Quantitative analysis of DNA methylation profiles in lung cancer identifies aberrant DNA methylation of specific genes and its association with gender and cancer risk factors.
The global increase in lung cancer burden, together with its poor survival and resistance to classical chemotherapy, underscores the need for identification of critical molecular events involved in lung carcinogenesis. Here, we have applied quantitative profiling of DNA methylation states in a panel of five cancer-associated genes (CDH1, CDKN2A, GSTP1, MTHFR, and RASSF1A) to a large case-control study of lung cancer. Our analyses revealed a high frequency of aberrant hypermethylation of MTHFR, RASSF1A, and CDKN2A in lung tumors as compared with control blood samples, whereas no significant increase in methylation levels of GSTP1 and CDH1 was observed, consistent with the notion that aberrant DNA methylation occurs in a tumor-specific and gene-specific manner. Importantly, we found that tobacco smoking, sex, and alcohol intake had a strong influence on the methylation levels of distinct genes (RASSF1A and MTHFR), whereas folate intake, age, and histologic subtype had no significant influence on methylation states. We observed a strong association between MTHFR hypermethylation in lung cancer and tobacco smoking, whereas methylation levels of CDH1, CDKN2A, GSTP1, and RASSF1A were not associated with smoking, indicating that tobacco smoke targets specific genes for hypermethylation. We also found that methylation levels in RASSF1A, but not the other genes under study, were influenced by sex, with males showing higher levels of methylation. Together, this study identifies aberrant DNA methylation patterns in lung cancer and thus exemplifies the mechanism by which environmental factors may interact with key genes involved in tumor suppression and contribute to lung cancer.
Vaissière
Thomas
T
Epigenetics Group, IARC, 150 cours Albert Thomas, Lyon cedex 08, France.
Hung
Rayjean J
RJ
Zaridze
David
D
Moukeria
Anush
A
Cuenin
Cyrille
C
Fasolo
Virginie
V
Ferro
Gilles
G
Paliwal
Anupam
A
Hainaut
Pierre
P
Brennan
Paul
P
Tost
Jörg
J
Boffetta
Paolo
P
Herceg
Zdenko
Z
D002282:Adenocarcinoma, Bronchiolo-Alveolar / Q000235:genetics / Q000473:pathology; D000328:Adult; D000368:Aged; D015703:Antigens, CD; D015820:Cadherins / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D019175:DNA Methylation; D005260:Female; D015870:Gene Expression; D019942:Genes, p16; D020022:Genetic Predisposition to Disease; D051549:Glutathione S-Transferase pi / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D008875:Middle Aged; D012307:Risk Factors; D012737:Sex Factors; D012907:Smoking; D025521:Tumor Suppressor Proteins / Q000235:genetics
D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; C411762:RASSF1 protein, human; D025521:Tumor Suppressor Proteins; D042965:Methylenetetrahydrofolate Reductase (NADPH2); C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi