Natural History of Familial Carcinoid Tumor

类癌是罕见的，没有或很少引起非特异性症状。因此，类癌肿瘤患者通常出现在病程晚期，此时由于转移性疾病已经进展到无法治愈的状态。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，大规模的遗传分析和开发敏感和特异性的诊断测试尚未成功。虽然不能归因于已知遗传综合征的家族性类癌非常罕见，但它们为促进鉴定相关基因突变提供了独特的机会。此外，罕见家族形式的突变基因也可能是更常见的散发性类癌肿瘤起源的基础。我们建议研究至少有两名已知成员患有类癌肿瘤的家庭。我们的目标是诊断患者早期，因此潜在的可治愈的隐匿性疾病。因此，对于一生中罹患类癌风险高达50%的家庭成员，在最初和随后的两年随访中，将使用生化、内窥镜和成像方式进行密集的诊断评估。受影响家庭成员的早期表型分配以及来自多个种类的种系和肿瘤DNA的收集也应有助于导致疾病基因身份的遗传分析。在疾病的不同阶段对受影响的家庭成员进行评估，将有助于我们了解类癌肿瘤的自然史，以及各种诊断和监测测试的相对效用。希望这些知识也适用于零星发生的类癌或其他家族性癌症综合征的患者。到目前为止，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多发同步原发肿瘤。50岁以上无症状亲属中有近34%发现有隐匿性肿瘤；87%的患者（23人中的20人）可以通过手术清除这些肿瘤。在一个大家族中，连锁分析和全外显子组测序发现，肌醇多磷酸多激酶（IPMK）基因存在4 bp的缺失，导致该蛋白截断。在所有11名小肠类癌患者和35名类癌状况未知的家族成员中的17名中检测到该突变。与全长蛋白相比，突变型IPMK的激酶活性和核定位降低。这减少了p53的激活，增加了细胞存活率。总之，我们发现小肠类癌可以作为一种遗传性常染色体显性疾病发生。家族型的特点是多发同步原发肿瘤，可能占以前认为的散发病例的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单倍体不足促进类癌发生。我们继续招募和筛选新的家庭，并应用连锁分析和WGS来确定其他易感基因，随访手术治疗的复发性疾病患者，筛查隐匿性肿瘤的携带者。

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. Thus 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. We continue to enroll and screen new families and apply linkage analysis and WGS to identify other susceptibility genes, follow surgically treated patients for recurrent disease and screen carriers for emergence of occult tumor. Patient derived samples and mouse studies suggest that pathological stem cell dynamics in the small intestine of the +4 reserve ISC and altered stem cell dynamics of the intestinal epithelium may contribute to the development of EC derived small intestinal tumors. 1. IPMK is highly expressed in intestinal epithelial cells (IEC). Deleting IPMK in IEC reduced AKT phosphorylation and diminished the number of Paneth cells. Ablation of IPMK impaired IEC regeneration both basally and after chemotherapy-induced damage, suggesting a broad role for IPMK in activating AKT and intestinal tissue regeneration. PI3k activity of IPMK is necessary for PDK1-mediated AKT activation and intestinal homeostasis. IPMK dependent injury to Paneth cells that contribute to the crypt niche supporting intestinal stem cells may lead to altered stem cell dynamics and increased recruitment of +4 EC reserve stem cells that may ultimately increase the odds for EC cell tumor formation. 2.Small intestinal neuroendocrine tumors (SI-NETs) develop from deep crypt enterochromaffin cells (EC) cells to become aberrant crypt containing endocrine cell clusters (ACECs), micro-tumors, and ultimately gross tumors. This process occurs widely throughout the distal small intestine in patients with familial SI-NETs consistent with but not exclusively explained by germline disease. Finally, analysis of crypts from ileal biopsies could contribute in part to earlier diagnostic screening processes avoiding late-stage presentation of incurable disease. 3.Fully-automated detection of small bowel carcinoid tumors in CT scans using deep learning showed reasonable sensitivity at small numbers of false positives for lesion-level detection. It also achieved a promising AUC for patient-level detection. The method may have clinical application in patients with this rare and difficult to detect disease.