title: Short telomeres are frequent in hereditary breast tumors and are associated with high tumor grade.
abstract: 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.
authors.affiliation: Human Genetics Group, Spanish National Cancer Research Centre (CNIO) and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain, bmartinezd@isciii.es.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Martinez-Delgado
authors.forename: Mercedes
authors.initials: M
authors.lastname: Gallardo
authors.forename: Miljana
authors.initials: M
authors.lastname: Tanic
authors.forename: Kira
authors.initials: K
authors.lastname: Yanowsky
authors.forename: Lucia
authors.initials: L
authors.lastname: Inglada-Perez
authors.forename: Alicia
authors.initials: A
authors.lastname: Barroso
authors.forename: Maria
authors.initials: M
authors.lastname: Rodriguez-Pinilla
authors.forename: Marta
authors.initials: M
authors.lastname: Cañamero
authors.forename: Maria A
authors.initials: MA
authors.lastname: Blasco
authors.forename: Javier
authors.initials: J
authors.lastname: Benitez
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D009154:Mutation; D060787:Neoplasm Grading; D059506:Telomere Shortening
chemical_list: D014408:Biomarkers, Tumor