CANCER AND MORTALITY IN NEUROFIBROMATOSIS BY GENOTYPE

神经纤维瘤病1(NF1)的表现甚至在家庭内部也有很大的不同，进展可能是快速或静止的，早期或晚期，或不稳定。NF1患者中良性肿瘤和恶性肿瘤的发生率很高，但估计的比率差异很大。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NF1基因内的特定突变联系起来，我们将跟踪调查早在1924年就发现的全国范围内的神经纤维瘤病患者。这三个具体目标是：1)对全国NF1患者队列进行跟踪，最近一次更新为1983年6月，以将每个受影响的谱系扩大到所有后续后代，并建立一个持续的后续机制；2)针对队列中的所有NF1患者，确定特定死因死亡率和癌症发病率，并将其与丹麦癌症登记中心的预期数字进行比较；以及3)确定所有78个谱系中个体的NF1基因的特定突变，以探索可能的突变与死亡率和癌症发病率的特定关联。根据1980年代初我们研究的成功方案，将通过个人接触、临床检查、检索教堂记录、丹麦中央人口登记册、死亡证明、医院、病理和尸检报告以及丹麦癌症登记处进行后续行动。生存曲线将通过标准寿命表方法编制；人的风险年分析和相对风险计算将评估可能的癌症过剩。开展肿瘤家族聚集性可行性分析。所有受试者以及患有或不患有NF1的相关配偶都将采集血液中的DNA和RNA，老年受试者和患有危及生命的疾病的患者的淋巴细胞将被EB病毒转化。哥本哈根和匹兹堡将建立重复的标本储存库。将通过蛋白质截断分析、单链构象多态凝胶和自动荧光测序来寻找NF1基因突变。死亡率和癌症发病率的模式将通过NF1基因进行比较。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.