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Genomic changes in patients and their relatives with hereditary colorectal cancer syndrome

Grant number: 11/07742-7
Support Opportunities:Scholarships in Brazil - Doctorate
Effective date (Start): July 01, 2011
Effective date (End): June 30, 2015
Field of knowledge:Biological Sciences - Genetics - Human and Medical Genetics
Principal Investigator:Silvia Regina Rogatto
Grantee:Rolando André Rios Villacis
Host Institution: A C Camargo Cancer Center. Fundação Antonio Prudente (FAP). São Paulo , SP, Brazil
Associated research grant:08/57887-9 - National Institute of Oncogenomics, AP.TEM


Colorectal cancer (CRC) is one of the most common tumors worldwide and represents the fourth leading cause of cancer mortality. The development of colorectal tumors is the result of complex interaction between genetic and environmental factors. Approximately 20-30% of all CRC cases have a hereditary component, but only 5% are associated with inherited mutations in known genes with high penetrance. The Lynch syndrome is the most common hereditary syndrome of CRC and is caused by mutations in mismatch repair genes, mainly MLH1 and MSH2. Patients with this syndrome have an estimated risk of 50-80% of develop CRC throughout life, as well as 30% risk of developing a second tumor in 10 years. The Bethesda and Amsterdam criteria were developed to identify families with Lynch syndrome, and it is surprising that approximately 50% of families that meet the strict Amsterdam criteria not show germline mutations in mismatch repair genes, suggesting that other genetic factors poorly understood are associated with predisposition to CRC in these families. Recently, new methodologies such as array comparative genomic hybridization technique (aCGH) revealed extensive structural variations, termed CNVs (copy number variations), which cover around 13% of the genome and play a significant role in the phenotypic variation of human beings. Mutations in some rare constitutional CNVs may affect genes or major pathways associated with cancer, offering an explanation for families with high cancer risk. In CRC, the large scale analysis of germline CNVs in patients and their relatives can allow the identification of new genes involved in tumor predisposition. In this project Lynch syndrome patients (in particular cases, their relatives) without pathogenic mutations in mismatch repair genes, will be evaluated by aCGH aiming to identify CNVs associated with CRC predisposition. In addition, the study will to contibute to the understanding of the genetic basis to this syndrome that predisposes to higher risk of CRC in these families. (AU)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
VILLACIS, ROLANDO A. R.; MIRANDA, PRISCILA M.; GOMY, ISRAEL; SANTOS, ERIKA M. M.; CARRARO, DIRCE M.; ACHATZ, MARIA I.; ROSSI, BENEDITO M.; ROGATTO, SILVIA R.. Contribution of rare germline copy number variations and common susceptibility loci in Lynch syndrome patients negative for mutations in the mismatch repair genes. International Journal of Cancer, v. 138, n. 8, p. 1928-1935, . (11/07742-7, 08/57887-9)
VILLACIS, ROLANDO A. R.; ABREU, FRANCINE B.; MIRANDA, PRISCILA M.; DOMINGUES, MARIA A. C.; CARRARO, DIRCE M.; SANTOS, ERIKA M. M.; ANDRADE, VICTOR P.; ROSSI, BENEDITO M.; ACHATZ, MARIA I.; ROGATTO, SILVIA R.. ROBO1 deletion as a novel germline alteration in breast and colorectal cancer patients. TUMOR BIOLOGY, v. 37, n. 3, p. 3145-3153, . (11/07742-7, 10/15901-5, 08/57887-9)

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