MIcroRNA: A Novel Genetic Modifier for Breast Cancer Predisposition

描述(申请人提供)：在过去的十年中发现了microRNAs(MiRNAs)，并通过调节癌基因和肿瘤抑制基因(TSG)的转录实现了它们在癌症发生和癌症预后中日益重要的作用，这导致了一个关于这些小分子的令人兴奋的发现时代。虽然已知在包括乳腺癌在内的许多肿瘤组织中普遍存在miRNAs的错误表达，但关于miRNA基因及其靶基因中的反应元件的遗传变异性如何与癌症易感，目前还知之甚少。由于miRNAs功能的特殊方式--通过靶向一些功能上重要的蛋白质编码基因，如癌基因和TSGs--miRNA基因及其在靶基因中的反应元件的遗传变异可能在癌症易感性中起重要作用。MiRNAs的遗传变异可能与乳腺癌密切相关，因为家族病史一直被认为是乳腺癌的主要危险因素。目前已知的高危乳腺癌基因(如BRCA1/2等)的胚系突变在家族性乳腺癌中很常见，但它们最多可以解释总体超额家族风险的20%-25%，这表明存在其他未确定的易感基因，使人对乳腺癌具有易感性。人们已经做出了相当大的努力来发现乳房易感基因，但到目前为止还没有发现多少。这一困境可能是由于易感等位基因存在于蛋白质非编码基因中，如miRNAs或靶基因3‘UTR区的miRNA反应元件，这些基因在传统的遗传筛选中被忽视了。我们建议利用乳腺癌研究合作家族登记(CFRBCS)的宝贵资源，在遗传性乳腺癌家系中筛选选定的miRNA基因中的遗传变异及其靶基因中的反应元件，评估这些遗传变异在遗传性和/或散发性乳腺癌发生中的遗传易感性，并从功能上表征这些遗传变异。我们假设miRNA基因的遗传变异及其在靶基因中的反应元件通过影响miRNAs的生物学功能来改变各种生物学过程，从而改变乳腺癌的遗传易感性。由于这项研究嵌套在CFRBCS内，因此可以及时和具有成本效益的方式实现各项目标。这一创新而重要的领域还没有得到调查。这项研究将有助于我们阐明miRNA在乳腺癌中的生物学意义，探索这些遗传变异的功能意义，并为理解miRNA在乳腺癌易感性中的作用奠定坚实的基础。从临床角度来看，将这些信息长期应用于风险评估，从而在家庭和人群中预防和早期发现乳腺癌将具有重要意义。公共卫生相关性：拟议的研究将有助于我们阐明miRNA在乳腺癌中的生物学意义，探索这些遗传变异的功能意义，并为理解miRNA在乳腺癌易感性中的作用奠定坚实的基础。从临床角度来看，将这些信息长期应用于风险评估，从而在家庭和人群中预防和早期发现乳腺癌将具有重要意义。

DESCRIPTION (provided by applicant): The discovery of microRNAs (miRNAs) in the last decade, and the realization of their growing importance in carcinogenesis and cancer prognosis through regulation of transcription of oncogenes and tumor suppressor genes (TSGs), has led to an era of excitement of discovery regarding these small molecules. Although it is known that there is widespread misexpression of miRNAs in many cancer tissues, including breast cancer, little is known regarding how inherited variability in miRNA genes and their responsive elements in target genes may predispose to cancer. As a consequence of the particular way in which miRNAs function - by targeting a number of functionally important protein-coding genes, such as oncogenes and TSGs - genetic variations in miRNA genes and their responsive elements in target genes could be important in cancer predisposition. Inherited variability in miRNAs may be extremely relevant for breast cancer, as family history has consistently been regarded as a major risk factor for breast cancer. Germ-line mutations in the currently known high-risk breast cancer genes (such as BRCA1/2, etc) are common in familial breast cancer, but they can explain at best 20-25% of the overall excess familial risk, suggesting the presence of other unidentified predisposition genes, which confer susceptibility to breast cancer. Considerable efforts have been made to discover breast susceptibility genes, however so far few have been identified. The dilemma might be due to the fact that susceptibility alleles reside in protein non-encoding genes, such as miRNAs, or miRNA responsive elements at 3'UTR of the target genes, which are traditionally overlooked in genetic screening. We propose a study by utilizing valuable resource from Cooperative Familial Registry for Breast Cancer Studies (CFRBCS) to screen genetic variants in selected miRNA genes and their responsive elements in target genes in hereditary breast cancer families, to assess the genetic susceptibility of these genetic variants in the development of hereditary and/or sporadic breast cancer, and to functionally characterize these genetic variants. We hypothesize that genetic variations in miRNA genes and their responsive elements in target genes alter various biological processes by influencing the biological functions of miRNAs, and thereby modify genetic predisposition to breast cancer. Because this research is nested within the CFRBCS, the objectives can be addressed in a timely and cost effective manner. This innovative and important area has not been investigated yet. The proposed research will help us to elucidate the biological significance of miRNA in breast cancer, explore the functional significance of these inherited variations, and establish a solid foundation for understanding the role of miRNA in breast cancer predisposition. From a clinical perspective, the long-term application of this information to risk assessment and thus to the prevention and early detection of breast cancer in families as well as population will be significant. PUBLIC HEALTH RELEVANCE: The proposed research will help us to elucidate the biological significance of miRNA in breast cancer, explore the functional significance of these inherited variations, and establish a solid foundation for understanding the role of miRNA in breast cancer predisposition. From a clinical perspective, the long-term application of this information to risk assessment and thus to the prevention and early detection of breast cancer in families as well as population will be significant.