CANCER AND MORTALITY IN NEUROFIBROMATOSIS BY GENOTYPE

神经纤维瘤病1（NF 1）的表现甚至在家族内也有很大差异，进展可能是快速或静态的，早期或晚期，或不稳定的。 良性和恶性肿瘤在NF 1患者中发生过多，但估计的发病率差异很大。关于生存的预后信息很少。 为了解决这些问题，并开始将它们与NF 1基因内的特定突变联系起来，我们将对早在1924年就被确定的全国范围内的神经纤维瘤病患者进行随访。 这三个具体目标是：1）对全国NF 1患者队列进行随访，最后一次更新至1983年6月，将每个受影响的谱系扩展到所有后续后代，并建立持续的随访机制; 2）对于队列中的所有NF 1人群，根据具体死亡原因和癌症发病率确定死亡率，并将其与基于年龄、年龄、和来自丹麦癌症登记处的性别特异性癌症率;和3）确定所有78个谱系中个体的NF 1基因内的特异性突变，以探索与死亡率和癌症率的可能的突变特异性关联。根据我们在20世纪80年代早期的研究方案，将通过个人联系、临床检查、检索教会记录、丹麦中央人口登记处、死亡证明、医院、病理学和尸检报告以及丹麦癌症登记处进行随访。生存曲线将通过标准生命表方法绘制;人年风险分析和相对风险计算将评估可能的癌症过量。将进行癌症家族聚集性的可行性分析。 将采集所有受试者的血液用于DNA和RNA检测，并采集有或无NF 1的相关配偶的血液，并将对老年受试者和患有危及生命疾病的受试者进行EB病毒转化淋巴细胞。 将在哥本哈根和匹兹堡建立复制标本库。 NF 1基因突变将通过蛋白质截短试验、单链构象多态性凝胶和自动荧光测序来寻找。 将通过NF 1基因型比较死亡率和癌症发病率的模式。 将为后续研究建立纵向队列。

Manifestations of neurofibromatosis 1 (NF1) vary widely even within families, and progression may be rapid or static, early or late, or erratic. Benign and malignant neoplasms occur to excess in persons with NF1, but estimated rates vary greatly. Prognostic information on survival is sparse. To address these issues and to begin relating them to specific mutations within the NF1 gene, we will follow up a nationwide cohort of patients with neurofibromatosis who were identified as far back as 1924. The three specific aims are: 1) to follow-up the national cohort of NF1 patients, last updated to June 1983, to extend each affected lineage to all subsequent descendants and to establish an ongoing mechanism of follow-up; 2) for all NF1 persons in the cohort, to determine mortality by specific causes of death and cancer incidence and to compare it with expected numbers, based on age-, year-, and sex-specific cancer rates from the Danish Cancer Registry; and 3) to determine the specific mutation within the NF1 gene in individuals in all 78 lineages to explore possible mutation-specific associations with mortality and cancer rates. Following the successful protocol from our study in the early 1980s, follow-up will take place by personal contact, clinical examinations, retrieval of church records, the Danish Central Population Register, death certificates, and hospital, pathology, and postmortem reports, as well as at the Danish Cancer Registry. Survival curves will be prepared by standard life-table methods; a person-years-at-risk analysis and relative risk calculation will assess a possible excess of cancers. Feasibility analysis of familial aggregation of cancer will be conducted. Blood for DNA and RNA will be collected on all subjects, and relevant spouses with or without NF1, and lymphocytes will be transformed by Epstein-Barr virus on older subjects and those with life-threatening disease. Duplicate specimen repositories will be established in Copenhagen and Pittsburgh. NF1 gene mutations will be sought by protein truncation assay, single-stranded conformation polymorphism gels, and automatic fluorescent sequencing. Patterns of mortality and cancer incidence will be compared by NF1 genotype. A longitudinal cohort will be established for subsequent studies.