Evolution of neoplastic cell lineages in Barrett oesophagus

Abstract

It has been hypothesized that neoplastic progression develops as a consequence of an acquired genetic instability and the subsequent evolution of clonal populations with accumulated genetic errors. Accordingly, human cancers and some premalignant lesions contain multiple genetic abnormalities not present in the normal tissues from which the neoplasms arose. Barrett oesophagus (BE) is a premalignant condition which predisposes to oesophageal adenocarcinoma (EA) that can be biopsied prospectively over time because endoscopic surveillance is recommended for early detection of cancer. In addition, oesophagectomy specimens frequently contain the premalignant epithelium from which the cancer arose. Neoplastic progression in BE is associated with alterations in TP53 (also known as p53) and CDKN2A (also known as p16) and non-random losses of heterozygosity (LOH). Aneuploid or increased 4N populations occur in more than 90-95% of EAs, arise in premalignant epithelium and predict progression. We have previously shown in small numbers of patients that disruption of TP53 and CDKN2A typically occurs before aneuploidy and cancer. Here, we determine the evolutionary relationships of non-random LOH, TP53 and CDKN2A mutations, CDKN2A CpG-island methylation and ploidy during neoplastic progression. Diploid cell progenitors with somatic genetic or epigenetic abnormalities in TP53 and CDKN2A were capable of clonal expansion, spreading to large regions of oesophageal mucosa. The subsequent evolution of neoplastic progeny frequently involved bifurcations and LOH at 5q, 13q and 18q that occurred in no obligate order relative to each other, DNA-content aneuploidy or cancer. Our results indicate that clonal evolution is more complex than predicted by linear models.

A common p73 polymorphism is associated with a reduced incidence of oesophageal carcinoma

“…Existing evidence shows that p73 plays a role in the regulation of the cell cycle, apoptosis and possibly control of differentiation (Jost et al, 1997;Kaghad et al, 1997;DeLaurenzi et al, 1998;Zhu et al, 1998;Gong et al, 1999), all of which are critical in the oncogenic process. These existing data suggest that p73 activity may be capable of compensating, to some extent, for the early loss of p53 function (through mutation) observed in pre-cancerous oesophageal lesions (Barrett et al, 1999). Indeed, supporting this hypothesis, is the observation that increased expression of p73 was found in oesophageal squamous cancers compared to matched normal tissues; moreover, increased p73 expression significantly correlated with the presence of a p53 defect (Cai et al, 2000).…”

“…In contrast with other tumour types, p53 mutation is an early event in oesophageal carcinogenesis (Montesano et al, 1996;Barrett et al, 1999). P53 is a critical regulator of the cell cycle (Levine, 1997) and p73 shares significant functional homology with p53 (Kaghad et al, 1997;Zhu et al, 1998).…”

“…Tumours are often described at an advanced stage, by which time they have accumulated a diversity of mutations and deletions. In contrast with other tumour types however, p53 mutation appears to be an early event in oesophageal carcinogenesis (Montesano et al, 1996;Barrett et al, 1999). A recent study has indicated that the evolution of neoplastic cell lineages in Barrett's oesophagus and oesophageal adenocarcinoma is complex, involving non-random loss of heterozygosity (LOH), duplications and mutations which do not occur in a particular obligate order (Barrett et al, 1999).…”

Distinctive patterns of Her‐2/neu, c‐myc, and cyclin D1 gene amplification by fluorescence in situ hybridization in primary human breast cancers

“…Second, individual members of genophenotypic clusters of abnormalities have occurred in preferred sequences in relation to other members of the cluster (10) and often have emerged preferentially in early or late histopathologic stages of disease (7,10 -12). In studies of patients with Barrett's esophagus, p53 abnormalities appeared early, in predysplastic diploid cells; during the course of evolution from the premalignant state to invasive disease, tumors with p53 abnormalities progressed through an intermediate stage of tetraploidy (13) to gross aneuploidy (14,15). A similar sequence of events was reported in individual human colon cancers (16,17).…”

Characterisation of p53 status at the gene, chromosomal and protein levels in oesophageal adenocarcinoma

“…Complete loss of wild-type p53 protein within a cell rarely occurs as a result of homozygous deletions or a double mutation, the second allele is usually inactivated by an alternate mechanism to the first. When Barrett's metaplastic tissue was examined, it was found that 95 -100% of cases with 17p LOH also had p53 gene mutations (Gleeson et al, 1998;Barrett et al, 1999), while patients without LOH of the gene still carried a mutated p53 allele (Dolan et al, 1999). This suggests a mutation in one allele of the p53 gene probably occurs first followed by allelic loss of the second during neoplastic progression, resulting in a p53 null phenotype that can promote tumorigenesis in Barrett's oesophagus.…”