Genetic evolutionary staging of early non-small cell lung cancer: The p53 -> Her-2/neu -> ras sequence

Introduction: The sequence of genetic evolutionary abnormalities that have occurred in a given lung cancer tumor before tumor sampling can be inferred from patterns of intracellular co-occurrence of these abnormalities in tum or cell subpopulations at the time of sampling. The same evolutionary seque nces that are present within each lung cancer were evident in intertumor co mparisons. Methods: Correlated cell by cell measurements of cell DNA conten t, p53, Her-2/neu, and ras proteins were obtained by multiparameter flow cy tometry on 46 surgically resected stage I-m primary non-small cell lung can cers. Early evolutionary changes were identified by the fact that they coul d appear alone in individual cells. Later appearing abnormalities were iden tified by the fact that they were accompanied by early abnormalities in the same cells. Patients were followed prospectively. Evolutionary patterns ob served in individual tumors were correlated with subsequent clinical outcom e of patients undergoing surgical resection, Results: Three common patterns were identified: (I) a diploid DNA pathway consisting of the sequence p53 overexpression --> Her-2/neu overexpression --> ras overexpression, (II) an aneuploid DNA pathway with the same p53 --> Her-2/neu --> ras sequence, an d (III) a pathway in which none of the intracellular protein measurements m ade here were abnormal. Fourteen tumors recurred after 11.5 months' median study time. Nine of 12 recurrences in pathways I and II occurred in patient s whose tumors were far advanced along these molecular genetic pathways. Co nclusions: Multiparameter cell-based genetic evolutionary studies may be a promising approach for identifying patients with stage I-III non-small cell lung cancer at high risk for recurrence.