Multiple Hereditary Infundibulocystic Basal Cell Carcinoma Syndrome Associated With a Germline SUFU Mutation
Multiple Hereditary Infundibulocystic Basal Cell Carcinoma Syndrome Associated With a Germline SUFU Mutation
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DOI：
10.1001/jamadermatol.2015.4233
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发表时间：
2016-03-01
期刊：
影响因子：
10.9
通讯作者：
Cho, Raymond J.
中科院分区：
文献类型：
--
作者：
Schulman, Joshua M.;Oh, Dennis H.;Cho, Raymond J.
多发性遗传性漏斗囊性基底细胞癌综合征（MHIBCC）是一种罕见的遗传性皮肤病，其中许多惰性，分化良好的基底细胞癌主要发生在面部和生殖器，没有基底细胞痣综合征的其他特征。原因不明。本研究的目的是确定一个遗传基础的综合征和相关的肿瘤development.Observations全外显子组测序的5个肿瘤和正常的颊粘膜样品从患者MHIBCC的机制进行。在所有肿瘤和正常组织样本中均发现融合基因抑制子（SUFU）的1个拷贝中存在一个保守的剪接位点突变。在所有的肿瘤样本中，没有一个是存在于normal samples.Conclusions和RELEVANCE一个生殖系SUFU突变的反SUFU等位基因的其他不同的缺失被确定在MHIBCC患者，和额外的收购SUFU突变的基础上的漏斗囊性基底细胞癌的发展。SUFU基因在音刺猬通路中的下游位置可以解释为什么它的丢失与相对分化良好的肿瘤相关，并表明MHIBCC不会对靶向该通路上游组分的治疗策略（如smoothened抑制剂）产生反应。
IMPORTANCE Multiple hereditary infundibulocystic basal cell carcinoma syndrome (MHIBCC) is a rare genodermatosis in which numerous indolent, well-differentiated basal cell carcinomas develop primarily on the face and genitals, without other features characteristic of basal cell nevus syndrome. The cause is unknown. The purpose of the study was to identify a genetic basis for the syndrome and a mechanism by which the associated tumors develop.OBSERVATIONS Whole-exome sequencing of 5 tumors and a normal buccal mucosal sample from a patient with MHIBCC was performed. A conserved splice-site mutation in 1 copy of the suppressor of fused gene (SUFU) was identified in all tumor and normal tissue samples. Additional distinct deletions of the trans SUFU allele were identified in all tumor samples, none of which were present in the normal sample.CONCLUSIONS AND RELEVANCE A germline SUFU mutation was present in a patient with MHIBCC, and additional acquired SUFU mutations underlie the development of infundibulocystic basal cell carcinomas. The downstream location of the SUFU gene within the sonic hedgehog pathway may explain why its loss is associated with relatively well-differentiated tumors and suggests that MHIBCC will not respond to therapeutic strategies, such as smoothened inhibitors, that target upstream components of this pathway.