Project 4: Secondary Cancers Among NF1 Cancer Survivors

项目摘要-项目4：后续恶性肿瘤(SMN)在组织学上是不同的 在成功治疗原发肿瘤后发展起来的肿瘤。之前的小病例系列表明 有原发肿瘤的NF1患者患SMN的风险可能会增加。然而，SMN在中国的风险 在非NF1癌症患者中观察到的NF1个体的数量超过了观察到的数量尚不清楚。此外，是否 NF1患者中特定的遗传毒性物质增加SMN的风险尚不清楚。尽管如此，辐射 对于NF1患者的非恶性肿瘤通常会避免-只有作为最后的手段才保留- 由于对辐射诱导的恶性转化的担忧；尽管对于零星的视神经 途径胶质瘤(OPG)/低级别胶质瘤(LGG)患者，放射治疗可改善肿瘤控制 与化疗相比。此外，在NF1恶性周围神经鞘瘤患者中 (MPNST)，辐射的使用不一致(主要基于地区偏好)，尽管人们知道 这种放射(与手术相比)提供了优越的神经保护/改善的功能结果和 是零星MPNST的标准疗法；在实践中这种不一致在很大程度上是因为缺乏定论 在这种情况下，关于SMN风险的证据。同样，烷化剂在NF1患者中的使用也很少， 因为可能增加与治疗相关的白血病的风险，从而限制了治疗选择 OPG患者。我们将利用儿童癌症幸存者研究(CCSS)和 肿瘤和NF1在费城儿童医院(CHOP)的登记，以确定两个大的队列：i) 患有NF1和原发肿瘤的儿童(NF1+队列：n=575)；II)患有肿瘤但没有NF1的儿童 (非NF1队列：n=24,000)。我们将测试NF1原发肿瘤患者的假设 与非NF1患者相比，SMN的风险增加，放射和烷化剂增加 NF1患者中发生SMN的风险。为了研究辐射诱导的SMN的发病机制，我们 在NF1+/-小鼠中开发了新的SMN小鼠模型，作为高度连贯的研究平台 电离辐射如何促进NF1突变背景下的肿瘤发生。大白菜的综合基因组分析 我们小鼠模型中的肿瘤表明，离散生物路径中的突变丰富，这可能 NF1患者的SMN也同样丰富。我们建议定义促进 NF1患者和丛状神经纤维瘤模型放射治疗个体的放射诱导肿瘤发生 (PNS)-NF1患者的一种潜在治疗选择，利用率较低。我们假设SMN NF1患者的发展需要保守信号通路的遗传改变。我们将对此进行测试 通过确定这些通路是否在来自NF1的SMN中发生类似的体细胞突变而提出假说 个体(如小鼠模型)，并测试它们对肿瘤生长的重要性。此外，我们将测试是否 在体内，分次聚焦照射可促进三七总皂苷转化为MPNSTs。

PROJECT SUMMARY – PROJECT 4: Subsequent malignant neoplasms (SMNs) are histologically distinct tumors that develop after successful treatment of a primary neoplasm. Previous small case series indicate that NF1 patients with a primary tumor may be at increased risk of SMNs. However, whether the risk of SMN in NF1 individuals is in excess of that observed in non-NF1 cancer patients is unclear. Furthermore, whether specific genotoxic agents increase the risk of SMNs in NF1 patients is unknown. Nonetheless, radiation is generally avoided for non-malignant tumors in NF1 patients – being reserved only as a last resort measure – due to concern about radiation-induced malignant transformation; this is despite the fact that for sporadic optic pathway glioma (OPG)/low-grade glioma (LGG) patients, radiation results in improved tumor control when compared to chemotherapy. Furthermore, in NF1 patients with malignant peripheral nerve sheath tumors (MPNST), radiation is used inconsistently (largely based upon regional preferences), despite the knowledge that radiation (when compared to surgery) provides superior nerve-sparing/ improved functional outcomes and is standard therapy in sporadic MPNSTs; this inconsistency in practice is largely because of lack of conclusive evidence regarding the risk of SMNs in this setting. Similarly, alkylators are used sparingly in NF1 patients, because of the potential for increased risk of therapy-related leukemia, thus limiting therapeutic options for OPG patients. We will leverage the resources offered by Childhood Cancer Survivor Study (CCSS) and the Tumor and NF1 Registries at Children's Hospital of Philadelphia (CHOP), to identify two large cohorts: i) Children with NF1 and primary neoplasia (NF1+cohort: n=575); ii) Children with neoplasia, but without NF1 (non-NF1cohort: n=24,000). We will test the hypotheses that NF1 patients with a primary neoplasm are at increased risk of SMNs as compared with non-NF1 patients, and that radiation and alkylating agents increase the risk of SMNs among NF1 patients. To investigate the pathogenesis of radiation-induced SMNs, we developed novel mouse models of SMNs in Nf1+/- mice that function as highly coherent platforms for studying how ionizing radiation promotes tumorigenesis in the Nf1 mutant background. Integrated genomic analysis of tumors from our mouse models suggests enrichment of mutations in discrete biological pathways, which may be similarly enriched in SMNs from individuals with NF1. We propose to define mechanisms that promote radiation-induced tumorigenesis in individuals with NF1 and model radiotherapy to plexiform neurofibromas (PNs) – a potential treatment option in NF1 individuals that is poorly utilized. We hypothesize that SMN development in NF1 patients requires genetic alterations in the conserved signaling pathways. We will test this hypothesis by determining whether these pathways are similarly somatically mutated in SMNs from NF1 individuals (as in mouse model) and test their importance to tumor growth. Further, we will test whether fractionated focal irradiation promotes transformation of PNs into MPNSTs in vivo.