Human Genetics Group, Spanish National Cancer Research Centre (CNIO) and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain,
Breast Cancer Res Treat. 2013 Sep;141(2):231-42. doi: 10.1007/s10549-013-2696-6. Epub 2013 Sep 15.
Telomere shortening is a common event involved in malignant transformation. Critically short telomeres may trigger chromosomal aberrations and produce genomic instability leading to cancer development. Therefore, telomere shortening is a frequent molecular alteration in early stages of many epithelial tumors and in breast cancer correlates with stage and prognosis. A better understanding of the involvement of short telomeres in tumors may have a significant impact on patient management and the design of more specific treatments. To understand the role of telomere length (TL) in breast cancer etiology we measured the length of individual telomere signals in single cells by using quantitative telomere in situ hybridization in paraffin-embedded tissue from hereditary and sporadic breast cancers. A total of 104 tumor tissue samples from 75 familial breast tumors (BRCA1, n = 14; BRCA2, n = 13; non-BRCA1/2, n = 48) and 29 sporadic tumors were analyzed. Assessment of telomere signal intensity allowed estimation of the mean TL and related variables, such as percentage of critically short telomeres and percentage of cells with short telomeres. These data were correlated with the immunohistochemical expression of molecular breast cancer markers. Hereditary BRCA1, BRCA2, and non-BRCA1/2 tumors were characterized by shorter TL comparing to sporadic tumors. Considering all tumors, tumor grade was a strong risk factor determining the proportion of short telomeres or short telomere cells. Moreover, some histopathological features appeared to be differentially associated to hereditary or sporadic subgroups. Short telomeres correlated with ER-negative tumors in sporadic cases but not in familial cases, whereas a high level of apoptosis was associated with shorter telomeres in hereditary BRCA1 and BRCA2 tumors. In addition, TL helped to define a subset of non-BRCA1/2 tumors with short telomeres associated with increased expression of antiapoptotic proteins. These findings highlight the potential interest of TL measurements as markers of aggressiveness in breast cancer.
端粒缩短是恶性转化中常见的事件。关键的短端粒可能会触发染色体畸变并产生基因组不稳定性，从而导致癌症的发展。因此，端粒缩短是许多上皮肿瘤早期和乳腺癌中常见的分子改变，与分期和预后相关。更好地理解短端粒在肿瘤中的作用可能会对患者的管理和更具针对性的治疗方案的设计产生重大影响。为了了解端粒长度（TL）在乳腺癌发病机制中的作用，我们使用定量端粒原位杂交技术在遗传性和散发性乳腺癌的石蜡包埋组织中测量了单个细胞中端粒信号的长度。总共分析了 75 例家族性乳腺癌（BRCA1，n=14；BRCA2，n=13；非 BRCA1/2，n=48）和 29 例散发性肿瘤的 104 个肿瘤组织样本。评估端粒信号强度可以估计平均 TL 及其相关变量，如临界短端粒的百分比和短端粒细胞的百分比。这些数据与分子乳腺癌标志物的免疫组织化学表达相关。与散发性肿瘤相比，遗传性 BRCA1、BRCA2 和非 BRCA1/2 肿瘤的 TL 较短。考虑到所有肿瘤，肿瘤分级是确定短端粒或短端粒细胞比例的强危险因素。此外，一些组织病理学特征似乎与遗传性或散发性亚组有不同的关联。在散发性病例中，短端粒与 ER 阴性肿瘤相关，但在家族性病例中不相关，而在遗传性 BRCA1 和 BRCA2 肿瘤中，高水平的凋亡与短端粒相关。此外，TL 有助于定义一组非 BRCA1/2 肿瘤，这些肿瘤的短端粒与抗凋亡蛋白表达增加相关。这些发现强调了 TL 测量作为乳腺癌侵袭性标志物的潜在意义。
