Evidence is accumulating that breast cancer has an early life component. Intrauterine programming may underlie the developmental origins of breast cancer and may be governed by epigenetic mechanisms. The 15.5 region of chromosome 11 harbors one of the largest imprinted clusters in the human genome, and all its imprinted genes govern placental and fetal growth (PHLDA2, SLC22A18, CDKN1C, KCNQ1DN, KCNQ1, IGF2 and H19). Because genomic imprinting is established in gametes, it can be found in most tissues including systemic blood cells. Therefore, loss of imprinting (LOI) lends itself to develop risk and early detection markers for cancer. We propose to: 1. Establish the proportion of LOI among the imprinted genes on the imprinting cluster on chromosome 11p15.5 in blood and mammary tissue of healthy adult women and compare these frequencies in the two tissue types. 2. Explore whether LOI of one or more of the imprinted genes on the imprinted cluster on chromosome 11p15.5 in blood and mammary tissue is associated with an increased risk of breast cancer, independent of age, family history of breast cancer, and several reproductive and lifestyle factors associated with breast cancer risk. 3. Explore whether the frequency of LOI of the imprinted genes on the imprinted cluster on chromosome 11p15.5 in blood and tissue from women with benign breast disease is higher than that of healthy women but lower than that found in women with invasive breast cancer. 4. Examine whether these epigenetic marks are highly consistent in blood and mammary tissue and can therefore be used as risk and early detection markers for breast cancer. We propose to use the unique resource of the Clinical Breast Care Program (CBCP) at Walter Reed Medical Center encompassing 30,077 readily available specimen from U.S. Department of Defense members and their families to determine imprinting status at chromosome 11p15.5 among 150 women with invasive breast cancer, 150 women with benign breast disease and 50 women free of breast disease.
Narrative A significant difference in imprinting pattern between women with breast cancer and healthy controls on the chromosomal region dominating fetal growth would provide a mechanism explaining the intrauterine origins of breast cancer. If we are able to confirm that the imprinting pattern among women with benign breast disease is an intermediate between the pattern found in healthy women and in women with breast cancer this would confirm that LOI is an early process in tumorigenesis and lends itself as a marker of early disease detection.
| Barrow, Timothy M; Barault, Ludovic; Ellsworth, Rachel E et al. (2015) Aberrant methylation of imprinted genes is associated with negative hormone receptor status in invasive breast cancer. Int J Cancer 137:537-47 |
| Barault, Ludovic; Ellsworth, Rachel E; Harris, Holly R et al. (2013) Leukocyte DNA as surrogate for the evaluation of imprinted Loci methylation in mammary tissue DNA. PLoS One 8:e55896 |
