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Profile definition of sequences alterations of APC, B-catenin, WT1, WTX and PLCG2 genes in Wilms tumor.

Grant number: 08/08879-3
Support type:Scholarships in Brazil - Master
Effective date (Start): March 01, 2009
Effective date (End): July 31, 2010
Field of knowledge:Biological Sciences - Biochemistry
Principal Investigator:Dirce Maria Carraro
Grantee:Bruna Durães de Figueiredo Barros
Home Institution: Hospital A C Camargo. Fundação Antonio Prudente (FAP). São Paulo , SP, Brazil

Abstract

Normal kidney differentiation is a result of several successive molecular events that are coordinately regulated. Mutation or disruption of any crucial step of this morphogenetic progression may lead to kidney malformation and disease, including cancer. Wilms tumor (WT) originates from pluripotent embryonic kidney precursor cells and analyses of the molecular and cellular biology of this malignancy have provided important clues about the relationship of early renal development and WT biology. There are some molecular evidences that specific genes and downstream effector pathways are involved in both kidney development and WT, suggesting that both processes are related. WT1 encodes a zinc finger transcription factor expressed in a highly coordinated manner during kidney development, and mutations in this gene are related to approximately 10% of WT cases. Deregulation in level expression or mutations in other genes such as B-catenin, also contributes for the connection evidences between WT and nephrogenesis. Recently, despite no evidence of association of the WTX with kidney differentiation, mutations in WTX were found in approximately 30% of WT cases. However, latter studies suggested that this number is over-estimated, and that mutations in WTX, B-catenin and WT1 together are associated to 30% of the WT cases, remaining the majority of the cases without associated genes.Results from a project developed in this laboratory pointed APC and PLCG2 as possible candidates to be altered in WT. APC gene is associated with other cancers, such as colorectal carcinoma, where mutations appeared in more than 80% of the cases while PLCG2 was associated to a disease for the first time.Our group has been establishing libraries where patients are individually marked allowing the evaluation of several patients in one run of 454 Sequencer FLX System (Roche), becoming viable to perform this methodology in this project. Using the next generation technology of sequencing it is interesting the evaluation of genomic regions in a reasonable time and cost.Therefore the goal of this study is to verify genomic sequence alterations, including introns and exons, of the 5 genes APC, B-catenina, WT1, WTX e PLCG2 in WT samples.The five genes (WT1, B-catenin, WTX, APC and PLCG2) of this study have 262 Kb, including the genomic region. Therefore, the use of new generation sequencers and librarys patients-specifics become attractive to use these methodologys for sequencing the four genes in a great number of WT patients.