Evaluation of genomic copy number variation of genes that predispose patients with hereditary breast and colorrectal cancer syndrome screened for mutations in BRCA1, BRCA2, TP53 and CHEK2

Abstract

Approximately 5-10% of all cancers are inherited. Some tumors and inherited syndroms are related to germline mutations in specific genes. Hereditary breast cancer results from mutation in BRCA1 and BRCA2, and a deletion in CHEK2 is associated with a two fold increased risk to develop this desease. The Lynch Syndrom is associated with mutation in the repare genes and constitutes a risk factor for the development of extracolonic tumors. According to the Hereditary Colorectal Cancer Registry of the AC Camargo Hospital, breast cancer is the most frequent extracolonic tumor among women with hereditary colorectal cancer, sugesting a possible hereditary syndrome called Hereditary Breast and Colorectal Cancer Syndrome. On this study will be evaluated genomic alterations in women and their families with this syndrome and in patients with breast or colorectal tumors and their families, using CGH array. This study is composed of 24 patients with breast or colorectal cancer and their families, and the second is composed of 23 patients with breast and colorectal cancer and their families. Preliminary results showed 371 alterations on these patients. In the control group, composed of brazilian healthy women, it was found 569 alterations. After the exclusion of the common genomic alterations, it was identified 11 alterations envolving genes related to cancer. Among them, two cases had deletion at 3p12.3, two cases had amplification at 20q13.33 and other two cases had a big deletion at 19p. Aditional analysis will be done to confirm the deletion at 3p12.3 and at 19p. This study will evaluate the relatives of these patients using quantitative Real Time PCR in order to confirm the alterations found using the CGH array technique. Besides, will be done qRT-PCR to evaluate the expression of the genes and immunohistochemistry to analyse the protein express. The final goal of this project is to identify genes that predisposes to the development of breast and colorrectal cancer in patients that did not had mutations in genes with high penetrance already known, such as BRCA1, BRCA2, TP53 and CHEK2. Besides this, genes related to genes repare associated to Lynch Syndrome, such as MLH1 and MSH2 will be evaluated. This study is a subprojet of the Institute of Science and Technology in Oncogenomics (INCITO) already aproved by FAPESP/CNPq. (AU)