Damineni Surekha, Rao Vadlamudi Raghavendra, Kumar Satish, Ravuri Rajasekar Reddy, Kagitha Sailaja, Dunna Nageswara Rao, Digumarthi Raghunadharao, Satti Vishnupriya
Department of Genetics, Osmania University, Hyderabad, 500007, India,
Tumour Biol. 2014 Sep;35(9):9219-27. doi: 10.1007/s13277-014-2176-6. Epub 2014 Jun 15.
Germline alterations of the TP53 gene encoding the p53 protein have been observed in the majority of families with the Li-Fraumeni syndrome, a rare dominantly inherited disorder with breast cancer. Genomic DNA samples of 182 breast cancer cases and 186 controls were sequenced for TP53 mutations in the exon 5-9 and intervening introns 5, 7-9. Direct sequencing was done using Applied Biosystem 3730 DNA analyzer. In the present study, we observed nine mutations in the sequenced region, of which five were novel. Hardy-Weinberg equilibrium (HWE) was done for all the mutations; C14181T, T14201G, and G13203A have shown deviation from HWE. High linkage disequilibrium (LD) was observed between C14181T (rs129547788) and T14201G (rs12951053) (r (2) = 0.98.3; D' = 1.00), whereas other observed mutations do not show strong LD with any of the other mutations. None of the intronic mutations has shown significant association with the breast cancer, two exonic mutations G13203A (rs28934578) and A14572G are significantly (P = 0.04, P = 0.007) associated with breast cancer. Germline mutations observed in DNA-binding domain of the gene showed significant association with breast cancer. This study reports five novel germline mutations in the TP53 gene out of which one mutation may confer significant risk to the breast cancer. Mutations in DNA-binding domain of TP53 gene may play role in the early onset and prognosis of breast cancer. The population-based studies of germline mutations in DNA-binding domain of TP53 gene helps in identification of individuals and families who are at risk of developing cancers.
在大多数患有李-佛美尼综合征（一种罕见的遗传性乳腺癌显性疾病）的家族中，已观察到编码p53蛋白的TP53基因的种系改变。对182例乳腺癌病例和186例对照的基因组DNA样本进行了第5至9外显子以及内含子5、7至9中TP53突变的测序。使用Applied Biosystem 3730 DNA分析仪进行直接测序。在本研究中，我们在测序区域观察到9个突变，其中5个是新突变。对所有突变进行了哈迪-温伯格平衡（HWE）分析；C14181T、T14201G和G13203A显示偏离HWE。在C14181T（rs129547788）和T14201G（rs12951053）之间观察到高连锁不平衡（LD）（r² = 0.983；D' = 1.00），而其他观察到的突变与任何其他突变均未显示出强LD。内含子突变均未显示与乳腺癌有显著关联，两个外显子突变G13203A（rs28934578）和A14572G与乳腺癌显著相关（P = 0.04，P = 0.007）。在该基因的DNA结合域中观察到的种系突变与乳腺癌显著相关。本研究报告了TP53基因中的5个新的种系突变，其中一个突变可能赋予乳腺癌显著风险。TP53基因DNA结合域中的突变可能在乳腺癌的早期发病和预后中起作用。基于人群的TP53基因DNA结合域种系突变研究有助于识别有患癌风险的个体和家族。
