Molecular alterations in spontaneous sputum of cancer-free heavy smokers: results from a large screening program.

Abstract

PURPOSE:

The high mortality rate for lung cancer is likely to be reduced by the development of a panel of sensitive biological markers able to identify early-stage lung cancers or subjects at high risk. The aim of this study was to establish the frequency of K-ras and p53 mutations and p16(INK4A), RASSF1A, and NORE1A hypermethylation in sputum of a large cohort of cancer-free heavy smokers and to assess whether these markers are suitable for a routine use in the clinical practice for the early diagnosis of pulmonary cancer.

EXPERIMENTAL DESIGN:

Sputum samples were collected from 820 heavy smokers. Inclusion criteria consisted of radiologic and cytologic absence of pulmonary lesions, age at least 60 years, male gender, and a smoking history of at least 20 pack-years.

RESULTS:

The analysis identified 56 individuals (6.9%) with one molecular alteration. p53 mutation and p16(INK4A), RASSF1A, and NORE1A methylation frequencies were 1.9%, 5.1%, 0.8%, and 1.0%, respectively; no K-ras mutations were found. One patient with p53 mutations was diagnosed with an early-stage lung cancer after 3-years of follow-up. The molecular analysis of bronchoscopy samples confirmed in half of the cases alterations present in sputum without revealing additional molecular changes.

CONCLUSIONS:

Genetic and epigenetic abnormalities can be detected in cancer-free heavy smokers. Although the predictive value of the cancer risk is still to be established as it requires not less than 5 years of follow-up, p53 and p16(INK4A) are more promising candidates than K-ras, RASSF1A, and NORE1A for the pulmonary molecular screening of heavy smokers healthy individuals.

• Authors: Ekaterina Baryshnikova, Annarita Destro, Maurizio Valentino Infante, Silvio Cavuto, Umberto Cariboni, Marco Alloisio, Giovanni Luca Ceresoli, Romano Lutman, Giorgio Brambilla, Giuseppe Chiesa, Gianni Ravasi, Massimo Roncalli
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 14 Issue 6 Pg. 1913-9 (Mar 15 2008) ISSN: 1078-0432 [Print] United States
• PMID: 18347195 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• Apoptosis Regulatory Proteins
• RASSF1 protein, human
• RASSF5 protein, human
• Tumor Suppressor Proteins
• Monomeric GTP-Binding Proteins

Topics

• Adaptor Proteins, Signal Transducing
• Apoptosis Regulatory Proteins
• Base Sequence
• Bronchoscopy
• Cohort Studies
• DNA Methylation
• DNA Mutational Analysis
• Early Diagnosis
• Follow-Up Studies
• Genes, p16
• Genes, p53
• Genes, ras
• Genetic Testing
• Humans
• Lung Neoplasms (diagnosis, genetics)
• Male
• Middle Aged
• Monomeric GTP-Binding Proteins (genetics)
• Precancerous Conditions (genetics, metabolism)
• Smoking (genetics)
• Sputum (cytology, metabolism)
• Tumor Suppressor Proteins (genetics)