Title Exome Sequencing Identifies TSC22D2 as the Candidate Susceptibility Genes of Multi-Cancer Pedigree

[Previous findings]Cancer family is is a kind of complex diseases with the characteristics which is diverse tumor genesis aggregated in pedigree. The molecular genetics mechanism has not yet clear. It may involve multiple tumor susceptibility genes which mediated the occurrence and development of tumor molecular events. At present the report of cancer pedigree is very little, the main reason is lack of pedigree samples and the lack of effective means to detect and studies the key role of molecular in cancer family. Dr. Lan Xiao in our lab had found a rare large multi-cancer pedigree, including six generations and 15 patients, in Changsha, Hunan. There are many kinds of cancers or tumors, such as colon carcinoma, gastric cancer, breast carcinoma, endometrial cancer, breast fibroids, et al.Some patients were suffered from several kinds of tumors in his lifetime. After the collection for this pedigree 24 core members of the peripheral blood sample, Dr. Lan Xiao had chosen high throughput SNP array to do genome-wide scan and linkage analysis in 24 core members of this pedigree. In her study she confirmed chromosome 3q24-26 was closely linkage with disease loci, piont out an important direction for screen virulence genes and mutation site.[The purpose of this paper]It is too much subjective to test and verify mutation of susceptibility genes using functional annotion and traditional sequencing on predisposition region 3q24-26. We tried several times but failed to find anything. Now we carry out exome sequencing to find mutation sites which linkage with disease. First, we utilize the sequence chip to capture exome with the representative member of the cancer family. Then we select potential mutation sites through high throughput sequencing, sequence comparison and advance data analysis combined with predisposition region chromosome 3q24-26. Moreover, sequence the mutation sites in the cancer family to validate whether they are segregated with the disease haplotype. At last, we will carry out the large sample screen in local population.[The results of this paper]1、Exome Sequencing found three potential mutation sites on 3q24-26Exome Sequencing is a sort of new-style genome analysis technology, which applied to DNA in exon of the whole genome. We utilized Nimblegen HD2 array that can covers 18,000 human coding exons and 551 coding miRNA to test and verify exome sequence of three representative family members, which include single cancer patient, a multi cancers patient and non-carrier of disease haplotype. We initially selected 386 mutation sites through Illumina GA high-throughput sequencing, data comparing to reference gene sequences, as well as adopting NCBI db SNP databases, Hapmap8 database 1,000 genome project, YanHuang project to screen. We narrow down the region chromosome 3q24-26 that is linkaged with pedigree disease and pick up three potential mutation sites 2、Screening mutation among the multi-cancer pedigree and normal population suggested TSC22D2 gene (c.-91T> C) could be a morbigenous gene and mutationValidating the results of exons sequencing by using direct sequencing among the multi-cancer pedigree, we find that TSC22D2 gene (c.-91T>C) in 3q24-26 region is segregated with disease phonotype. Further research should be taken to screen the mutation in local population test. We collected peripheral blood gDNA of 500 normal people to test the mutation and no mutation to be found. Genetically, the morbigenous gene and mutation of the cancer pedigree was confirmed initially.

Category Oncology
Keywords exome, exon, multi-cancer pedigree, mutation, mutation screen, sequencing,
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Pages 181
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