K-ras and p16INK4Aalterations in sputum of NSCLC patients and in heavy asymptomatic chronic smokers
- 1 April 2004
- journal article
- research article
- Published by Elsevier BV in Lung Cancer
- Vol. 44 (1), 23-32
- https://doi.org/10.1016/j.lungcan.2003.10.002
Abstract
NSCLC rates among the most frequent and lethal neoplasm world-wide and a significant decrease in morbidity and mortality relies only upon effective early diagnostic strategies. We investigated K-ras mutations and p16INK4A hypermethylation in tumor tissue and sputum of 50 patients with NSCLC and correlated them with sputum cytology and with tumor staging, grading and location, to ascertain, in sputum, their potential diagnostic impact. The same genetic/epigenetic abnormalities and cytological features were also evaluated in sputum from 100 chronic heavy smokers. Genetic analysis identified molecular abnormalities in 64% tumors (14/50 K-ras mutations and 24/50 p16INK4A hypermethylation) and in 48% sputum (11/50 K-ras mutations and 16/50 p16INK4A hypermethylation). In tumors K-ras mutations and p16INK4A hypermethylation were mostly mutually exclusive, being found in the same patients in 3 cases only. Genetic abnormalities in sputum were detected only in molecular abnormal tumors. Molecular changes in sputum had rates of detection similar to cytology (42%) but the cyto-molecular combination increased the diagnostic yield up to 60%. Interestingly, the rate of detection of genetic changes in sputum of tumors at early stage (T1) was not significantly different from that of tumors at more advanced stage (T2–T4). In fact K-ras point mutations were frequently recognised in tumors at early stage while p16INK4A inactivation prevailed in tumors at advanced stage ( P=0.0063). As expected, diagnostic cytological findings were more frequently found in tumors at advanced stage ( P=0.004). No correlation was found between tumor grading and location (central versus peripheral) and molecular changes. p16INK4A hypermethylation, but not K-ras mutations, was documented in sporadic cases of asymptomatic heavy smokers (4%) where it was uncoupled from cytological abnormalities. In conclusion the cyto-molecular diagnostic strategy adopted in this study was able to detect the majority of tumors but in order to be proposed as effective and early diagnostic tool, this molecular panel needs to be tested in prospective studies with adequate follow-up.Keywords
This publication has 27 references indexed in Scilit:
- Inactivation of the INK4A/ARF locus frequently coexists with TP53 mutations in non-small cell lung cancerOncogene, 1999
- Expression of p16INK4a/p16α and p19ARF/p16β is frequently altered in non-small cell lung cancer and correlates with p53 overexpressionOncogene, 1998
- Detection of K-ras point mutations in sputum from patients with adenocarcinoma of the lung by point-EXACCT.Journal of Clinical Oncology, 1998
- Intragenic mutations of the
p16
INK4
, p15
INK4B
and p18 genes in primary non‐small‐cell lung cancersInternational Journal of Cancer, 1996
- Alterations of CDKN2 (p16) in non‐small cell lung cancerGenes, Chromosomes and Cancer, 1995
- K-ras gene point mutation: a stable tumor marker in non-small cell lung carcinomaLung Cancer, 1994
- A Cell Cycle Regulator Potentially Involved in Genesis of Many Tumor TypesScience, 1994
- Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancersNature, 1994
- K‐ras mutations in human adenocarcinoma of the lung: Association with smoking and occupational exposure to asbestosInternational Journal of Cancer, 1993
- TherasOncogenes in Human Lung CancerAmerican Review of Respiratory Disease, 1990