测时或检测前，对这些患者的一部分进行了巴雷特段肿瘤抑制基因CDKN2A/p16和TP53的失活评估（通过突变和杂合性缺失[LOH]），并在诱变敏感性和进展分析中根据CDKN2A/p16和TP53状态对患者进行分层。
发现博来霉素敏感患者发生非整倍体的风险显著更高（调整后的风险比为3.71；95%置信区间为1.44 - 9.53），患癌风险更高但无统计学意义（调整后的风险比为1.63；95%置信区间为0.71 - 3.75）。在TP53基因座（位于17号染色体短臂）存在可检测到的LOH的患者中，博来霉素敏感性增加与患癌风险增加（P趋势<0.001）和非整倍体风险增加（P趋势 = 0.005）相关。
本研究支持以下假设，即对诱变剂的敏感性会增加巴雷特食管患者，特别是那些包括TP53在内有17p LOH的患者发生肿瘤进展的风险。
