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DNA methylation changes measured in pre‐diagnostic peripheral blood samples are associated with smoking and lung cancer risk
Author(s) -
Baglietto Laura,
Ponzi Erica,
Haycock Philip,
Hodge Allison,
Bianca Assumma Manuela,
Jung CholHee,
Chung Jessica,
Fasanelli Francesca,
Guida Florence,
Campanella Gianluca,
ChadeauHyam Marc,
Grankvist Kjell,
Johansson Mikael,
Ala Ugo,
Provero Paolo,
Wong Ee Ming,
Joo Jihoon,
English Dallas R.,
Kazmi Nabila,
Lund Eiliv,
Faltus Christian,
Kaaks Rudolf,
Risch Angela,
Barrdahl Myrto,
Sandanger Torkjel M.,
Southey Melissa C.,
Giles Graham G.,
Johansson Mattias,
Vineis Paolo,
Polidoro Silvia,
Relton Caroline L.,
Severi Gianluca
Publication year - 2016
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.30431
Subject(s) - dna methylation , lung cancer , methylation , cohort , medicine , case control study , oncology , cancer , nested case control study , biology , gene , genetics , gene expression
DNA methylation changes are associated with cigarette smoking. We used the Illumina Infinium HumanMethylation450 array to determine whether methylation in DNA from pre‐diagnostic, peripheral blood samples is associated with lung cancer risk. We used a case‐control study nested within the EPIC‐Italy cohort and a study within the MCCS cohort as discovery sets (a total of 552 case‐control pairs). We validated the top signals in 429 case‐control pairs from another 3 studies. We identified six CpGs for which hypomethylation was associated with lung cancer risk: cg05575921 in the AHRR gene ( p ‐value pooled  = 4 × 10 −17 ), cg03636183 in the F2RL3 gene ( p ‐value pooled  = 2 × 10 − 13 ), cg21566642 and cg05951221 in 2q37.1 ( p ‐value pooled  = 7 × 10 −16 and 1 × 10 −11 respectively), cg06126421 in 6p21.33 ( p ‐value pooled  = 2 × 10 −15 ) and cg23387569 in 12q14.1 ( p ‐value pooled  = 5 × 10 −7 ). For cg05951221 and cg23387569 the strength of association was virtually identical in never and current smokers. For all these CpGs except for cg23387569, the methylation levels were different across smoking categories in controls ( p ‐values heterogeneity  ≤ 1.8 x10 − 7 ), were lowest for current smokers and increased with time since quitting for former smokers. We observed a gain in discrimination between cases and controls measured by the area under the ROC curve of at least 8% ( p ‐values ≥ 0.003) in former smokers by adding methylation at the 6 CpGs into risk prediction models including smoking status and number of pack‐years. Our findings provide convincing evidence that smoking and possibly other factors lead to DNA methylation changes measurable in peripheral blood that may improve prediction of lung cancer risk.

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