Schildkraut J M, Bastos E, Berchuck A
Department of Community and Family Medicine, Duke Comprehensive Cancer Center, Duke University Medical Center, Durham, NC 27710, USA.
J Natl Cancer Inst. 1997 Jul 2;89(13):932-8. doi: 10.1093/jnci/89.13.932.
Several lines of evidence have suggested a relationship between a woman's number of ovulatory cycles and the development of ovarian epithelial cancer. Repair of the ovarian surface after ovulation requires cellular proliferation, and spontaneous mutations arising during the DNA synthesis that accompanies this proliferation may play a role in carcinogenesis.
We conducted a molecular epidemiologic study to test the hypothesis that a greater number of ovulatory cycles increases the risk of ovarian cancer by inducing proliferation-associated DNA damage. In particular, we examined the association between the lifetime number of ovulatory cycles and mutation of the p53 tumor-suppressor gene (also known as TP53) in ovarian tumors.
Case-case and case-control analyses involving participants in the Cancer and Steroid Hormone study were used to examine the association between p53 gene mutation in ovarian tumors and the lifetime number of ovulatory cycles. The women in our study were 20-54 years of age and included 197 case patients with invasive ovarian epithelial cancer and 3363 control subjects. Mutation of the p53 gene was indicated by overexpression of p53 protein (i.e., cellular accumulation of mutant p53 protein) in paraffin-embedded ovarian cancer tissue blocks; the mutant protein was detected by means of standard immunohistochemical techniques. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by employing multivariate analyses, with the use of logistic regression. Reported P values are two-sided.
Women whose cancers overexpressed p53 protein (p53 positive) had a greater mean number of lifetime ovulatory cycles (388 +/- 77.4 cycles [mean +/- standard deviation]) than women whose cancers did not overexpress p53 protein (p53 negative) (342 +/- 119.0 cycles) (P = .0025). Furthermore, women with p53-positive tumors were more likely to have had moderate (i.e., 235-375) or high (i.e., 376-533) numbers of ovulatory cycles than women with p53-negative tumors (age-adjusted ORs = 7.0 [95% CI = 1.6-30.5] and 7.7 [95% CI = 1.4-41.2], respectively) (< or = 234 cycles was the referent category). After controlling for age, menopausal status, and nulliparity, women with p53-positive tumors were found to be significantly more likely to have had moderate or high numbers of ovulatory cycles than control subjects (ORs = 4.3 [95% CI = 1.4-13.0] and 9.1 [95% CI = 2.7-30.9], respectively); the corresponding ORs for women with p53-negative tumors compared with control subjects were 0.6 (95% CI = 0.3-1.4) and 1.3 (95% CI = 0.5-3.2), respectively.
A higher number of ovulatory cycles may be associated with increased amounts of proliferation-associated DNA damage and increased risk of developing p53-positive but not p53-negative epithelial ovarian cancer. Our results are consistent with more than one developmental pathway in the pathogenesis of this type of cancer.
多项证据表明女性排卵周期的数量与卵巢上皮癌的发生之间存在关联。排卵后卵巢表面的修复需要细胞增殖，而伴随这种增殖的DNA合成过程中产生的自发突变可能在致癌过程中起作用。
我们开展了一项分子流行病学研究，以检验排卵周期数量增多通过诱导与增殖相关的DNA损伤而增加卵巢癌风险这一假说。特别是，我们研究了卵巢肿瘤中排卵周期的终生数量与p53肿瘤抑制基因（也称为TP53）突变之间的关联。
采用癌症与类固醇激素研究参与者的病例-病例分析和病例对照分析，来研究卵巢肿瘤中p53基因突变与排卵周期的终生数量之间的关联。我们研究中的女性年龄在20至54岁之间，包括197例浸润性卵巢上皮癌病例患者和3363名对照对象。p53基因的突变通过石蜡包埋的卵巢癌组织块中p53蛋白的过表达（即突变型p53蛋白的细胞积聚）来表明；采用标准免疫组织化学技术检测突变蛋白。通过多变量分析并运用逻辑回归来估计比值比（OR）和95%置信区间（CI）。报告的P值为双侧。
癌症中p53蛋白过表达（p53阳性）的女性，其排卵周期的终生平均数量（388±77.4个周期[均值±标准差]）高于癌症中p53蛋白未过表达（p53阴性）的女性（342±119.0个周期）（P = 0.0025）。此外，与p53阴性肿瘤的女性相比，p53阳性肿瘤的女性更有可能经历中等（即235 - 375个）或高（即376 - 533个）数量的排卵周期（年龄调整后的OR分别为7.0 [95% CI = 1.6 - 30.5]和7.7 [95% CI = 1.4 - 41.2]）（≤234个周期为参照类别）。在控制年龄、绝经状态和未生育因素后，发现p53阳性肿瘤的女性经历中等或高数量排卵周期的可能性显著高于对照对象（OR分别为4.3 [95% CI = 1.4 - 13.0]和9.1 [95% CI = 2.7 - 30.9]）；p53阴性肿瘤的女性与对照对象相比，相应的OR分别为0.6（95% CI = 0.3 - 1.4）和1.3（95% CI = 0.5 - 3.2）。
排卵周期数量较多可能与增殖相关的DNA损伤量增加以及发生p53阳性而非p53阴性上皮性卵巢癌的风险增加有关。我们的结果与这类癌症发病机制中的多种发展途径一致。
