Centrosomal abnormalities, multipolar mitoses, and chromosomal instability in head and neck tumours with dysfunctional telomeres

Abstract

Carcinomas of the head and neck typically exhibit complex chromosome aberrations but the underlying mutational mechanisms remain obscure. Evaluation of cell division dynamics in low-passage cell lines from three benign and five malignant head and neck tumours revealed a strong positive correlation between multipolarity of the mitotic spindle and the formation of bridges at anaphase in both benign and malignant tumours. Cells exhibiting a high rate of mitotic abnormalities also showed several chromosome termini lacking TTAGGG repeats and a high frequency of dicentric chromosomes. Multicolour karyotyping demonstrated a preferential involvement in structural rearrangements of chromosomes with deficient telomeres. The majority of malignant, mitotically unstable tumours expressed the reverse transcriptase subunit of telomerase. These data indicate that some of the genomic instability in head and neck tumours is initiated by telomere dysfunction, leading to the formation of dicentric chromosomes. These form chromosome bridges at mitosis that could prevent the normal anaphasetelophase transition. In turn, this may cause an accumulation of centrosomes and mitotic multipolarity. Telomerase expression does not confer total stability to the tumour genome but could be crucial for moderating the rate of chromosomal evolution.

Defective Chromosome Segregation and Telomere Dysfunction in Aggressive Wilms' Tumors

“…Furthermore, all MMs that were analyzed by immunofluorescence in the present study showed two or more centrosomes. The frequencies of AB and MM are positively correlated in many types of neoplasia (20,34,35). In the present study, MM was never present in the cultured WT cells or tissue sections without AB being present as well.…”

Altered mRNA Expression of Telomere-Associated Genes in Monoclonal Gammopathy of Undetermined Significance and Multiple Myeloma

“…Telomere shortening has been demonstrated to contribute directly to the presence of chromosomal abnormalities usually found in diverse types of cancer. This telomere reduction may trigger the formation of telomeric fusions between chromosome arms, which may result in novel karyotypic rearrangements (32,33). Different reports showed similar genetic alterations in MGUS and MM, which suggests a model for MGUS evolution based on genomic instability manifested by aneuploidy as the permissive event for the occurrence of chromosome alterations (34,35).…”

Localization of TEIF in the centrosome and its functional association with centrosome amplification in DNA damage, telomere dysfunction and human cancers

“…The concurrence of telomere dysfunction and centrosome amplification plays an important role in the generation of chromosomal abnormalities that are characteristically found in neoplasia, but the mechanistic link of these two distinct cellular events is still unclear. Recently, Gisselsson proposes a hypothesis that focused on this question after analysis of a series of genetic alterations in various kinds of human cancers (Gisselsson et al, 2002(Gisselsson et al, , 2004Gisselsson, 2005). According to his concept, telomeric erosion can initially induce chromosomal bridging secondary to telomeric fusion in anaphase with resultant failure in cytokinesis, giving rise to cells with supernumerary centrosomes, which consequently leads to numerical chromosomal aberrations by causing multipolar divisions.…”