title: Hypermethylation of ASC/TMS1 is a sputum marker for late-stage lung cancer.
abstract: DNA hypermethylated gene promoter sequences are extremely promising cancer markers. Their use for risk assessment, early diagnosis, or prognosis depends on the timing of this gene change during tumor progression. We studied this for the proapoptotic gene ASC/TMS1 in lung cancer and used the findings to develop a sputum marker. ASC/TMS1 protein levels are reduced in all lung cancer types (30 of 40; 75%) but not in 10 preinvasive lesions. Hypermethylation of ASC/TMS1 is also associated with invasive cancers (41 of 152 or 27.0% of all lung cancer types) with variation in incidence between histopathologic types including 32.1% (26 of 81) of adenocarcinomas, 13.2% (7 of 53) of squamous cell carcinomas, 38.5% (5 of 13) of large-cell carcinomas, and 60% (3 of 5) of small-cell lung cancers. The hypermethylation is particularly correlated with late tumor stages being present in only 14% of stage I but 60% of later-stage tumors. The incidence of ASC/TMS1 hypermethylation in sputum DNA fully mimics the tissue findings being present in only 2% (2 of 85) of high-risk, cancer-free smokers, 15% (3 of 18) of patients with stage I non-small-cell lung cancer (NSCLC), but 41% of patients with stage III NSCLC (18 of 44), including 56% (10 of 18) of those with adenocarcinoma. Importantly, sputum is positive for this marker in 24% (10 of 42) of very high risk, clinically cancer-free individuals previously resected for stage I NSCLC. Thus, hypermethylation of ASC/TMS1 is a marker for late-stage lung cancer and, in sputum, could predict prognosis in patients resected for early-stage disease.
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland 21231, USA.
authors.forename: Emi Ota
authors.initials: EO
authors.lastname: Machida
authors.forename: Malcolm V
authors.initials: MV
authors.lastname: Brock
authors.forename: Craig M
authors.initials: CM
authors.lastname: Hooker
authors.forename: Jun
authors.initials: J
authors.lastname: Nakayama
authors.forename: Akiko
authors.initials: A
authors.lastname: Ishida
authors.forename: Jun
authors.initials: J
authors.lastname: Amano
authors.forename: Maria A
authors.initials: MA
authors.lastname: Picchi
authors.forename: Steven A
authors.initials: SA
authors.lastname: Belinsky
authors.forename: James G
authors.initials: JG
authors.lastname: Herman
authors.forename: Shun'ichiro
authors.initials: S
authors.lastname: Taniguchi
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Baylin
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000368:Aged; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics*; D053468:CARD Signaling Adaptor Proteins; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003598:Cytoskeletal Proteins / Q000096:biosynthesis / Q000235:genetics*; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D012307:Risk Factors; D013183:Sputum / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D053468:CARD Signaling Adaptor Proteins; D003598:Cytoskeletal Proteins; D004273:DNA, Neoplasm; C402202:PYCARD protein, human