Correlation between DNA ploidy by flow cytometry and chromosome 3 aberration in oral squamous cell carcinoma

Abstract

Abstract. Although flow cytometric DNA ploidy has turned out as a significant predictor of survival in oral squamous cell carcinoma, little is known about the underlying karyotypic structure of gross aneuploidy. We therefore analysed one diploid and 9 aneuploid carcinomas with relative DNA contents between 1.1 and 2.8 by fluorescence in situ hybridization with topologic markers for the centromere (3cen) and the terminal regions (3p, 3q) of chromosome 3. Progressing deviation of aberrant DNA contents from the normal diploid value correlated with increasing 3cen copy numbers per cell. A pronounced marker heterogeneity suggested that DNA-aneuploid cell populations consisted of karyotypically different clones. Monosomy of 3p was the only chromosomal alteration in the DNA diploid tumour. A significant 3p underrepresentation was a recurrent finding also in 7 of 9 aneuploid carcinomas while a subset of cells in each of 2 other cases showed a complete loss of one sister chromosome 3. In contrast, 7 of 9 aneuploid tumours exposed corresponding 3q and 3cen copy numbers, 2 showed a substantial 3q overrepresentation. It appears that amplification of chromosome 3 plays a role in the development of aneuploidy and the concurrent overexpression of 3q target genes. Acquired loss of the short arm of chromosome 3 in DNA-diploid tumour cells may contribute to the manifestation of recurrent 3q deletions in aneuploid cell populations. IntroductionWhile a multistep carcinogenetic process, in which mutations of tumour suppressor genes and oncogenes may play a critical role, has been proposed for the development of oral squamous cell carcinoma (1), DNA flow cytometric studies provided evidence that gross karyotype rearrangements contribute to the acquisition of invasive and metastatic behaviour (2,3). Aneuploidy has actually turned out as an independent predictor of survival in oral squamous cell carcinoma (3-6). The outcome of patients is essentially determined by a several-fold increase in risk of local and regional recurrence after the emergence of DNA-aneuploid cell populations (4,6-9).DNA content aberrations signify a fundamental reorganisation of the tumour cell genome in which gains and losses of chromosomes substantially contribute to the expression of altered DNA contents (10). Remarkably, although DNA contents vary in wide range, thus implying corresponding karyotypic disparities, neither the metastatic behaviour of tumours nor the outcome of patients correlate with the degree of aneuploidy (2,7). A conceivable explanation is that aneuploid clones, despite their overall differences in chromosomal composition, may share discrete karyotypic aberrations that are decisive for the expression of malignant behaviour. As multiple studies suggested that mutations involving the short arm of chromosome 3 may be critical for the progression of squamous cell carcinomas of the head and neck (11-19), we analysed the pattern and frequency of rearrangements of chromosome 3 by fluorescence in situ hybridization in oral squamous cell carcinomas ...

Analysis of PIK3CA and Akt/protein kinase B in head and neck squamous cell carcinoma

“…The different incidences of amplification found by us and Pedrero et al could be explained by the reference genes used in the PCR approaches (TRAT1 situated at 3q13 and COL7A1 situated at 3p21, respectively). The short arm of chromosome 3 (3p) shows frequent genomic losses in HNSCC (3-5) and the monosomy of 3p was described as the only chromosomal alteration in diploid oral squamous cell carcinoma (33). Therefore, choosing the reference gene on 3p could introduce bias in the evaluation of PIK3CA amplification.…”

Mapping oral cancer research in South Africa

“…34,40,51 One case series investigated alterations in chromosome 3 in relation to OSCC and suggested that mutations in the short arm of chromosome 3 may play a role in the progression of OSCC. 42 Globally, low socio economic status has been associated with increased odds ratio for development of oral cancer (OR up to 2.4), measured as low income, educational level and social class. 88 Furthermore, a pooled analysis of 16 studies showed that each portion of fruit or vegetables consumed per day decreases the risk for oral cancer (OR 0.5).89 In a country with much inequity such as South Africa, it is surprising that no study has evaluated the role of low socio economic status and dietary deficiency for oral cancer.…”

DNA-Ploidie und proliferative Aktivität bei Speicheldrüsentumoren

“…[24,25]. Solche Strukturanomalien können zwar in einem gewissen Umfang durch vergleichende genomische Hybridisierung (CGH) oder durch Fluorezenz in situ Hybridisierung mit Chromosomen-spezifischen DNA-Proben sichtbar gemacht werden [27], für den Nachweis reiner Chromosomenzahl-Aberrationen sind diese zudem arbeitsaufwendigen Methoden aber nur eingeschränkt geeignet. Tatsächlich gehen aber besonders bei soliden Malignomen numerische Chromosomen-Anomalien häufig mit simultanen Veränderungen der chromosomalen Architektur einher [27].…”