Screening for Breast Cancer Using Molecular Signatures

描述（由申请人提供）：目前，没有可用的分子筛查工具可以识别乳腺癌发展或局部复发的高风险患者。然而，令人感兴趣的是，许多研究表明，在高达60%的患者中，组织学非恶性乳腺组织中存在遗传改变（洛缺失、染色体异常、特定基因突变），与在相邻肿瘤中发现的遗传改变相同。这些数据表明，在癌症的组织学发展之前，有许多遗传改变积累，尽管这些改变在正常乳房中的频率，身份和位置仍然知之甚少。我们假设非恶性乳腺组织中存在遗传改变，它们将产生基因表达的表型改变，这可能有助于预测乳腺癌风险。cDNA微阵列将用于鉴定一组基因，其表达谱预测组织学非恶性乳腺组织中的癌症风险。作为检测散发性乳腺癌分子筛查标志物的第一步，我们计划研究已知同侧和对侧乳腺癌复发风险增加的患者的癌旁非恶性乳腺组织。这将通过对乳腺肿瘤和正常相关乳腺组织同时进行遗传、表观遗传和基因表达改变的综合分析来实现。虽然主要目标是确定正常组织的基因表达模式，在发展癌症的高风险，我们还将开发丰富的数据库，以破译模式特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。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。具体目标一。确定乳腺切除术标本（n = 100）中浸润性癌相邻组织学非恶性乳腺组织区域内异常遗传（DNA）、表观遗传（DNA甲基化）和分子（RNA）特征的频率和地理分布。具体目标二。确定是否可以在因同侧癌症接受双侧乳房切除术的患者（n = 50）的对侧正常乳房中检测到目标I中确定的遗传和表观遗传改变以及基因表达改变。具体目标三。确定接受乳腺切除术治疗导管内瘤变的患者（n = 50）的正常和肿瘤组织中的遗传、表观遗传和基因表达改变。具体目标四。在治疗前和治疗后采集的系列活检标本（n = 50）中，确定对侧未治疗乳腺中高危基因集（在目标I、II和III中确定）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.