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J Thorac Cardiovasc Surg 1999;118:259-269
© 1999 Mosby, Inc.

GENERAL THORACIC SURGERY

GENETIC EVOLUTIONARY STAGING OF EARLY NON–SMALL CELL LUNG CANCER: THE P53 HER-2/NEU ras SEQUENCE

From the Laboratory of Cancer Cell Biology and Genetics, Department of Human Oncology (C.A.S., A.A.P., L.S., S.E.S.) and Human Genetics (S.E.S), Department of Human Oncology (M.L.), Department of Surgery (R.J.L., J.M., R.J.W.), and Department of Laboratory Medicine (J.S.), Allegheny University of the Health Sciences, Pittsburgh, Pa.

Address for reprints: Allegheny University of the Health Sciences, Allegheny General Hospital, 320 East North Ave, Pittsburgh, PA 15212.

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 tumor cell subpopulations at the time of sampling. The same evolutionary sequences that are present within each lung cancer were evident in intertumor comparisons.
Methods: Correlated cell by cell measurements of cell DNA content, p53, Her-2/neu, and ras proteins were obtained by multiparameter flow cytometry on 46 surgically resected stage I-III primary non–small cell lung cancers. Early evolutionary changes were identified by the fact that they could appear alone in individual cells. Later appearing abnormalities were identified by the fact that they were accompanied by early abnormalities in the same cells. Patients were followed prospectively. Evolutionary patterns observed in individual tumors were correlated with subsequent clinical outcome 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, and (III) a pathway in which none of the intracellular protein measurements made here were abnormal. Fourteen tumors recurred after 11.5 months’ median study time. Nine of 12 recurrences in pathways I and II occurred in patients whose tumors were far advanced along these molecular genetic pathways.
Conclusions: 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.

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