PDF(Pubmed)
Abstract：
Familial non-medullary thyroid cancer (FNMTC) is a well-differentiated thyroid cancer (DTC) of follicular cell origin in two or more first-degree relatives. Patients typically demonstrate an autosomal dominant inheritance pattern with incomplete penetrance. While known genes and chromosomal loci account for some FNMTC, the molecular basis for most FNMTC remains elusive. To identify the variation(s) causing FNMTC in an extended consanguineous family consisting of 16 papillary thyroid carcinoma (PTC) cases, we performed whole exome sequence (WES) analysis of six family patients. We demonstrated an association of ARHGEF28, FBXW10, and SLC47A1 genes with FNMTC. The variations in these genes may affect the structures of their encoded proteins and, thus, their function. The most promising causative gene is ARHGEF28, which has high expression in the thyroid, and its protein-protein interactions (PPIs) suggest predisposition of PTC through ARHGEF28-SQSTM1-TP53 or ARHGEF28-PTCSC2-FOXE1-TP53 associations. Using DNA from a patient\'s thyroid malignant tissue, we analyzed the possible cooperation of somatic variations with these genes. We revealed two somatic heterozygote variations in XRCC1 and HRAS genes known to implicate thyroid cancer. Thus, the predisposition by the germline variations and a second hit by somatic variations could lead to the progression to PTC.
摘要：
家族性非甲状腺髓样癌（FNMTC）是两个或多个一级亲属的滤泡细胞起源的高分化甲状腺癌（DTC）。患者通常表现出常染色体显性遗传模式，外显率不完全。虽然已知基因和染色体基因座占一些FNMTC，大多数FNMTC的分子基础仍然难以捉摸。在由16例甲状腺乳头状癌（PTC）组成的扩展近亲家族中，确定引起FNMTC的变异，我们对6例家庭患者进行了全外显子组序列(WES)分析.我们证明了ARHGEF28，FBXW10和SLC47A1基因与FNMTC的关联。这些基因的变异可能会影响其编码蛋白质的结构,因此，他们的功能。最有希望的致病基因是ARHGEF28，它在甲状腺中具有高表达，及其蛋白质-蛋白质相互作用（PPI）表明PTC通过ARHGEF28-SQSTM1-TP53或ARHGEF28-PTCSC2-FOXE1-TP53关联而易感。利用患者甲状腺恶性组织的DNA,我们分析了体细胞变异与这些基因的可能合作。我们揭示了已知与甲状腺癌有关的XRCC1和HRAS基因中的两个体细胞杂合子变异。因此，种系变异的易感性和体细胞变异的第二次打击可能导致向PTC的进展。
