Natural History of Familial Carcinoid Tumor

类癌瘤是罕见的，并导致要么没有或很少非特异性症状。 因此，患有类癌肿瘤的患者通常在其疾病过程的后期出现，此时由于转移性疾病已经进展到不可治愈的状态。 目前，既没有实用的人群筛查试验，也没有有效的治疗方法，因此5年生存率很低。 由于散发性类癌的罕见性，大规模的基因分析和敏感性和特异性诊断测试的开发尚未成功。 虽然与家族性类癌肿瘤，不归因于已知的遗传综合征是非常罕见的，他们提供了一个独特的机会，以促进责任基因突变的鉴定。 此外，罕见的家族性形式中的突变基因也可能是更常见的散发性类癌发生的起源的基础。 我们建议研究家族中至少有两个已知的受影响的成员与类癌肿瘤。我们的目标是早期诊断患者，因此有可能治愈隐匿性疾病。因此，具有高达50%的携带类癌肿瘤的终生风险的家庭成员将在初始和随后的两年随访中使用生化，内窥镜和成像方式进行强化诊断评估。 受影响的家庭成员的早期表型分配和生殖系和肿瘤DNA的收集，从多个激酶也应该促进遗传分析，导致疾病基因的身份。 在疾病的不同阶段评估受影响的家庭成员将有助于我们了解类癌肿瘤的自然史和各种诊断和监测测试的相对效用。希望这些知识也能应用于偶发性类癌或其他家族性癌症综合征的患者。 迄今为止，我们发现家族性和散发性类癌在临床上难以区分，除了在大多数家族性病例中观察到的多个同步原发性肿瘤。近34%的年龄大于50岁的无症状亲属被发现患有隐匿性肿瘤;这些肿瘤可以从这些个体的87%（23人中的20人）手术清除。在一个大家族中，连锁分析和全外显子组测序确定了基因肌醇多磷酸多激酶（IPMK）中的种系4-bp缺失，该基因截短了蛋白质。在所有11例小肠类癌患者和35个类癌状态未知的家族成员中的17个中检测到这种突变。与全长蛋白相比，突变体IPMK具有降低的激酶活性和核定位。这减少了p53的激活并增加了细胞存活。总之，我们发现小肠类癌是一种常染色体显性遗传疾病。家族型的特点是多个同时发生的原发性肿瘤，可能占以前认为散发病例的22%-35%。家族性类癌患者的亲属应进行筛查，以发现可治愈的早期疾病。IPMK单倍不足促进类癌肿瘤发生。

Carcinoid tumors are rare and cause either no or few nonspecific symptoms. Therefore, patients with carcinoid tumors most often present late in the course of their illness when there is already progression to an incurable state as a result of metastatic disease. At present there are neither practical population screening tests nor effective therapies and hence the 5 year survival rate is low. Due to the rareness of sporadic carcinoid tumors, large scale genetic analysis and development of sensitive and specific diagnostic tests have not been successful. While kindreds with familial carcinoid tumors that are not ascribable to known genetic syndromes are exceedingly rare, they provide a unique opportunity to facilitate the identification of the responsible gene mutation. In addition, the mutated gene in the rare familial form may also underlie the origin of the more common sporadic occurrence of carcinoid tumors. We propose to study families in which there are at least two known affected members with carcinoid tumors. We aim to diagnose patients with early and therefore potentially curable occult disease. Therefore, family members who have up to a 50% lifetime risk of harboring a carcinoid tumor will undergo an intensive diagnostic evaluation using biochemical, endoscopic and imaging modalities at initial and subsequent two year follow up encounters. Early phenotypic assignment of affected family members and collection of germline and tumoral DNA from multiple kindreds should also facilitate the genetic analysis leading to the identity of the disease gene. Evaluation of affected family members at varying stages of disease will contribute to our understanding of the natural history of carcinoid tumors and the relative utility of a variety of diagnostic and surveillance tests. Hopefully, such knowledge gained will also be applicable to patients with carcinoid tumors occurring sporadically or in the setting of other familial cancer syndromes. This far we have found that familial and sporadic carcinoids are clinically indistinguishable except for the multiple synchronous primary tumors observed in most familial cases. Nearly 34% of asymptomatic relatives older than age 50 were found to have occult tumors; these tumors could be cleared surgically from 87% of these individuals (20 of 23). In one large family, linkage analysis and whole-exome sequencing identified a germline 4-bp deletion in the gene inositol polyphosphate multikinase (IPMK), which truncates the protein. This mutation was detected in all 11 individuals with small intestinal carcinoids and in 17 of 35 family members whose carcinoid status was unknown. Mutant IPMK had reduced kinase activity and nuclear localization, compared with the full-length protein. This reduced activation of p53 and increased cell survival. In summary, we found that small intestinal carcinoids can occur as an inherited autosomal dominant disease. The familial form is characterized by multiple synchronous primary tumors, which might account for 22%-35% of cases previously considered sporadic. Relatives of patients with familial carcinoids should be screened to detect curable early stage disease. IPMK haploinsufficiency promotes carcinoid tumorigenesis.