Telomere DNA content and allelic imbalance demonstrate field cancerization in histologically normal tissue adjacent to breast tumors

Abstract

Cancer arises from an accumulation of mutations that promote the selection of cells with progressively malignant phenotypes. Previous studies have shown that genomic instability, a hallmark of cancer cells, is a driving force in this process. In the present study, two markers of genomic instability, telomere DNA content and allelic imbalance, were examined in two independent cohorts of mammary carcinomas. Altered telomeres and unbalanced allelic loci were present in both tumors and surrounding histologically normal tissues at distances at least 1 cm from the visible tumor margins. Although the extent of these genetic changes decreases as a function of the distance from the visible tumor margin, unbalanced loci are conserved between the surrounding tissues and the tumors, implying cellular clonal evolution. Our results are in agreement with the concepts of ''field cancerization'' and ''cancer field effect,'' concepts that were previously introduced to describe areas within tissues consisting of histologically normal, yet genetically aberrant, cells that represent fertile grounds for tumorigenesis. The finding that genomic instability occurs in fields of histologically normal tissues surrounding the tumor is of clinical importance, as it has implications for the definition of appropriate tumor margins and the assessment of recurrence risk factors in the context of breast-sparing surgery. ' 2006 Wiley-Liss, Inc.Key words: telomere loss; allelic imbalance; genomic instability; cancer field effect; breast cancer Genomic instability is an important factor in the progression of human cancers. [1][2][3][4] One mechanism that underlies genomic instability is loss of telomere function. [5][6][7] Telomeres are nucleoprotein complexes located at the ends of eukaryotic chromosomes. Telomeres in human somatic cells are composed of 1,000 to 2,000 tandemly repeated copies of the hexanucleotide DNA sequence, TTAGGG. 8 Numerous telomere binding proteins are associated with these repeat regions and are important for telomere maintenance. 9,10 Telomeres stabilize chromosome ends and prevent them from being recognized by the cell as DNA double-strand breaks, thereby preventing degradation and recombination. 11 However, telomeres can be critically shortened, and thereby become dysfunctional, by several mechanisms, including incomplete replication of the lagging strand during DNA synthesis, 12 loss or alterations of telomere-binding proteins involved in telomere maintenance, 13 and oxidative stress leading to DNA damage. 14 Alternatively, telomere loss may be compensated for by recombination 15,16 or, as seen in the majority of human cancers, by the enzyme telomerase. 17,18 Telomeres in tumors are frequently shorter than in the matched adjacent normal tissues, presumably reflecting their extensive replicative histories. [19][20][21] The cause-and-effect relation between dysfunctional telomeres and genomic instability implies that shortened telomeres are also associated with altered gene expression. The latter is a primary source of p...

Telomeres: Prognostic markers for solid tumors

“…Median TC in men with cancer recurrence within 6 years was~50% of TC in men who remained disease-free in tumor (p 5 0.012), and surprisingly, also in tumor adjacent histologically normal tissues (p 5 0.024). As mentioned earlier, the latter supports the concept, shown previously by us and others, 12,15,45 that telomere attrition takes place in histologically normal tissue adjacent to the corresponding tumors, and may thus represent an early event in tumor formation. This phenomenon may reflect ''field cancerization,'' a concept that was introduced to explain the occurrence of genetic alterations in histologically normal tissues adjacent to tumors.…”

“…The latter is in agreement with studies in breast and prostate cancers, which show that telomere attrition takes place in histologically normal tissue adjacent to the corresponding tumors, and thus may represent an early event in the carcinogenic process. 15,45 At the time of their report, the authors hypothesized that telomere alterations may initiate and promote the development of malignancy. 12 In this context, Meeker et al recently observed that telomere length abnormalities represent early and prevalent genetic alterations in the multistep process of malignant transformation in several types of cancer, including breast cancer.…”

Correlation of telomere length shortening with promoter methylation profile of p16/Rb and p53/p21 pathways in breast cancer

“…33,34 It was reported that telomere length is reduced in histologically normal tissues distant at least 1 cm from the adjacent tumor margins. 35 Although the tissue appears normal, it harbors various genetic changes, including telomere dysfunction, that are reflective of the adjacent carcinogenesis process. This seriously complicates the use of histologically normal tissue as control.…”

“…This seriously complicates the use of histologically normal tissue as control. 35,36 Also examining whole tissue sections rather than examining telomere lengths by in-situ methodology, which permits distinction of lesional tissue from contaminating normal tissues is one of the limitations of used methodology. 37 To reduce the challenge of contaminating normal tissues, the paired normal samples in our study were selected with distances more than 1.5 cm to the adjacent tumor tissues.…”

Differential gene expression in tumor adjacent histologically normal prostatic tissue indicates field cancerization

“…Our laboratory has previously investigated the nature of field cancerization in both prostate and breast cancers using markers of genomic instability, including telomere DNA content (TC), an established surrogate measure of telomere length and the extent of allelic imbalance (AI) (11,12). These studies have shown telomere alterations and the presence of AI in both tumor and TAHN tissues.…”