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Molecular Oncology, Markers, Clinical Correlates |
Department of Experimental Oncology, Unit 10 [A. B., N. Z., M. G. D.] and Unit 5 [D. C., F. A., G. S.], Department of Anatomical Pathology and Cytology, Laboratory of Molecular Diagnosis [M. F., D. B.], and Unit of Thoracic Surgery [L. T.], Istituto Nazionale Tumori, 20133 Milan, Italy
Purpose: The p16INK4A tumor suppressor gene is inactivated in many solid tumors, including non-small cell lung cancers (NSCLCs), through promoter hypermethylation. Presence of p16INK4A hypermethylation in precursor lesions of NSCLC and in body fluids of individuals at risk makes it a potential candidate for early disease detection. However, the current low sensitivity of p16INK4A hypermethylation detection in plasma limits its consideration in a diagnostic grid.
Experimental Design: A fluorescent methylation-specific PCR assay (F-MSP) was established to evaluate p16INK4A promoter hypermethylation in 35 NSCLC and paired plasma samples and in 15 plasmas from healthy donors. F-MSP sensitivity was investigated in combination with microsatellite alterations on 3p (evaluated by fluorescent PCR), K-ras mutations (determined by a mutant-enriched PCR), and quantification of circulating DNA. Assay results were analyzed by two-sided 
2 or Fisher’s exact tests.
Results: p16INK4A promoter hypermethylation, detectable by F-MSP in 22 of 35 NSLCs (63%) and in 12 of 22 (55%) plasmas from patients with methylated tumors, was independent of microsatellite alterations (detectable in 57% of tumors and 50% of paired plasmas), K-ras mutations (detectable in 31% of tumors but in no paired plasma), or amount of circulating DNA. p16INK4A methylation in association with microsatellite alterations identified 62% (18 of 29) of plasma samples from patients presenting the same alteration in their tumors, and its sensitivity increased to 80% when combined with the amount of circulating DNA.
Conclusions: The establishment of F-MSP remarkably improved p16INK4A promoter hypermethylation detection in plasmas from NSCLC patients. Microsatellite alterations, circulating DNA quantification, and p16INK4A hypermethylation might contribute to a diagnostic grid for NSCLC.
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