Fanconi Defects in Pancreatic Cancer Oncogenesis

描述（由申请人提供）：FA（范可尼贫血）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突变，这是高频低外显率人群风险的典型例子，具有很高的临床重要性。FA基因突变传达了对某些药物和辐射的超敏反应，但当我们观察到敏感性水平不同时，临床上重要的问题出现了，这取决于哪种FA基因突变。我们最近启动了一项试验，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，这是美国临床癌症试验中首次通过对生殖细胞DNA突变的分析来指定药物。然而，试验的实验室组成部分及其设计从未获得特定赠款的资助。如果能够以适当的速度追求转化研究目标，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方面的经验提高了对有害突变的正确分类的兴趣。我们遇到了许多未分类意义的遗传错义种系FA基因突变。它们在普通人群中很常见，但对于大多数人来说，它们是正常的多态性还是致癌的尚不清楚。我们最近探索了关键的技术突破，以更好地允许FA缺陷的诊断和测试，以及加速这一研究的细胞模型。我们的具体目标是采用一种新的实验模型，在癌细胞中敲除和敲入错义变异的体细胞FA基因，产生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，准确了解不同基因突变产生的临床相关表型变化之间的差异，并确定临床重要的患者亚组。公共卫生相关性：家族性胰腺癌最常见的已知原因是范可尼基因突变（特别是BRCA2）。我们在胰腺癌中发现了BRCA2和其他范可尼基因的突变；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，现在有时也决定了患者可以参加的治疗方案。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.