Fanconi Defects in Pancreatic Cancer Oncogenesis

描述(由申请人提供)：FA(Fanconi贫血)基因的肿瘤相关突变为胰腺癌、卵巢癌和乳腺癌的化学预防、诊断和定制治疗提供了令人兴奋的机会。没有一种癌症比胰腺癌有更高比例的FA突变肿瘤。十年前，我们启动了第一个具有FA突变的胰腺癌家族的登记。我们在胰腺癌中发现了BRCA2、FANCC和FANCG的突变，这是一个具有高度临床重要性的高频低外显性人群风险的经典例子。FA基因突变表现出对某些药物和辐射的超敏，但当我们观察到不同的FA基因突变的敏感性水平时，临床上出现了重要的问题。我们最近启动了一项试验，使用一种对FA缺乏的癌症特别敏感的药物来治疗它们。据我们所知，这是美国第一次通过对生殖系DNA突变的分析来确定所指示药物的临床癌症试验。然而，这项试验及其设计的实验室部分从未通过特定的拨款获得资金。如果转化性研究的目标能够以适当的速度进行，试验设计可能会有相当大的改进。我们在家族登记和新试验中的经验提高了人们对有害突变正确分类的兴趣。我们遇到了许多遗传性错义胚系FA基因突变，这些突变具有不可分类的意义。它们在普通人群中非常常见，但对于大多数人来说，还不知道它们是正常的多态还是致癌的。我们最近探索了关键的技术突破，以更好地诊断和测试FA缺陷，细胞模型加速了这一研究。我们的具体目标是采用一种新的体细胞FA基因敲除和错义变异敲入的实验模型，生成和评估突变特异性和基因特异性表型，并通过改进的诊断和等位基因解释技术帮助患者管理。我们的长期目标是了解FA缺陷在肿瘤进展中的作用，准确地了解由不同基因突变产生的临床相关表型变化之间的差异，并识别临床上重要的患者亚群。公共卫生相关性：家族性胰腺癌最常见的已知原因是Fanconi基因(特别是BRCA2)的突变。我们在胰腺癌中发现了BRCA2和其他Fanconi基因的突变；这些突变具有很高的临床重要性，因为它们决定了患癌症的风险，现在有时还决定了患者可以登记的治疗方案。最近的进展将使我们现在能够有效地探索改善对这些患者的诊断和治疗分配。

DESCRIPTION (provided by applicant): Tumor-associated mutations in the FA (Fanconi anemia) genes offer exciting opportunities for chemoprevention, diagnosis, and tailored therapy for pancreatic, ovarian, and breast cancer. No cancer type has a higher proportion of FA-mutated tumors than pancreatic cancer. A decade ago, we initiated the first registry of pancreatic cancer families having FA mutations. We found mutations in BRCA2, FANCC, and FANCG in pancreatic cancers, a classic example of a high-frequency low-penetrance population risk with high clinical importance. The FA gene mutations convey a hypersensitivity to certain drugs and radiation, but clinically important questions arose when we observed the level of sensitivity to differ, depending on which FA gene was mutated. We recently initiated a trial to treat FA-deficient cancers using a drug to which they are specifically hypersensitivity. To our knowledge this is the first U.S. clinical cancer trial in which the indicated drug is specified by an analysis of germline DNA mutations. Yet, the laboratory components of the trial and its design have never attained funding by a specific grant. Considerable improvements in trial design are likely if translational research aims can be pursued at an appropriate pace. Interest in the correct classification of deleterious mutations is raised by our experience with familial registry and the new trial. We encounter many inherited missense germline FA gene mutations of unclassified significance. They are very common within the general population, but for most it is not known whether they are normal polymorphisms or cancer-causing. We recently explored key technical breakthroughs to better to permit diagnosis and testing of FA defects, and cellular models accelerating this research. Our specific aims employ a new experimental model of somatic cell FA genes knockouts and knock-in of missense variants in cancer cells, generating and evaluating mutation-specific and gene-specific phenotypes and aiding patient management through improved diagnostic and allele-interpretive techniques. Our long-term goal is to understand the roles of FA defects in tumor progression, to understand with precision the distinctions among clinically relevant phenotypic changes produced by different gene mutations, and to identify clinically important patient subgroups. PUBLIC HEALTH RELEVANCE: The most common known causes of familial pancreatic cancer are mutations in a Fanconi gene (specifically, BRCA2). We found mutations of BRCA2 and other Fanconi genes in pancreatic cancers; the mutations are of high clinical importance, for they determine the risk of developing cancer and now also sometimes determine the treatment protocol to which a patient can enroll. Recent advances will allow us now to efficiently explore improved diagnosis and therapeutic assignment of these patients.