Gene-environment interactions in 7610 women with breast cancer: prospective evidence from the Million Women Study.
BACKGROUND
Information is scarce about the combined effects on breast cancer incidence of low-penetrance genetic susceptibility polymorphisms and environmental factors (reproductive, behavioural, and anthropometric risk factors for breast cancer). To test for evidence of gene-environment interactions, we compared genotypic relative risks for breast cancer across the other risk factors in a large UK prospective study.


METHODS
We tested gene-environment interactions in 7610 women who developed breast cancer and 10 196 controls without the disease, studying the effects of 12 polymorphisms (FGFR2-rs2981582, TNRC9-rs3803662, 2q35-rs13387042, MAP3K1-rs889312, 8q24-rs13281615, 2p-rs4666451, 5p12-rs981782, CASP8-rs1045485, LSP1-rs3817198, 5q-rs30099, TGFB1-rs1982073, and ATM-rs1800054) in relation to prospectively collected information about ten established environmental risk factors (age at menarche, parity, age at first birth, breastfeeding, menopausal status, age at menopause, use of hormone replacement therapy, body-mass index, height, and alcohol consumption).


RESULTS
After allowance for multiple testing none of the 120 comparisons yielded significant evidence of a gene-environment interaction. By contrast with previous suggestions, there was little evidence that the genotypic relative risks were affected by use of hormone replacement therapy, either overall or for oestrogen-receptor-positive disease. Only one of the 12 polymorphisms was correlated with any of the ten other risk factors: carriers of the high-risk C allele of MAP3K1-rs889312 were significantly shorter than non-carriers (mean height 162.4 cm [95% CI 162.1-162.7] vs 163.1 cm [162.9-163.2]; p=0.01 after allowance for multiple testing).


CONCLUSIONS
Risks of breast cancer associated with low-penetrance susceptibility polymorphisms do not vary significantly with these ten established environmental risk factors.


BACKGROUND
Cancer Research UK and the UK Medical Research Council.
Travis
Ruth C
RC
Cancer Epidemiology Unit, University of Oxford, Oxford, UK. ruth.travis@ceu.ox.ac.uk
Reeves
Gillian K
GK
Green
Jane
J
Bull
Diana
D
Tipper
Sarah J
SJ
Baker
Krys
K
Beral
Valerie
V
Peto
Richard
R
Bell
John
J
Zelenika
Diana
D
Lathrop
Mark
M
D000225:Adenine; D000367:Age Factors; D000428:Alcohol Drinking; D051017:Apoptosis Regulatory Proteins; D064007:Ataxia Telangiectasia Mutated Proteins; D001827:Body Height; D015992:Body Mass Index; D001942:Breast Feeding; D001943:Breast Neoplasms / Q000209:etiology / Q000235:genetics*; D053181:Caspase 8 / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics; D003596:Cytosine; D004268:DNA-Binding Proteins / Q000235:genetics; D004777:Environment; D005260:Female; D005838:Genotype; D006609:High Mobility Group Proteins; D020249:Hormone Replacement Therapy; D006801:Humans; D016350:Leucine Zippers / Q000235:genetics; D048728:MAP Kinase Kinase Kinase 1 / Q000235:genetics; D008572:Menarche / Q000502:physiology; D008593:Menopause / Q000502:physiology; D008840:Microfilament Proteins / Q000235:genetics; D008875:Middle Aged; D010298:Parity; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D010750:Phosphoproteins / Q000235:genetics; D011110:Polymorphism, Genetic / Q000235:genetics; D011247:Pregnancy; D011446:Prospective Studies; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics; D011980:Receptors, Progesterone / Q000235:genetics; D012307:Risk Factors; D015534:Trans-Activators; D053773:Transforming Growth Factor beta1 / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics; D055815:Young Adult
D000225:Adenine; D051017:Apoptosis Regulatory Proteins; D064007:Ataxia Telangiectasia Mutated Proteins; D053181:Caspase 8; D018797:Cell Cycle Proteins; D003596:Cytosine; D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; D048728:MAP Kinase Kinase Kinase 1; D008840:Microfilament Proteins; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D051497:Receptor, Fibroblast Growth Factor, Type 2; D011980:Receptors, Progesterone; D015534:Trans-Activators; D053773:Transforming Growth Factor beta1; D025521:Tumor Suppressor Proteins; C489183:LSP1 protein, human; C508960:TGFB1 protein, human; C521752:TOX3 protein, human; C496353:FGFR2 protein, human; C576324:ATM protein, human; C482576:MAP3K1 protein, human; C505530:CASP8 protein, human