Prognostic Significance of Telomere Attrition in Ductal Carcinoma in situ of the Breast

摘要

We are using an innovative, quantitative assay for telomere DNA content (TC) developed and characterized by the PI, to test the hypothesis that TC predicts the likelihood of disease recurrence in women with ductal carcinoma in situ (DCIS). In Year One, we collaborated to determine whether TC measured in bulk DCIS tumor tissue is comparable to that measured in tumor epithelial cells purified by laser-capture microscopy. In 7/10 instances, TC in microdissected specimens was 72-112% of that in the undissected control. In Years Two and Three, we confirmed and extended these results in our own laboratory. TC in microdissected samples was compared to TC in unfractionated samples; in 10/10 instances, TC in the microdissected sample was 75-124% of that in the undissected (i.e. bulk) control. These results confirm that it is not necessary to microdissect DCIS specimens prior to TC analysis. In Years One- Three, we measured TC in 75 normal breast, 126 DCIS and 657 breast tumor specimens. In Year Two, we used a Kaplan-Meier plot and log-rank test to show that low TC predicts a shorter survival interval. TC was not associated with ethnicity, menopausal status, or the expression of several other markers, including ER, PR, p53, Ki67, and Her2. In Years Three-Four, we demonstrated an association between TC, the extent of allelic imbalance and tumor stage. In Year Four, we obtained longer follow-up to confirm and extend these results. In summary, we have shown that (i) meaningful TC measurements can be obtained with bulk DCIS tissues, (ii) TC is associated with tumor stage and (iii) TC in DCIS is associated with breast cancer-free survival.