Somatically acquired hypomethylation of IGF2 in breast and colorectal cancer

• Published in: Human molecular genetics Vol. 17; no. 17; pp. 2633 - 2643
• Main Authors: Ito, Yoko, Koessler, Thibaud, Ibrahim, Ashraf E.K., Rai, Sushma, Vowler, Sarah L., Abu-Amero, Sayeda, Silva, Ana-Luisa, Maia, Ana-Teresa, Huddleston, Joanna E., Uribe-Lewis, Santiago, Woodfine, Kathryn, Jagodic, Maja, Nativio, Raffaella, Dunning, Alison, Moore, Gudrun, Klenova, Elena, Bingham, Sheila, Pharoah, Paul D.P., Brenton, James D., Beck, Stephan, Sandhu, Manjinder S., Murrell, Adele
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01-09-2008; Oxford Publishing Limited (England)
• Subjects: Biological and medical sciences; Breast Neoplasms - genetics; Case-Control Studies; Colorectal cancer; Colorectal Neoplasms - genetics; DNA Methylation; Female; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Neoplastic; Genetics of eukaryotes. Biological and molecular evolution; Genomic Imprinting; Gynecology. Andrology. Obstetrics; Humans; Insulin-Like Growth Factor II - genetics; Insulin-Like Growth Factor II - metabolism; Mammary gland diseases; Medical sciences; Molecular and cellular biology; Tumors; Rectal disease; Breast disease; Colorectal cancer; Breast cancer; Malignant tumor; Insulin like growth factor 2; Colonic disease; Mammary gland diseases; Digestive diseases; Intestinal disease; Genetics; Methylation; Cancer
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddn163

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.