Modifiers of Intestinal Tumor Progression

描述（由申请人提供）：胃肠道癌症占美国所有癌症诊断的10%以上（www.cancer.org）。疾病的发病率和表型受遗传和环境的影响。虽然接受结肠镜检查的人数正在增加，但结直肠癌的发病率并没有下降。小肠癌的发病率不到结直肠癌的5%，但五年生存率非常低。家族性腺瘤性息肉病（FAP）是一种显性遗传疾病，使个体易患结直肠癌（Groden et al. 1991）。在家族性腺瘤性息肉病（APC）中，肿瘤抑制基因发生突变。患有FAP也是小肠癌的一个危险因素，因为FAP患者的肿瘤往往在十二指肠或十二指肠附近形成。小鼠小肠和结直肠癌模型对于理解肿瘤发生过程和发现干扰恶性肿瘤进展的机制是非常宝贵的。ApcMin/+小鼠在Apc基因中含有一个点突变，导致一个截断的蛋白（Moser et al. 1990; Su et al. 1992）。遗传背景在决定ApcMin/+小鼠的表型中起着重要作用（Siracusa et al. 2004综述），复杂性状分析已经确定了几个Min （Mom）位点的修饰因子，可以改变肠道肿瘤表型（Kwong和Dove 2008综述）。这个探索性R21的重点是使用ApcMin/+小鼠模型来识别影响肿瘤进展的基因。当我们有一个令人兴奋的发现时，我们产生了这项研究的想法，即近交系间杂交的后代寿命长，并且对肿瘤进展具有很高的抵抗力，即使它们携带ApcMin突变。在这些特殊小鼠中发展的少数肿瘤几乎完全是低级别腺瘤，不会发展到更高级的阶段。该模型挑战了肿瘤进展是年龄函数的现有范式。因此，我们有一个独特的模型系统，它在几个方面模仿人类疾病：1)这些杂交小鼠的基因组几乎在每个位点都是杂合的（就像人类的情况一样），2)这些小鼠的寿命与50岁及以上的人类相当（肠道癌症的危险因素），3)肿瘤的发展不会失去携带Apc+等位基因的整个染色体（类似于人类肿瘤的机制）。负责抵抗进展的因素似乎仅限于单个染色体；我们的研究旨在定义这种修饰基因和防止肿瘤进展的途径。将这项工作转化为人类癌症可能最终导致更好的预防和治疗肠癌的选择。

DESCRIPTION (provided by applicant): Cancers of the gastrointestinal tract comprise more than 10% of all cancers diagnosed in the U.S. (www.cancer.org). Disease incidence and phenotype are influenced by genetics and the environment. Although the number of people having colonoscopy screenings is increasing, the incidence of colorectal cancer has not decreased. Cancers of the small intestine total less than 5% of colorectal cancers, but the five year survival rate is very low. The adenomatous polyposis coli (APC) tumor suppressor gene is mutated in Familial Adenomatous Polyposis (FAP), a dominant inherited disorder that predisposes individuals to developing colorectal cancer (Groden et al. 1991). Having FAP is also a risk factor for small intestinal cancer, as tumors tend to form at or near the duodenum in FAP patients. Mouse models of small intestine and colorectal cancers are invaluable for understanding the process of tumorigenesis and discovering mechanisms that interfere with progression to malignancy. The ApcMin/+ mouse contains a point mutation in the Apc gene that results in a truncated protein (Moser et al. 1990; Su et al. 1992). Genetic background has a significant role in determining the phenotypes of ApcMin/+ mice (reviewed in Siracusa et al. 2004) and complex trait analyses have identified several Modifier of Min (Mom) loci that alter intestinal tumor phenotypes (reviewed in Kwong and Dove 2008). This exploratory R21 is focused on using the ApcMin/+ mouse model to identify genes that influence tumor progression. The idea for this study arose when we had an exciting finding, namely that hybrid progeny from an intercross between inbred strains had a long lifespan and were highly resistant to tumor progression, even though they carried the ApcMin mutation. The few tumors that develop in these exceptional mice remain almost exclusively low grade adenomas and do not progress to more advanced stages. This model challenges the existing paradigm that tumor progression is a function of age. We, therefore, have a unique model system that mimics human disease in several ways: 1) the genome of these hybrid mice is heterozygous at virtually every locus (as is the case in humans), 2) the lifespan of these mice is comparable to humans 50 years of age and beyond (a risk factor for intestinal cancers), and 3) tumors develop without losing the entire chromosome carrying the Apc+ allele (a mechanism similar to human tumors). The factor responsible for resistance to progression appears limited to a single chromosome; our research is designed to define this modifier gene and pathways that protect against tumor progression. Translation of this work to human cancers could ultimately lead to better prevention and treatment options for intestinal cancers. PUBLIC HEALTH RELEVANCE: Many steps and changes along the way are responsible for turning a benign tumor growth into a life-threatening cancer. This research is designed to uncover genes that function during the intermediate steps of this process. The goal is to identify genes that can prevent the progression of tumors into cancers in the small intestine and colon. With this knowledge, we can move towards developing novel preventive and therapeutic options for patients.