Natural History of Familial Carcinoid Tumor

家族性类癌的自然史

• 批准号: 10919467
• 负责人: Stephen Wank
• 金额: $ 84.13万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10919467
• 关键词: Ablation; Affect; Age of Onset; Biochemical; Biopsy; Carcinoid Tumor; Cell Survival; Cells; Clinical; Collection; Colonoscopy; DNA; Detection; Development; Diagnosis; Diagnostic; Diagnostic tests; Disease; Distal; Endocrine; Endoscopy; Enrollment; Enterochromaffin Cells; Epithelial Cells; Esophagogastroduodenoscopy; Evaluation; Excision; Family; Family Study; Family member; Gastrointestinal Carcinoid Tumor; Gene Mutation; Genes; Genetic; Genotype; Hereditary Malignant Neoplasm; Histology; Image; Impairment; Incidence; Individual; Inherited; Injury; Intention; Intestinal Neuroendocrine Neoplasm; Intestines; Knowledge; Length; Lesion; Location; Magnetic Resonance Imaging; Mediating; Metabolic; Methods; Modality; Morbidity - disease rate; Mucous Membrane; Mus; Mutate; Mutation; Natural History; Nuclear; Operative Surgical Procedures; PDPK1 gene; PIK3CG gene; Paneth Cells; Pathologic; Patients; Phenotype; Phosphorylation; Phosphotransferases; Population; Primary Neoplasm; Process; Prognostic Factor; Protein Truncation; Proteins; Proto-Oncogene Proteins c-akt; Recurrent disease; Reserve Stem Cell; Role; Sampling; Scanning; Sensitivity and Specificity; Small Intestinal Carcinoid Tumor; Small Intestinal Neoplasm; Small Intestines; Specimen; Survival Rate; Susceptibility Gene; Symptoms; Syndrome; TP53 gene; Testing; X-Ray Computed Tomography; autosome; capsule; carrier testing; cell regeneration; chemotherapy; clinical application; deep learning; diagnostic screening; effective therapy; exome sequencing; follow-up; genetic analysis; genetic linkage analysis; histological specimens; human old age (65+); imaging modality; improved; indexing; inositol polyphosphate multikinase; intestinal epithelium; intestinal homeostasis; kindred; lifetime risk; member; mortality; mutant; neoplastic cell; peripheral blood; proband; rare cancer; recruit; screening; somatostatin analog; stem cells; tissue regeneration; tumor; tumor DNA; tumorigenesis

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.

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。 到目前为止，我们发现家族性和散发性类癌在临床上是难以区分的，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。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，随访手术治疗的患者复发疾病，并筛选携带者出现隐匿性肿瘤。 患者来源的样品和小鼠研究表明，+4储备ISC的小肠中的病理性干细胞动力学和肠上皮的改变的干细胞动力学可能有助于EC来源的小肠肿瘤的发展。 1. IPMK在肠上皮细胞（IEC）中高度表达。在IEC中删除IPMK减少了AKT磷酸化并减少了潘氏细胞的数量。IPMK的消融损害了IEC再生的基础和化疗诱导的损伤后，这表明IPMK在激活AKT和肠组织再生中的广泛作用。IPMK的PI 3 k活性对于PDK 1介导的AKT活化和肠道内稳态是必需的。对有助于支持肠干细胞的隐窝小生境的潘氏细胞的IPMK依赖性损伤可能导致干细胞动力学改变和+4 EC储备干细胞的募集增加，这可能最终增加EC细胞肿瘤形成的几率。 2.小肠神经内分泌肿瘤（SI-NET）由深隐窝肠嗜铬细胞（EC）细胞发展为异常隐窝内分泌细胞簇（ACEC）、微小肿瘤和最终的肉眼肿瘤。这一过程广泛发生在患有家族性SI-NET的患者的整个远端小肠中，这与生殖系疾病一致，但并非完全由生殖系疾病解释。最后，回肠活检的隐窝分析可能有助于早期诊断筛查过程，避免晚期不治之症的出现。 3.使用深度学习在CT扫描中对小肠类癌肿瘤的全自动检测在病变水平检测的少量假阳性下显示出合理的灵敏度。它还实现了用于患者水平检测的有希望的AUC。该方法可能在这种罕见且难以检测的疾病患者中具有临床应用。

项目成果

Role of an active reserve stem cell subset of enteroendocrine cells in intestinal stem cell dynamics and the genesis of small intestinal neuroendocrine tumors.

肠内分泌细胞的活性储备干细胞亚群在肠干细胞动力学和小肠神经内分泌肿瘤发生中的作用。

• DOI: 10.1152/ajpgi.00278.2020
• 发表时间: 2020
• 期刊: American journal of physiology. Gastrointestinal and liver physiology
• 作者: Sei,Yoshitatsu;Feng,Jianying;Zhao,Xilin;Wank,StephenA
• 通讯作者: Wank,StephenA

Improving Small Lesion Segmentation in CT Scans using Intensity Distribution Supervision: Application to Small Bowel Carcinoid Tumor.

使用强度分布监督改进 CT 扫描中的小病灶分割：在小肠类癌中的应用。

• DOI: 10.1117/12.2651979
• 发表时间: 2023
• 期刊: Proceedings of SPIE--the International Society for Optical Engineering
• 作者: Shin,SeungYeon;Shen,ThomasC;Wank,StephenA;Summers,RonaldM
• 通讯作者: Summers,RonaldM

Loss of PI3k activity of inositol polyphosphate multikinase impairs PDK1-mediated AKT activation, cell migration, and intestinal homeostasis.

• DOI: 10.1016/j.isci.2023.106623
• 发表时间: 2023-05-19
• 期刊: ISCIENCE
• 影响因子: 5.8
• 作者: Reilly, Luke;Semenza, Evan R.;Koshkaryan, George;Mishra, Subrata;Chatterjee, Sujan;Abramson, Efrat;Mishra, Pamela;Sei, Yoshitasu;Wank, Stephen A.;Donowitz, Mark;Snyder, Solomon H.;Guha, Prasun
• 通讯作者: Guha, Prasun

Diagnostic value of whole-mount crypt analysis of ileal biopsy specimens for the patients with familial small intestinal neuroendocrine tumors.

• DOI: 10.1177/17588359231156871
• 发表时间: 2023
• 期刊: THERAPEUTIC ADVANCES IN MEDICAL ONCOLOGY
• 影响因子: 4.9
• 作者: Sei, Yoshitatsu;Forbes, Joanne;Da, Ben;Chitsaz, Ehsan;Feng, Jianying;Zhao, Xilin;Hughes, Marybeth S.;Wank, Stephen A.
• 通讯作者: Wank, Stephen A.