Genetic Deletions in Sputum as Diagnostic Markers for Early Detection of Stage I Non–Small Cell Lung Cancer

Abstract

Purpose: Analysis of molecular genetic markers in biological fluids has been proposed as a powerful tool for cancer diagnosis. We have characterized in detail the genetic signatures in primary non^small cell lung cancer, which provided potential diagnostic biomarkers for lung cancer. The aim of this study was to determine whether the genetic changes can be used as markers in sputum specimen for the early detection of lung cancer. Experimental Design: Genetic aberrations in the genes HYAL2, FHIT, and SFTPC were evaluated in paired tumors and sputum samples from 38 patients with stage I non^small cell lung cancer and in sputum samples from 36 cancer-free smokers and 28 healthy nonsmokers by using fluorescence in situ hybridization. Results: HYAL2 and FHIT were deleted in 84% and 79% tumors and in 45% and 40% paired sputum, respectively. SFTPC was deleted exclusively in tumor tissues (71%). There was concordance of HYAL2 or FHIT deletions in matched sputum and tumor tissues from lung cancer patients (r = 0.82, P = 0.04; r = 0.84, P = 0.03), suggesting that the genetic changes in sputum might indicate the presence of the same genetic aberrations in lung tumors. Furthermore, abnormal cells were found in 76% sputum by detecting combined HYAL2 and FHIT deletions whereas in 47% sputum by cytology, of the cancer cases, implying that detecting the combination of HYAL2 and FHIT deletions had higher sensitivity than that of sputum cytology for lung cancer diagnosis. In addition, HYAL2 and FHIT deletions in sputum were associated with smoking history of cancer patients and smokers (both P < 0.05).Conclusions: Tobacco-related HYAL2 and FHIT deletions in sputum may constitute diagnostic markers for early-stage lung cancer.

A Panel of Sputum-Based Genomic Marker for Early Detection of Lung Cancer

“…Of the 6 genes, 3 genes (FHIT, HYAL2, and P16) were previously investigated in sputum of lung cancer patients for their genomic copy number alterations by our group (6,7,9,(14)(15)(16). The present observations of the genes are consistent with our earlier findings, confirming their potential role as biomarkers for early NSCLC.…”

“…Collecting, processing, and cytologic studying sputum All participants in the 2 different medical centers underwent the same sputum collection using an induced protocol over the same interval of time (6,7,9,(14)(15)(16). Sputum was collected from lung cancer patients before they had received preoperative adjuvant chemotherapy or radiotherapy.…”

“…One slide was used for checking quality of the specimen. The main variables applied to select sputum for the study were high cellularity, good nuclear morphology, and lack of purulence, debris, and residual cytoplasm (9,15). Another one was stained with Papanicolaou stain for cytologic diagnosis using the classification of Saccomanno (17).…”

“…In addition, using high-resolution comparative genomic hybridization microarrays, we identified a set of genetic signatures whose copy number changes were associated with early stage NSCLC (8). We further demonstrated that assessing changes of some genes of the signatures could identify cancer cells not only in the cytologically positive sputum, but also in cytologically negative sputum of NSCLC patients (9). However, the sensitivity obtained by examining the individual genes is not, as yet, high enough for clinical applications.…”

Gene signatures of pulmonary metastases of renal cell carcinoma reflect the disease‐free interval and the number of metastases per patient

“…SFTPC, located on the chromosome arm 8p21 and expressed in several normal tissues like nasal, gastric and intestinal mucosa, is frequently deleted in nonsmall cell lung cancer. 29 This chromosomal region is also found to be lost in many clear-cell RCC. 30,31 The important role of SFTPC in host defense mechanisms in the lung might contribute to the inhibition of tumour cell proliferation and therefore, retard the growth of Mets.…”