Selectively advantageous mutations and hitchhikers in neoplasms: p16 lesions are selected in Barrett's esophagus

Carlo C. Maley, Patricia C. Galipeau, Xiaohong Li, Carissa A. Sanchez, Thomas G. Paulson, Brian J. Reid

Research output: Contribution to journalArticle

169 Scopus citations

Abstract

Neoplastic progression is an evolutionary process characterized by genomic instability and waves of clonal expansions carrying genetic and epigenetic lesions to fixation (100% of the cell population). However, an evolutionarily neutral lesion may also reach fixation if it spreads as a hitchhiker on a selective sweep. We sought to distinguish advantageous lesions from hitchhikers in the premalignant condition Barrett's esophagus. Patients (211) had biopsies taken at 2-cm intervals in their Barrett's segments. Purified epithelial cells were assayed for loss of heterozygosity and microsatellite shifts on chromosomes 9 and 17, sequence mutations in CDKN2A/MTS1/INK4a (p16) and TP53 (p53), and methylation of the p16 promoter. We measured the expanse of a lesion in a Barrett's segment as the proportion of proliferating cells that carried a lesion in that locus. We then selected the lesion having expanses >90% in the greatest number of patients as our first putative advantageous lesion. We filtered out hitch-hikers by removing all expanses of other lesions that did not occur independent of the advantageous lesion. The entire process was repeated on the remaining expanses to identify additional advantageous lesions. p16 loss of heterozygosity, promoter methylation, and sequence mutations have strong, independent, advantageous effects on Barrett's cells early in progression. Second lesions in p16 and p53 are associated with later selective sweeps. Virtually all of the other lesion expansions, including microsatellite shifts, could be explained as hitchhikers on p16 lesion clonal expansions. These techniques can be applied to any neoplasm.

Original languageEnglish (US)
Pages (from-to)3414-3427
Number of pages14
JournalCancer Research
Volume64
Issue number10
DOIs
StatePublished - May 15 2004

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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