Natural History of Familial Carcinoid Tumor

类癌是一种罕见的肿瘤，不会或很少引起非特异性症状。因此，类癌患者通常出现在他们病程的晚期，此时由于转移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，5年生存率低。由于散发性类癌的罕见，大规模的基因分析和开发敏感和特异的诊断试验一直没有成功。虽然不能归因于已知遗传综合征的家族性类癌家族非常罕见，但它们提供了一个独特的机会来促进对相关基因突变的识别。此外，罕见的家族性形式的突变基因也可能是更常见的零星发生类癌的原因。我们建议研究至少有两个已知的受影响成员患有类癌的家庭。我们的目标是诊断患有早期隐匿性疾病的患者，因此有可能治愈。因此，患有类癌肿瘤的终生风险高达50%的家庭成员在最初和随后两年的随访中将接受使用生化、内窥镜和成像手段的密集诊断评估。对受影响的家庭成员的早期表型分配以及从多个家系收集生殖系和肿瘤DNA也应有助于遗传分析导致疾病基因的识别。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历史以及各种诊断和监测试验的相对有效性。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，我们已经发现家族性和散发性类癌在临床上是无法区分的，除了在大多数家族性病例中观察到的多个同步原发肿瘤。年龄超过50岁的无症状亲属中，近34%被发现患有隐匿性肿瘤；87%的人(23人中的20人)可以通过手术清除这些肿瘤。在一个大的家系中，连锁分析和全外显子组测序发现，在肌醇多聚磷酸多激酶(IPMK)基因中有一个胚系4-bp的缺失，该基因截断了该蛋白。这一突变在所有11名患有小肠类癌的个体中都被检测到，在35名类癌状态未知的家族成员中有17名被检测到。与全长蛋白相比，突变的IPMK蛋白具有较低的激酶活性和核定位。这降低了P53的活性，提高了细胞存活率。综上所述，我们发现小肠类癌可以作为一种遗传性常染色体显性遗传病发生。家族性形式的特点是多个同步的原发肿瘤，这可能占以前被认为是散发性的病例的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的发生。我们继续招募和筛选新的家系，并应用连锁分析和WGS来确定其他易感基因，跟踪手术治疗的患者是否复发，并筛查隐匿性肿瘤的携带者。 患者来源的样本和小鼠的研究表明，+4储备ISC的小肠中的病理干细胞动力学和肠上皮干细胞动力学的改变可能有助于EC来源的小肠肿瘤的发展。 1.肠上皮细胞高表达IPMK。IEC中IPMK的缺失减少了AKT的磷酸化，减少了Paneth细胞的数量。IPMK的消融在基础和化疗损伤后均损害IEC的再生，提示IPMK在激活AKT和肠组织再生方面具有广泛的作用。IPMK的PI3K活性是PDK1介导的AKT激活和肠道内环境稳定所必需的。对Paneth细胞的IPMK依赖损伤可能导致干细胞动力学改变和+4 EC储备干细胞募集增加，最终可能增加EC细胞肿瘤形成的几率。 2.小肠神经内分泌肿瘤(SI-Nets)由深隐窝的肠嗜铬细胞(EC)细胞发展为异常隐窝，内含内分泌细胞团(ACECs)、微小肿瘤，最终发展为大体肿瘤。这一过程广泛发生在家族性SI-Net患者的整个小肠末端，这与生殖系疾病一致，但不是唯一的解释。最后，回肠活检隐窝的分析可以部分有助于早期诊断筛查过程，避免晚期不治之症的出现。 3.利用深度学习对CT扫描中的小肠类癌进行全自动检测，对于病变平面的检测，对少量的假阳性表现出了合理的敏感性。它还实现了一个很有前途的患者级检测的AUC。该方法可能对这种罕见且难以发现的疾病的患者具有临床应用价值。

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.