Loss of chromosome arms 3p and 9p and inactivation of P16^INK4a in normal epithelium of patients with primary lung cancer

Abstract

The accumulation of genetic alterations in the respiratory epithelium may give rise to cancer and often is accompanied by a series of histologic alterations over a period of several years. Recent studies have identified some molecular alterations in histologically normal-appearing epithelium among patients with lung cancer. To extend these observations, we investigated clonal genetic alterations by using fluorescence in situ hybridization (FISH) analysis and immunohistochemistry in 69 biopsy samples of histologically normal-appearing bronchial epithelium from 22 patients with or without lung cancer. Thirty-seven biopsy specimens from 13 patients were examined for loss of 3p14, and 48 biopsy specimens from 18 patients were examined for loss at 9p21 by FISH. P16(INK4a) expression was analyzed in 54 biopsy samples from 19 patients. In at least one biopsy specimen from five of the 13 patients with primary lung cancer, FISH or immunohistochemistry detected loss of the 3p14 or 9p21 region. In contrast, no alterations were detected for the same regions in the nine patients without primary lung cancer. Our results support the concept that the normal epithelial surface of large bronchi of patients with lung cancer has molecular changes suggestive of the outgrowth of numerous clonal foci.

Prognostic significance of p16INK4aalterations and 9p21 loss of heterozigosity in locally advanced laryngeal squamous cell carcinoma

“…Genetic alterations involving the 9p21 region are common in human cancers and the p16 gene is considered to be a target in this region . This gene, in fact, can be inactivated by different mechanisms, most of which lead to the complete absence of the protein, for example, homozygous deletion, loss of heterozygosity (LOH), methylation of the promoter region, point mutations (generally nonsense) and frameshift, with an extremely variable incidence according to the type of tumor Herman et al, 1995;Jares et al, 1999;Caballero et al, 2001). Homozygous deletions of large fragments which eliminate the INK4a locus frequently occur in bladder, breast, and prostate carcinomas, glioblastomas, mesotheliomas (Cheng et al, 1994;Cairns et al, 1995;Balazs et al, 1997;Stadler et al, 2001).…”

Cyclin D1 Overexpression in Bronchial Epithelia of Patients With Lung Cancer Is Associated With Smoking and Predicts Survival

“…In recent studies, loss of one allele of chromosomes 3p, 9p, and 17p was observed in normal bronchial mucosa at different locations of current and former smokers. [4][5][6][7][8] Similarly, the mutation TP53 has been detected in the histologically normal lung tissue of lung cancer patients. 9 Conversely, loss-of-heterozygosity analysis of multiple sites from a number of patients failed to show a common clonal change in such lesions, an observation that would be consistent with independence of origin.…”

A case‐control analysis of lymphocytic chromosome 9 aberrations in lung cancer

“…In addition, chromosome 9 aberrations in normal bronchial epithelium or in normal lung tissue of lung cancer patients have been observed by several investigators. 14,23 Moreover, chromosomal instability in lymphocytes has been recently shown to be associated with oral premalignant lesions. 24 These studies suggest that the presence of chromosome 9 aberrations in lymphocytes (nontarget tissue) might represent the cause and not a consequence of the disease.…”