Genomic screening in Li-Fraumeni and Li-Fraumeni like families with unknown causes

Abstract

Germline mutations in TP53 are associated with Li-Fraumeni syndrome (LFS), a complex and autosomal dominant syndrome, characterized by familial association of sarcomas. Breast cancer, brain tumors and adrenocortical carcinomas, are often diagnosed in these patients before they reach the age of 45. Just over 50% of individuals diagnosed with LFS have mutations in TP53, where as, the other 50% have no known cause. It was recently shown that TP53 mutations carriers have a statistically significant increase in the variation of copy numbers of DNA segments (copy number variation or CNVs) compared with the wild type individuals from LFS families or control groups. The investigation of CNVs in familial cancer patients for the discovery of new genes involved in the etiology of these diseases is almost unexplored. However, the contribution of CNVs to cancer is not yet fully understood. Supposedly, the most frequent predisposition mechanism is the haplo-insufficient of tumor suppressor genes. Deletion is the most obvious CNV to be found, although duplications with changes in the gene structures can also lead to loss of gene function. In this study, we evaluated the DNA segments copy numbers variation in DNA extracted from peripheral blood lymphocytes of individuals, both affected and unaffected, from families with LFS in which no mutations were detected in the TP53 gene. This study is part of the project "Hereditary Cancer and Familial Aggregation: Clinical and Molecular Profiles of Brazilian patients and their relatives at high risk of cancer" recently approved in the announcement of the National Institutes of Science and Technology CNPq / FAPESP (National Institute of Science and Technology in Oncogenetics - INCiTO). The CNVs profile will be evaluated through the technique of array-CGH using microarrays of oligonucleotides of 60 mers of Agilent's 180K. We expect to identify new genes responsible for predisposition to cancer in these families. It is likely that some of these genes also have role in sporadic cancers. These genes can be used as predisposition markers to identify the fraction of the population with increased risk of developing cancer. Furthermore, the genotype / phenotype correlations derived from this particular study will improvethe strategies for screening and management of patients and their families, since reports of the molecular profile of the main syndromes of inherited predisposition to cancer in Brazil are scarce. (AU)