Inactivation of the Fanconi anemia/BRCA pathway in lung and oral cancers: implications for treatment and survival.
Inactivation of the FANC-BRCA pathway via promoter methylation of the FANCF gene renders cells sensitive to DNA crosslinking agents, and has been identified in ovarian cancer cell lines and sporadic primary tumor tissues. We investigated epigenetic alterations in the FANC-BRCA pathway in head and neck squamous cell carcinomas (HNSCC) and non-small-cell lung cancers (NSCLC) using methylation-specific PCR. Promoter methylation of FANCF occurred in 15% (13/89) of HNSCCs and 14% (22/158) of NSCLCs. Methylation of BRCA1 occurred only in 6/158 NSCLC, and was limited to adenocarcinomas and large-cell carcinomas of the lung. No methylation of BRCA2 was detected. FANCF methylation was associated with a shorter duration of tobacco use (P=0.03) and a younger age of starting smoking (P=0.06) in NSCLC, and with a greater number of years of alcohol drinking (P=0.02) in HNSCC. In adenocarcinomas of the lung, FANCF promoter methylation was a significant predictor of poor survival with a hazard ratio of 3.1 (95% CI 1.2-7.9). This study demonstrates that inactivation of the FANC-BRCA pathway is relatively common in solid tumors and may be related to tobacco and alcohol exposure and survival of these patients.
Marsit
Carmen J
CJ
Department of Cancer Cell Biology, Harvard School of Public Health, Boston, MA 02115, USA.
Liu
Mei
M
Nelson
Heather H
HH
Posner
Marshall
M
Suzuki
Makoto
M
Kelsey
Karl T
KT
D000368:Aged; D000428:Alcohol Drinking; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000628:therapy; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000628:therapy; D018797:Cell Cycle Proteins; D019175:DNA Methylation; D004268:DNA-Binding Proteins; D051856:Fanconi Anemia Complementation Group Proteins; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000628:therapy; D008297:Male; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000235:genetics* / Q000628:therapy; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D012907:Smoking; D016019:Survival Analysis
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D051856:Fanconi Anemia Complementation Group Proteins; D009687:Nuclear Proteins; D011506:Proteins