title: Common patterns of genetic evolution in human solid tumors.
abstract: Human solid tumors develop multiple genetic evolutionary abnormalities as they evolve. Studies that have focused primarily on early colorectal cancer have suggested that genetic instability is a prominent feature of preinvasive disease. At least two separate mechanisms for the generation of genetic instability have been identified. The first, which involves widespread microsatellite instability in near-diploid cells, affects less than one-fifth of colon cancers. The second form of genetic instability is characterized by the development of p53 gene abnormalities that result in gross aneuploidy and multiple structural chromosomal changes. p53/aneuploidy affects most colon cancers, breast cancers, and many other solid tumors. This genetic evolutionary change commonly occurs at the interface between severe dysplasia and invasive disease. Specific post-aneuploid sequences of genetic changes that are relevant to tumor progression often involve the accumulation of multiple gain-of-function abnormalities in individual cells. The co-occurrence of Her-2/neu overexpression and EGF receptor overexpression in the same aneuploid cells defines an adeno/squamous genetic evolutionary sequence that is common to ductal breast cancers, non-small cell lung cancers, and other solid tumors. Later steps in this sequence include ras and c-myc overexpression. The neuroendocrine genetic evolutionary sequence is a separate branch of the p53/aneuploidy sequence with distinctive features that include loss of Rb and raf1 overexpression. Her-2/neu overexpression is not characteristic of this sequence; c-myc amplification/overexpression is common to both p53-associated sequences. The neuroendocrine sequence is found in small cell carcinoma of the lung and in minor proportions of other solid tumors, including breast cancer. Multiparameter cell-based methods are especially well suited for elucidation in human solid tumors of the genetic evolutionary sequences that could provide a rational scientific basis for determining prognosis and for optimizing therapy in individual cancer patients.
authors.affiliation: Allegheny University of the Health Sciences, Department of Human Oncology, Allegheny Campus, Pittsburgh, Pennsylvania 15212, USA. shackney@pgh.AUHS.edu
authors.forename: S E
authors.initials: SE
authors.lastname: Shackney
authors.forename: T V
authors.initials: TV
authors.lastname: Shankey
mesh_terms: D000782:Aneuploidy; D004273:DNA, Neoplasm / Q000737:chemistry; D005434:Flow Cytometry; D018734:Genes, erbB-2; D016259:Genes, myc; D011905:Genes, ras; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008957:Models, Genetic; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D004273:DNA, Neoplasm; D016159:Tumor Suppressor Protein p53