DNA methylation changes measured in pre-diagnostic peripheral blood samples are associated with smoking and lung cancer risk

被引：102

作者：

Baglietto, Laura ^{[1
,2
,3
,4
]}

Ponzi, Erica ^{[5
,6
]}

Haycock, Philip ^{[7
]}

Hodge, Allison ^{[4
]}

Assumma, Manuela Bianca ^{[8
]}

Jung, Chol-Hee ^{[9
]}

Chung, Jessica ^{[9
]}

Fasanelli, Francesca ^{[8
,10
,11
]}

Guida, Florence ^{[12
]}

Campanella, Gianluca ^{[12
]}

Chadeau-Hyam, Marc ^{[12
]}

Grankvist, Kjell ^{[13
]}

Johansson, Mikael ^{[14
]}

Ala, Ugo ^{[15
]}

Provero, Paolo ^{[15
,16
]}

Wong, Ee Ming ^{[17
]}

Joo, Jihoon ^{[17
]}

English, Dallas R. ^{[3
,4
]}

Kazmi, Nabila ^{[7
]}

Lund, Eiliv ^{[18
]}

Faltus, Christian ^{[19
,20
]}

Kaaks, Rudolf ^{[21
,22
]}

Risch, Angela ^{[19
,20
,22
]}

Barrdahl, Myrto ^{[21
]}

Sandanger, Torkjel M. ^{[18
]}

Southey, Melissa C. ^{[17
]}

Giles, Graham G. ^{[3
,4
]}

Johansson, Mattias ^{[23
]}

Vineis, Paolo ^{[8
,12
]}

Polidoro, Silvia ^{[8
]}

Relton, Caroline L. ^{[7
]}

Severi, Gianluca ^{[1
,2
,3
,4
,8
]}

机构：

[1] Univ Paris Saclay, Univ Paris Sud, UVSQ, CESP,INSERM, Villejuif, France

[2] Gustave Roussy, F-94805 Villejuif, France

[3] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia

[4] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Epidemiol & Biostat, Melbourne, Vic, Australia

[5] Univ Zurich, Dept Evolutionary Biol & Environm Studies, Zurich, Switzerland

[6] Univ Zurich, Epidemiol Biostat & Prevent Inst, Zurich, Switzerland

[7] Univ Bristol, Sch Social & Community Med, MRC Integrat Epidemiol Unit, Bristol BS8 2BN, Avon, England

[8] Human Genet Fdn, HuGeF, I-10126 Turin, Italy

[9] Univ Melbourne, Victorian Life Sci Computat Initiat, Melbourne, Vic 3010, Australia

[10] Univ Turin, Citta Salute & Sci Hosp, Canc Epidemiol Unit, I-10126 Turin, Italy

[11] Ctr Canc Prevent CPO, I-10126 Turin, Italy

[12] Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, MRC PHE Ctr Environm & Hlth, Norfolk Pl, London W2 1PG, England

[13] Umea Univ, Dept Biobank Res, Umea, Sweden

[14] Umea Univ, Dept Radiat Sci, Umea, Sweden

[15] Univ Torino, Dept Mol Biotechnol & Hlth Sci, I-10126 Turin, Italy

[16] Ist Sci San Raffaele, Ctr Translat Genom & Bioinformat, Milan, Italy

[17] Univ Melbourne, Dept Pathol, Genet Epidemiol Lab, Melbourne, Vic, Australia

[18] UiT, Dept Community Med, Tromso, Norway

[19] Salzburg Univ, Dept Mol Biol, Div Canc Res & Epigenet, Salzburg, Austria

[20] DKFZ German Canc Res Ctr, Div Epigen & Canc Risk Factors, Heidelberg, Germany

[21] DKFZ German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany

[22] German Ctr Lung Res DZL, Translat Lung Res Ctr Heidelberg, Heidelberg, Germany

[23] Int Agcy Res Canc, Lyon, France

来源：

INTERNATIONAL JOURNAL OF CANCER | 2017年 / 140卷 / 01期

基金：

澳大利亚国家健康与医学研究理事会;

关键词：

DNA methylation; lung cancer risk; smoking; CIGARETTE-SMOKING; EPIGENOME; CELLS; PATTERNS; PROJECT; SITES; DIET;

D O I：

10.1002/ijc.30431

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 x 10(-17)), cg03636183 in the F2RL3 gene (p-value(pooled)=2 x 10 (- 13)), cg21566642 and cg05951221 in 2q37.1 (p-value(pooled)=7 x 10(-16) and 1 x 10(-11) respectively), cg06126421 in 6p21.33 (p-value(pooled)=2 x 10(-15)) and cg23387569 in 12q14.1 (p-value(pooled)=5 x 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-values0.003) 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. What's new? It is well known that smoking can cause lung cancer but the concept that it might do so by changing DNA methylation is only emerging. Here the authors identify six sites of methylation (CpGs), where methylation levels were associated with lung cancer risk after adjusting for smoking, current or former. Methylation of five of the CpGs was lowest in current smokers and increased in former smokers with time since quitting, supporting the growing evidence that smoking may lead to DNA methylation changes measurable in peripheral blood and useful as predictive markers for lung cancer risk, especially in former smokers.

引用

页码：50 / 61

页数：12

共 30 条

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