Imprinted genes as risk and early detection markers for breast cancer

描述(由申请者提供)：越来越多的抽象证据表明乳腺癌与早期生活有关。宫内程序化可能是乳腺癌发生发展的基础，并可能受表观遗传机制的支配。11号染色体的15.5区域含有人类基因组中最大的印迹簇之一，其所有印迹基因都控制着胎盘和胎儿的生长(PHLDA2、SLC22A18、CDKN1C、KCNQ1DN、KCNQ1、IGF2和H19)。由于基因组印迹是在配子中建立的，所以它可以在大多数组织中找到，包括全身血细胞。因此，印迹丢失(LOI)有助于开发癌症的风险和早期检测标志物。我们建议：1.建立健康成年女性血液和乳腺组织中11p15.5号染色体印迹簇上印迹基因间的LOI比例，并比较这两种组织类型的LOI频率。2.探讨血液和乳腺组织中11p15.5号染色体印迹簇上的一个或多个印记基因的LOI是否与乳腺癌风险增加有关，与年龄、乳腺癌家族史以及与乳腺癌风险相关的几个生殖和生活方式因素无关。3.探讨乳腺良性疾病患者外周血和组织中11p15.5号染色体印迹簇上印迹基因的LOI频率是否高于健康女性，但低于浸润性乳腺癌患者。4.检查这些表观遗传标记在血液和乳腺组织中是否高度一致，从而可以用作乳腺癌的风险和早期检测标记。我们建议利用沃尔特里德医学中心的临床乳房护理计划(CBCP)的独特资源，包括来自美国国防部成员及其家人的30,077份现成样本，来确定150名浸润性乳腺癌患者、150名良性乳腺疾病患者和50名非乳腺疾病女性的染色体11p15.5的印迹状态。 公共卫生相关性：叙事乳腺癌患者和健康对照组在控制胎儿生长的染色体区域印迹模式上的显著差异，将为解释乳腺癌的宫内起源提供一种机制。如果我们能够确认良性乳腺疾病女性的印记模式是健康女性和乳腺癌女性之间的中间模式，这将证实LOI是肿瘤发生的早期过程，并作为早期疾病检测的标志。

DESCRIPTION (provided by applicant): Abstract 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. PUBLIC HEALTH RELEVANCE: 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.