Widespread Molecular Alterations Present in Stage I Non-Small Cell Lung Carcinoma Fail to Predict Tumor Recurrence

Abstract

Stage I non-small cell carcinoma (NSCLC) of the lung is typically treated with surgery alone, but with a 30 to 40% recurrence rate. Prognostic factors to stratify these patients into high-and low-risk groups would be of significant clinical value, but published data are conflicting. We studied 39 Stage I NSCLC treated with resection alone, followed for a minimum of 5 years, and divided into recurrent (RC) and non-recurrent (NRC) groups (n ‫؍‬ 12 and 27, respectively). Allelic imbalance (loss of heterozygosity, LOH) involving genomic regions containing L-myc (1p32), hOGG1 (3p26), APC/MCC (5q21), c-fms (5q33.3), p53 (17p13), and DCC (18q21), and point mutational change in K-ras-2 (12p12) were studied by PCR-based microsatellite analysis and DNA sequencing. Mutations in k-ras-2 were seen in 25% and 19% of RC and NRC tumors, respectively, most frequently in adenocarcinomas. LOH in the RC and NRC respectively were 50% and 37% for L-myc, 60% and 33% for hOGG1, 60% and 50% for APC, 38% and 35% for c-fms, 78% and 75% for p53, and 17% and 45% for DCC. No statistical significance was seen comparing any of the allelic alterations with recurrence. LOH for hOGG1 and L-myc were more commonly seen in squamous cell carcinomas. Stage I NSCLC are genetically heterogeneous with respect to mutation acquisition. The approach of investigating a panel of genes for alterations can be applied to any given tumor type, and provides information on patterns of mutations/ LOH that can help us better understand the molecular biology of tumorigenesis.KEY WORDS: Loss of heterozygosity, Non-small cell lung carcinoma, Prognosis. Mod Pathol 2003;16(1):28 -34Carcinoma of the lung is the second most frequent malignancy in men and women and the most frequent cause of cancer-related death in both sexes (31% and 25%, respectively) (1). Therapeutic intervention is based on a number of factors including the predicted outcome of the patient. The medical literature thus abounds with factors that affect prognosis, and one of the most important is stage of disease (2). Stage I lung cancer includes the TNM-based T1N0M0 and T2N0M0 tumors (3) and is typically treated with surgical resection alone. However, approximately 50% of clinical Stage I and 30 -40% of pathologic Stage I patients have disease recurrence and die after surgical resection (4, 5). These data suggest that a significant number of patients may benefit from adjuvant therapy at the time of diagnosis. Several studies have therefore focused attention on patients with Stage I disease in an attempt to identify prognostic factors that will stratify these patients into high-and low-risk groups for recurrence, with variable results. The various clinical and pathological factors identified include patient performance status, tumor size, histological subtype, mitotic rate, proliferative index, tumor angiogenesis, DNA ploidy studies, and blood group expression (4, 6 -8).Overexpression of p53 and c-erb by immunohistochemistry has been determined to be an indicator of poorer outcome (7). The issue of prognosi...

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High rate of molecular alteration in histologically tumour-free bronchial epithelium of NSCLC patients detected by multicolour fluorescence in situ hybridisation

“…Certainly, a larger number of patients should be analysed to corroborate or disprove this assumption. Concerning the prognostic value of molecular alterations in the literature, conflicting results have been reported (66)(67)(68).…”

Gene Expression Signature Predicts Recurrence in Lung Adenocarcinoma

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