Imprinted genes as risk and early detection markers for breast cancer

描述（由申请人提供）：摘要证据正在积累，乳腺癌有一个早期生命的组成部分。子宫内编程可能是乳腺癌的发育起源的基础，并可能受到表观遗传机制的控制。11号染色体的15.5区域拥有人类基因组中最大的印记簇之一，其所有印记基因都控制胎盘和胎儿生长（PHLDA 2，SLC22A18，CDKN1C，KCNQ1DN，KCNQ1，IGF 2和H19）。因为基因组印记是在配子中建立的，所以它可以在包括全身血细胞在内的大多数组织中发现。因此，印记丧失（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染色体11p15.5上印迹簇上印迹基因中LOI的比例，并比较两种组织类型中的这些频率。 2.探索血液和乳腺组织中染色体11p15.5上印记簇上的一个或多个印记基因的LOI是否与乳腺癌风险增加相关，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.探索良性乳腺疾病女性血液和组织中染色体11p15.5上印记簇上印记基因的LOI频率是否高于健康女性，但低于浸润性乳腺癌女性。 4.检查这些表观遗传标记是否在血液和乳腺组织中高度一致，因此可以用作乳腺癌的风险和早期检测标记。我们建议使用沃尔特里德医疗中心临床乳腺护理计划（CBCP）的独特资源，包括来自美国国防部成员及其家属的30，077份现成标本，以确定150名浸润性乳腺癌女性，150名良性乳腺疾病女性和50名无乳腺疾病女性中染色体11p15.5的印迹状态。 公共卫生相关性：乳腺癌妇女和健康对照者在支配胎儿生长的染色体区域上印迹模式的显着差异将提供一种解释乳腺癌宫内起源的机制。如果我们能够证实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，并有助于作为早期疾病检测的标志物。

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.