Of what value are the genetic changes: are the loss of the Y-chromosome and deletions or mutations of the adenomatous polyposis coli gene on chromosome 5q2l important in the evolution of Barrett's dysplasia and carcinoma?
M.B.E. Menke-Pluymers, H.W. Tilanus (Rotterdam)
There is substantial evidence that the progression to malignancy in Barrett's esophagus is associated with a multistep process of genetic instability and clonal evolution [1-3]. There are a few reports of cytogenetic analysis of Barrett's epithelium and adenocarcinoma [4-7]. Karyotypes are often complex and contain multiple numerical and structural rearrangements. Barrett's metaplasia can contain cytogenetically abnormal clones that occupy extensive regions of the Barrett's segment, persist for several years, and progress to high grade dysplasia and adenocarcinoma .
The most consistent numerical chromosomal aberration is the loss of the Y-chromosome [4-9]. Loss of the Y-chromosome has been demonstrated in different gastrointestinal malignancies and brain tumors [10, 11]. It has been suggested that tissues retaining rapid cellular proliferation rates in elderly men are more prone to loss of the Y-chromosome . In our series loss of the Y-chromosome in Barrett's mucosa and adenocarcinoma occurred in 62% of the male patients, but not merely the oldest ones . Furthermore, cytogenetic analysis of periferal blood lymphocytes did not reveal Y-loss. Although there is a male predominance in the incidence of Barrett's esophagus and esophageal adenocarcinoma, the significance of Y-loss is unclear since there are no cancer genes linked to the Y-chromosome so far [13, 14].
It has been shown that neoplastic progression in Barrett's esophagus is associated with allelic losses that include tumor suppressor genes . Allelic losses of 17p occur in diploid cells as early events and typically precede the development of aneuploidy and other allelic losses during neoplastic progression in Barrett's esophagus . There is strong evidence that the target of 17p allelic losses is the p53 gene [3, 17]. Allelic losses of 17p or 5q were found in aneuploid cell populations from patients with Barrett's esophagus who had high grade dysplasia or cancer . Allelic losses of 17p were found in 92% of Barrett's adenocarcinoma and 5q allelic losses in 77% . It has been demonstrated that 17p allelic losses typically precede 5q allelic losses during neoplastic progression in Barrett's esophagus [3, 16]. Allelic losses of 5q in Barrett's adenocarcinoma involve both APC (adenomatous polyposis coli) and MCC (mutated in colon cancer) genes in the majority of tumors, suggesting that the gene on 5q involved in carcinogenesis in Barrett's esophagus may be APC, MCC or a closely linked gene.
Both loss of the Y chromosome and deletions or mutations of the APC gene on chromosome 5q2l seem to be important in the evolution of Barrett's dysplasia and carcinoma. Allelic losses involving chromosome 5q develop after 17p allelic losses and either after, or simultaneously with the development of aneuploid populations . Even though 5q allelic losses appear to be strongly selected during neoplastic progression, occurring in the majority of Barrett's adenocarcinomas, they are independent of events that cause invasion, because they can develop either before, simultaneously with or subsequent to cancer. The complex karyotypes with multiple numerical and structural abnormalities found in Barrett's adenocarcinoma suggest that progression to malignancy in Barrett's esophagus is associated with a multistep process of genetic instability that involves many chromosomal rearrangements . So far, the sequence of these genetic rearrangements or the events that cause invasion are not known. Therefore, it is not possible to determine the value of a single chromosomal abnormality such as loss of the Y-chromosome or deletion or mutation of the APC gene on chromosome 5q2l.
1. Reid BJ, Blount PL, Rubin CE, Levine DS, Haggitt RC, Rabinovitch PS. Flow-cytometric and histological progression to malignancy in Barrett's esophagus: prospective endoscopic surveillance of a cohort. Gastroenterology 1992;102:1212-1219.
7. Krishnadath KK, Tilanus HW, van Blankenstein M, Hop WCJ, Teygeman R, Mulder AH, Bosman FT, van Dekken H. A cumulation of genetic abnormalities during neoplastic progression in Barrett's esophagus. Cancer Res 1995;55:1971-1976.
9. Menke-Pluymers MBE, van Drunen E, Vissers KJ, Mulder AH, Tilanus HW, Hagemeijer-Hausman AMMJ. Cytogenetic analysis of Barrett's mucosa and adenocarcinoma of the distal esophagus and cardia. Cancer Genet Cytogenet; in press.
11. Bigner SH, Mark J, Bullard DE, Mahaley MS, Bigner DD. Chromosomal evolution in malignant human gliomas starts with specific and usually numerical deviations. Cancer Genet Cytogenet 1986;22:121-135.