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Comparison of Accumulated Allele Loss between Primary Tumor and Lymph Node Metastasis in Stage II Non-small Cell Lung Carcinoma

Implications for the Timing of Lymph Node Metastasis and Prognostic Value

Department of Pathology, Division of Anatomic Pathology [E. S., S. D. F., J. D. W., A. B., P. A. S., S. A. Y.] and Department of Surgery, Division of Thoracic Surgery [J. D. L., H. C. F.], University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15261

Although the Tumor-Node-Metastasis staging of non-small cell lung carcinoma (NSCLC) is the most effective predictor of survival, the clinical outcome of patients at each stage is variable on an individual case basis. We tested the value of incorporating information about the tumor heterogeneity of NSCLC into microsatellite allelotyping in a cohort of 48 node-positive stage II patients (T1N1M0 and T2N1M0). Microsatellite allelotyping involved microdissection of the invasive component of primary tumor and lymph node metastasis at multiple target sites followed by loss of heterozygosity (LOH) analysis at specific regions on chromosomes 1p, 3p, 5q, 7q, 8q, 9p, 10q, 17p, and 18q using 16 markers. All microsatellites manifested LOH ranging from 44 to 76% in primary tumor and showed various degree of heterogeneity between primary tumor and lymph node metastasis. LOH on 3p and 5q in the lymph node metastases was associated significantly with shortened survival of the patients (P = 0.033 and 0.004, respectively), whereas no single LOH in the primary tumors showed association with prognosis. For the analysis of the accumulated load of allele loss, fractional allele loss (FAL) was calculated for each sample. The maximal FAL of lymph node metastasis was significantly lower than that of primary tumor (P = 0.0015), possibly reflecting the early lymphatic spread. High maximal FAL of lymph node metastasis was significantly correlated with an adverse outcome (P = 0.012), whereas maximal FAL of primary tumor did not show any prognostic significance (P = 0.552). A composite mutational profile for each patient based on the allelotyping of the primary tumor and lymph node deposits may make a significant contribution to a more accurate prognosis of stage II NSCLC.

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