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. Author manuscript; available in PMC: 2006 Sep 5.
Published in final edited form as: Nat Genet. 1999 May;22(1):106–109. doi: 10.1038/8816

Fig. 2.

Fig. 2

Multiple genetic routes to cancer in BE. Each clone represents a cell population detected in this study, but the figure is not intended to be comprehensive because the lack of obligate orders creates multiple genetic pathways to cancer, only some of which are represented. Although there are multiple pathways to cancer, some general patterns appear to be consistent among many patients. LOH events arise in diploid Ki67-positive populations (2N) in Barrett metaplasia (M). We detected 2N populations that developed LOH without lesions involving either TP53 or CDKN2A in 4 patients, but these clones failed to progress. LOH at either 17p (17p-) or 9p (9p-) can occur in diploid populations and can precede mutations in TP53 and CDKN2A. Although both 17p and 9p LOH develop as early events, they occur in no obligate order. 2N clones with somatic genetic abnormalities involving TP53 (17p-/TP53-) and CDKN2A (9p-/CDKN2A-; 9p-) frequently give rise to populations with elevated 4N fractions (4N) that can evolve aneuploid cell populations (An). Methylation of the CDKN2A CpG island was also detected in diploid cells before the development of aneuploidy. The 4N abnormality was not always detected, possibly from sampling limitations or failure of a genetically unstable intermediate to persist. In some cases, such as patient 391 (Fig. 1), changes in ploidy may result in a clone with a 2N or near-2N DNA content, yet with multiple genetic abnormalities. 5q, 13q and 18q LOH have no obligate order relative to aneuploidy, cancer or each other. During evolution, neoplastic cell lineages may bifurcate, giving rise to mosaics with the same TP53 and CDKN2A abnormalities but different ploidies and additional LOHs. Some clones in these mosaics develop into cancer (Ca), whereas others either are delayed in their progression or represent dead ends. Subsequently, multiple malignant clones (Ca) with different ploidies and additional LOHs evolve as the cancer progresses.