Association of a novel point mutation in MSH2 gene with familial multiple primary cancers.
Association of a novel point mutation in MSH2 gene with familial multiple primary cancers.
复制标题
MSH2基因的新点突变与家族性多原发性癌症的关联
DOI：
10.1186/s13045-017-0523-y
复制
发表时间：
2017-10-03
影响因子：
28.5
通讯作者：
Wang L
中科院分区：
文献类型：
--
作者：
Hu H;Li H;Jiao F;Han T;Zhuo M;Cui J;Li Y;Wang L
多原发性癌症（MPC）是指两种或两种以上的癌症同时或异时发生在同一个体的相同或不同器官中，没有任何从属关系。林奇综合征是一种常染色体显性遗传疾病，增加了许多类型癌症的风险。患有两种以上癌症的Lynch综合征患者也可以被认为是MPC;这类患者提供了独特的资源来了解基因突变如何在不同组织中引起MPC。我们对林奇综合征患者的血细胞和两个肿瘤样本进行了全基因组测序，该患者被诊断患有五种原发性癌症。肿瘤的突变景观，包括体细胞点突变和拷贝数改变，进行了表征。我们还比较了林奇综合征与散发性癌症，并提出了一个模型来说明林奇综合征进展为MPC的突变过程。我们揭示了一种新的病理突变MSH 2基因（G504剪接），与林奇综合征。突变景观的系统比较显示，在先证者的多种癌症是进化独立的。综合分析显示，该患者的DNA错配修复（MMR）基因的截短突变明显富集。提出了一个突变进展模型，包括MMR基因的种系突变，MMR系统的双重打击，组织特异性驱动基因的突变，以及额外的乘客突变的快速积累，以说明如何在林奇综合征患者中发生MPC。我们的研究结果表明，生殖细胞和体细胞的改变是致癌的驱动力，这可能解决林奇综合征的致癌理论。本文的在线版本（10.1186/s13045-017-0523-y）包含补充材料，可供授权用户使用。
Multiple primary cancers (MPC) have been identified as two or more cancers without any subordinate relationship that occur either simultaneously or metachronously in the same or different organs of an individual. Lynch syndrome is an autosomal dominant genetic disorder that increases the risk of many types of cancers. Lynch syndrome patients who suffer more than two cancers can also be considered as MPC; patients of this kind provide unique resources to learn how genetic mutation causes MPC in different tissues. We performed a whole genome sequencing on blood cells and two tumor samples of a Lynch syndrome patient who was diagnosed with five primary cancers. The mutational landscape of the tumors, including somatic point mutations and copy number alternations, was characterized. We also compared Lynch syndrome with sporadic cancers and proposed a model to illustrate the mutational process by which Lynch syndrome progresses to MPC. We revealed a novel pathologic mutation on the MSH2 gene (G504 splicing) that associates with Lynch syndrome. Systematical comparison of the mutation landscape revealed that multiple cancers in the proband were evolutionarily independent. Integrative analysis showed that truncating mutations of DNA mismatch repair (MMR) genes were significantly enriched in the patient. A mutation progress model that included germline mutations of MMR genes, double hits of MMR system, mutations in tissue-specific driver genes, and rapid accumulation of additional passenger mutations was proposed to illustrate how MPC occurs in Lynch syndrome patients. Our findings demonstrate that both germline and somatic alterations are driving forces of carcinogenesis, which may resolve the carcinogenic theory of Lynch syndrome. The online version of this article (10.1186/s13045-017-0523-y) contains supplementary material, which is available to authorized users.
登录
查看更多内容
DOI：
10.1038/nrc1299
发表时间：
2004-03
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
影响因子：
12.3
作者：
Brannon AR;Vakiani E;Sylvester BE;Scott SN;McDermott G;Shah RH;Kania K;Viale A;Oschwald DM;Vacic V;Emde AK;Cercek A;Yaeger R;Kemeny NE;Saltz LB;Shia J;D'Angelica MI;Weiser MR;Solit DB;Berger MF
通讯作者：
Berger MF
影响因子：
30.8
作者：
HEMMINKI, A;PELTOMAKI, P;AALTONEN, LA
通讯作者：
AALTONEN, LA
长非编码 RNA MALAT-1 增强胰腺癌细胞中的干细胞样表型。
影响因子：
5.6
作者：
Jiao F;Hu H;Han T;Yuan C;Wang L;Jin Z;Guo Z;Wang L
通讯作者：
Wang L
影响因子：
8
作者：
Eshleman, JR;Casey, G;Markowitz, SD
通讯作者：
Markowitz, SD