Screening for Breast Cancer Using Molecular Signatures

描述(申请人提供)：目前，还没有可用的分子筛查工具来识别乳腺癌发展或局部复发的高危患者。然而，有趣的是，许多研究表明，高达60%的患者在组织学上的非恶性乳腺组织中存在与邻近肿瘤相同的遗传改变(杂合性缺失、染色体异常、特定基因突变)。这些数据表明，在癌症的组织学发展之前就积累了大量的基因变化，尽管这些变化在正常外观的乳房中的频率、身份和位置仍然鲜为人知。我们假设在非恶性乳腺组织中存在基因改变，这些改变将导致基因表达的表型改变，这可能有助于预测乳腺癌的风险。基因芯片将被用来识别一组基因，这些基因的表达谱预测组织学上非恶性乳腺组织的癌症风险。作为检测散发性乳腺癌分子筛查标志物的第一步，我们计划调查已知同侧和对侧乳腺癌复发风险增加的患者癌旁的非恶性乳腺组织。这将通过对乳腺肿瘤和正常相关乳腺组织同时进行的遗传、表观遗传和基因表达变化的全面分析来实现。虽然我们的主要目标是为发展为癌症高危的正常组织确定基因表达模式，但我们也将开发丰富的数据库，以破译表征乳腺肿瘤及其临床病理特征(包括生存和复发数据)以及良性乳腺病理的模式。然后，我们计划评估这些高危基因在接受辅助治疗以降低癌症风险的患者中的行为。具体目的1.确定异常遗传(DNA)、表观遗传(DNA甲基化)和分子(RNA)特征在组织学上非恶性乳腺组织中的频率和地理分布，这些特征来自乳腺癌切除标本(n=100)。特殊目的II.确定是否可以在接受双侧乳房切除术的同侧乳腺癌患者(n=50)的对侧正常乳腺中检测到AIM I中发现的遗传和表观遗传学改变以及基因表达改变。明确目的III.确定50例乳腺导管内瘤切除患者的正常组织和肿瘤组织中的遗传、表观遗传学和基因表达的变化。具体目的IV.在治疗前和治疗后采集的系列活检标本(n=50)中，确定高危基因组(在AIMS I、II和III中确定)在未治疗的对侧乳房中的表达是否受到辅助化疗和/或激素治疗的影响。

DESCRIPTION (provided by applicant): Currently, there are no molecular screening tools available that can identify the patients at high risk for breast cancer development or local recurrence. Of interest, however, is that numerous studies have suggested the existence of genetic alterations (LOH, chromosomal abnormalities, specific gene mutations) in histological non-malignant breast tissue, identical to those found in adjacent tumor, in up to 60% of patients. These data suggest that there are numerous genetic alterations that accumulate prior to the histological development of cancer, although the frequency, identity, and location of these alterations within the normal appearing breast are still poorly understood. We hypothesize that genetic alterations exist in non-malignant breast tissue and that they will produce phenotypic alterations in gene expression that may be useful in predicting breast cancer risk. cDNA microarrays will be used to identify a set of genes whose expression profile predicts cancer risk in histologically non-malignant breast tissue. As a first step towards the detection of molecular screening markers for sporadic breast cancer, we plan to investigate the non-malignant breast tissue adjacent to cancer in patients known to be at increased risk for cancer recurrence both in the ipsilateral and contralateral breasts. This will be accomplished by a comprehensive analysis of genetic, epigenetic and gene expression alterations performed simultaneously on breast tumors and normal associated breast tissue. Whereas the principal goal is identifying a gene expression pattern for normal tissues at high risk for developing cancer, we will also develop rich databases to decipher patterns characterizing breast tumors and their clinicopathologic features (including survival and recurrence data) as well as benign breast pathology. We then plan to evaluate the behavior of these high-risk genes in patients undergoing adjuvant therapy to reduce cancer risk. Specific Aim I. To identify the frequency and geographic distribution of abnormal genetic (DNA), epigenetic (DNA methylation) and molecular (RNA) signatures, within zones of histologically non-malignant breast tissue adjacent to invasive cancer derived from mastectomy specimens (n = 100). Specific Aim II. Determine if genetic and epigenetic alterations as well as gene expression alterations identified in Aim I can be detected in the contralateral normal breast in patients undergoing bilateral mastectomy for ipsilateral cancer(n = 50). Specific Aim III. To identify genetic, epigenetic and gene expression alterations in normal and tumor tissues from patients undergoing mastectomy for intraductal neoplasia (n = 50). Specific Aim IV. Determine if the expression of high-risk gene sets (identified in Aims I, II, and III) in the contralateral, untreated breast are affected by adjuvant chemotherapy and/or hormonal therapy in serial biopsy specimens (n = 50) taken pre- and post- therapy.