MIcroRNA: A Novel Genetic Modifier for Breast Cancer Predisposition

描述（由申请人提供）：在过去的十年中，微rna （miRNAs）的发现，以及它们通过调节癌基因和肿瘤抑制基因（TSGs）的转录在致癌和癌症预后中日益重要的认识，导致了一个关于这些小分子的令人兴奋的发现时代。虽然我们知道miRNA在包括乳腺癌在内的许多癌症组织中普遍存在错误表达，但关于miRNA基因的遗传变异性及其靶基因中的应答元件如何易患癌症，我们知之甚少。由于miRNA功能的特殊方式——通过靶向一些功能重要的蛋白质编码基因，如癌基因和TSGs——miRNA基因的遗传变异及其靶基因中的应答元件在癌症易感性中可能很重要。由于家族史一直被认为是乳腺癌的主要危险因素，mirna的遗传变异性可能与乳腺癌极其相关。目前已知的高危乳腺癌基因（如BRCA1/2等）的种系突变在家族性乳腺癌中很常见，但它们最多只能解释20-25%的总体过量家族性风险，这表明存在其他未识别的易感基因，这些基因赋予了乳腺癌的易感性。人们为发现乳腺易感基因做出了相当大的努力，但迄今为止发现的很少。这种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miRNA，或靶基因3'UTR处的miRNA应答元件，这在传统的遗传筛查中被忽视。我们拟利用CFRBCS （Cooperative Familial Registry for Breast Cancer Studies）的宝贵资源，筛选遗传性乳腺癌家族中选定的miRNA基因及其靶基因应答元件的遗传变异，以评估这些遗传变异在遗传性和/或散发性乳腺癌发展中的遗传易感性，并对这些遗传变异进行功能表征。我们假设miRNA基因及其靶基因中的应答元件的遗传变异通过影响miRNA的生物学功能改变了各种生物学过程，从而改变了乳腺癌的遗传易感性。由于本研究嵌套在CFRBCS中，因此可以以及时且具有成本效益的方式解决目标。这个创新而重要的领域还没有被研究过。本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，为了解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：本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，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.