Somatically acquired hypomethylation of IGF2 in breast and colorectal cancer.
The imprinted insulin-like growth factor 2 (IGF2) gene is expressed predominantly from the paternal allele. Loss of imprinting (LOI) associated with hypomethylation at the promoter proximal sequence (DMR0) of the IGF2 gene was proposed as a predisposing constitutive risk biomarker for colorectal cancer. We used pyrosequencing to assess whether IGF2 DMR0 methylation is either present constitutively prior to cancer or whether it is acquired tissue-specifically after the onset of cancer. DNA samples from tumour tissues and matched non-tumour tissues from 22 breast and 42 colorectal cancer patients as well as peripheral blood samples obtained from colorectal cancer patients [SEARCH (n=case 192, controls 96)], breast cancer patients [ABC (n=case 364, controls 96)] and the European Prospective Investigation of Cancer [EPIC-Norfolk (n=breast 228, colorectal 225, controls 895)] were analysed. The EPIC samples were collected 2-5 years prior to diagnosis of breast or colorectal cancer. IGF2 DMR0 methylation levels in tumours were lower than matched non-tumour tissue. Hypomethylation of DMR0 was detected in breast (33%) and colorectal (80%) tumour tissues with a higher frequency than LOI indicating that methylation levels are a better indicator of cancer than LOI. In the EPIC population, the prevalence of IGF2 DMR0 hypomethylation was 9.5% and this correlated with increased age not cancer risk. Thus, IGF2 DMR0 hypomethylation occurs as an acquired tissue-specific somatic event rather than a constitutive innate epimutation. These results indicate that IGF2 DMR0 hypomethylation has diagnostic potential for colon cancer rather than value as a surrogate biomarker for constitutive LOI.
Department of Oncology, University of Cambridge, CRUK Cambridge Research Institute, Li Ka- Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
Yoko
Y
Ito
Thibaud
T
Koessler
Ashraf E K
AE
Ibrahim
Sushma
S
Rai
Sarah L
SL
Vowler
Sayeda
S
Abu-Amero
Ana-Luisa
AL
Silva
Ana-Teresa
AT
Maia
Joanna E
JE
Huddleston
Santiago
S
Uribe-Lewis
Kathryn
K
Woodfine
Maja
M
Jagodic
Raffaella
R
Nativio
Alison
A
Dunning
Gudrun
G
Moore
Elena
E
Klenova
Sheila
S
Bingham
Paul D P
PD
Pharoah
James D
JD
Brenton
Stephan
S
Beck
Manjinder S
MS
Sandhu
Adele
A
Murrell
D001943:Breast Neoplasms / Q000235:genetics*; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000235:genetics*; D019175:DNA Methylation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018392:Genomic Imprinting; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics* / Q000378:metabolism
D007335:Insulin-Like Growth Factor II