Gastroenterology：NIH科学家探索小肠癌发病的家族史遗传关联

  遗传在小肠癌的发病中占35%，校肠癌是一种罕见的消化道癌症，近日发表在国际杂志Gastroenterology上的一篇研究论文中，来自NIH的研究人员检测了该疾病的家族病史，长期以来由于该疾病被认为是随即发生而并非遗传造成，而具有家族史的个体并没有进行一般的筛查。
  研究者Stephen Wank指出，小肠癌肿瘤通常生长非常缓慢而且并没有任何症状，一旦个体有症状表现并且寻求医疗帮助时该疾病就很难逆转了，而本文研究中我们建议携带小肠癌家族史的个体应当进行定期筛查，而且我们也希望该研究可以帮助成千上万存在风险的个体采取措施来有效预防该病发展成为不可逆转的癌症。
  遗传连锁分析法(Genetic linkage analysis)就可以帮助揭示大型家族中受影响个体机体的靶向DNA区域，而利用基因组测序的技术则可以帮助发现从上一代遗传给下一代的基因缺失，这就表明所发现的基因或许是小肠癌发病的遗传性风险因子；而研究整个家族则可提供一种独特的视角来帮助深入分析增加小肠癌发病的遗传风险因子。
  这项针对小肠癌的研究可以为科学家及卫生工作者提供一种强大的平台，来帮助开发设计小肠癌的积极主动的治疗方法；目前大约有3万美国人患有小肠癌，和其它很多癌症一样，早期疗法的开展可以极大地提高患者的生存率及生活质量，而具有小肠癌家族史的个体同时也非常有兴趣加入NIH的遗传性研究中。研究者希望通过他们后期不懈地努力可以解释小肠癌发病的分子机制以及为何会引发家族史的遗传现象，从而为后期开发新型干预及治疗方法提供一定的希望。（转化医学网360zhyx.com）
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转化医学网推荐的原文摘要：

A Hereditary Form of Small Intestinal Carcinoid Associated with a Germline Mutation in Inositol Polyphosphate Multikinase
Gastroenterology     doi:10.1053/j.gastro.2015.04.008
Yoshitatsu Sei12, Xilin Zhao12, Joanne Forbes12, Silke Szymczak, Qing Li, Apurva Trivedi, Mark Voellinger, Grishma Joy, Jianying Feng, Millie Whatley, MaryPat Sussex Jones, Ursula L. Harper, Stephen J. Marx, Aradhana M. Venkatesan, Settara C. Chandrasekharappa, Mark Raffeld, Martha M. Quezado, Adeline Louie, Clara C. Chen, Ramona M. Lim, Richa Agarwala, Alejandro A. Schäffer, Marybeth S. Hughes, Joan E. Bailey-Wilson, Stephen A. Wank
Background & Aims
Small intestinal carcinoids are rare and difficult to diagnose and patients often present with advanced, incurable disease. Although the disease occurs sporadically, there have been reports of family clusters. Hereditary small intestinal carcinoid has not been recognized and genetic factors have not been identified. We performed a genetic analysis of families with small intestinal carcinoids to establish a hereditary basis and find genes that might cause this cancer.
Methods
We performed a prospective study of 33 families with at least 2 cases of small intestinal carcinoids. Affected members were characterized clinically and asymptomatic relatives were screened and underwent exploratory laparotomy for suspected tumors. Disease-associated mutations were sought using linkage analysis, whole-exome sequencing, and copy number analyses of germline and tumor DNA collected from members of a single large family. We assessed expression of mutant protein, protein activity, and regulation of apoptosis and senescence in lymphoblasts derived from the cases.
Results
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 50 y were found to have occult tumors; the tumors were cleared surgically from 91% of these individuals (21/23). Linkage analysis and whole-exome sequencing identified a germline 4 bp deletion in the gene inositol polyphosphate multikinase (IPMK) that truncates the protein. This mutation was detected in all 11 individuals with small intestinal carcinoids and 17/35 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.
Conclusions
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 haplo-insufficiency promotes carcinoid tumorigenesis.