Molecular characterization of at high risk families for hereditary breast cancer, negatives for BRCA1/BRCA2: looking for the BRCAx

• Grant number: 13/24633-2
• Support Opportunities: Regular Research Grants
• Start date: November 01, 2014
• End date: April 30, 2017
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Edenir Inêz Palmero
• Grantee: Edenir Inêz Palmero
• Host Institution: Hospital do Câncer de Barretos. Fundação Pio XII (FP). Barretos , SP, Brazil
• Associated researchers: André Lopes Carvalho ; Cristovam Scapulatempo Neto ; Daniel Onofre Vidal ; Dirce Maria Carraro ; Elisa Napolitano e Ferreira ; Lucas Tadeu Bidinotto ; Matias Eliseo Melendez ; Patricia Ashton Prolla ; Raul Torrieri ; Rui Manuel Vieira Reis

Abstract

Breast cancer (BC) is considered a public health problem, being 5% to 10% hereditary. The identification of individuals at risk for hereditary cancer is important because: 1) affected individuals have a much higher cumulative cancer risk, 2) relatives of an affected individual may be at-risk for hereditary cancer, and 3) the existence of intensive screening and preventive intervention measures that can significantly lowers the risk of cancer in mutation carriers. However, although there are about 30 genetic loci associated with an increased predisposition/susceptibility to hereditary breast cancer (HBC), for a large proportion of cases (about 70%), the genetic cause remains unknown. Thus, given the high risk for cancer develpment of these individuals/families and the knowledge required about which mutation is causing the phenotype in order that preventive strategies can be devised, the main objective of this proposal is to perform a comprehensive molecular characterization of a group of 40 unrelated women (40 families) with high risk for HBC and negative for germline deleterious BRCA1/BRCA2 mutations. Aiming to homogenize the sample group, it was subdivided into: (a) 20 women with a personal history of BC and the presence of at least four BC cases before the age of 55 years old, at least two cancer affected generations, no cases of male BC and ovarian cancer, and (b) 20 women with breast and/or ovarian cancer and the presence of at least 4 BC cases and 1 ovarian cancer, at least two generations affected and no male BC. The strategies to be employed are: (i) next generation sequencing of constitutive DNA (analysis of the coding region of a gene panel classically associated with hereditary breast cancer), (ii) exome DNA sequencing (obtained from peripheral blood), (iii) analysis of the presence of microscopic and submicroscopic chromosomal alterations (in constitutive and tumoral DNA) by aCGH and (iv) large escale analysis of epigenetic changes (metiloma of normal and tumoral breast tissue). We hope, therefore, that this design allows for a greater understanding of the genetic and epigenetic mechanisms related to HBC, enabling a growing number of patients / families with a history suggestive of hereditary cancer may benefit from a specialized and personalized treatment. (AU)

Scientific publications

(10)

(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)

FERNANDES, GABRIELA C.; MICHELLI, RODRIGO A. D.; GALVAO, HENRIQUE C. R.; PAULA, ANDRE E.; PEREIRA, RUI; ANDRADE, CARLOS E.; FELICIO, PAULA S.; SOUZA, CRISTIANO P.; MENDES, DEISE R. P.; VOLC, SAHLUA; et al. Prevalence of BRCA1/BRCA2 mutations in a Brazilian population sample at-risk for hereditary breast cancer and characterization of its genetic ancestry. ONCOTARGET, v. 7, n. 49, p. 80465-80481, DEC 6 2016. (13/24633-2)

NIELSEN, SARAH M.; ECCLES, DIANA M.; ROMERO, IRIS L.; AL-MULLA, FAND; BALMANA, JUDITH; BIANCOLELLA, MICHELA; BLOK, RIEN; CALIGO, MARIA ADELAIDE; CALVELLO, MARIAROSARIA; CAPONE, GABRIELE LORENZO; et al. Genetic Testing and Clinical Management Practices for Variants in Non-BRCA1/2 Breast (and Breast/Ovarian) Cancer Susceptibility Genes: An International Survey by the Evidence-Based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) Clinical Working Group. JCO PRECISION ONCOLOGY, v. 2, OCT 26 2018. (13/24633-2)

CAMPACCI, NATALIA; DE LIMA, JULIANA O.; CARVALHO, ANDRE L.; MICHELLI, RODRIGO D.; HAIKEL, JR., RAFAEL; MAUAD, EDMUNDO; VIANA, DANILO V.; MELENDEZ, MATIAS E.; VAZQUEZ, FABIANA DE L.; ZANARDO, CLEYTON; et al. Identification of hereditary cancer in the general population: development and validation of a screening questionnaire for obtaining the family history of cancer. CANCER MEDICINE, v. 6, n. 12, p. 3014-3024, DEC 2017. (15/02444-9, 13/24633-2)

FELICIO, PAULA S.; GRASEL, REBECA S.; CAMPACCI, NATALIA; DE PAULA, ANDRE E.; GALVAO, HENRIQUE C. R.; TORREZAN, GIOVANA T.; SABATO, CRISTINA S.; FERNANDES, GABRIELA C.; SOUZA, CRISTIANO P.; MICHELLI, RODRIGO D.; et al. Whole-exome sequencing of non-BRCA1/BRCA2 mutation carrier cases at high-risk for hereditary breast/ovarian cancer. Human mutation, v. 42, n. 3, DEC 2020. (13/24633-2)

TORREZAN, GIOVANA T.; DE ALMEIDA, FERNANDA G. DOS SANTOS R.; FIGUEIREDO, MARCIA C. P.; DE FIGUEIREDO BARROS, BRUNA D.; DE PAULA, CLAUDIA A. A.; VALIERIS, RENAN; DE SOUZA, JORGE E. S.; RAMALHO, RODRIGO F.; DA SILVA, FELIPE C. C.; FERREIRA, ELISA N.; et al. Complex Landscape of Germline Variants in Brazilian Patients With Hereditary and Early Onset Breast Cancer. FRONTIERS IN GENETICS, v. 9, MAY 7 2018. (13/23277-8, 13/24633-2, 08/57887-9)

PALMERO, EDENIR I.; GALVAO, HENRIQUE C. R.; FERNANDES, GABRIELA C.; DE PAULA, ANDRE E.; OLIVEIRA, JUNEA C.; SOUZA, CRISTIANO P.; ANDRADE, CARLOS E.; ROMAGNOLO, LUIS G. C.; VOLC, SAHLUA; NETO, MAXIMILIANO C.; et al. Oncogenetics service and the Brazilian public health system: the experience of a reference Cancer Hospital. GENETICS AND MOLECULAR BIOLOGY, v. 39, n. 2, p. 168-177, APR-JUN 2016. (13/24633-2)

FELICIO, PAULA SILVA; ALEMAR, BARBARA; COELHO, ALINE SILVA; BERARDINELLI, GUSTAVO NORIZ; MELENDEZ, MATIAS ELISEO; LENGERT, ANDRE VAN HELVOORT; MICHE ILI, RODRIGO DEPIERI; REIS, RUI M.; FERNANDES, GABRIELA CARVALHO; EWALD, INGRID PETRONI; et al. Screening and characterization of BRCA2 c.156_157insAlu in Brazil: Results from 1380 individuals from the South and Southeast. CANCER GENETICS, v. 228, p. 93-97, DEC 2018. (13/24633-2)

PALMERO, EDENIR INEZ; CARRARO, DIRCE MARIA; ALEMAR, BARBARA; MARTINS MOREIRA, MIGUEL ANGELO; RIBEIRO-DOS-SANTOS, ANDREA; ABE-SANDES, KIYOKO; REIS GALVAO, HENRIQUE CAMPOS; REIS, RUI MANUEL; SOUZA, CRISTIANO DE PADUA; CAMPACCI, NATALIA; et al. The germline mutational landscape of BRCA1 and BRCA2 in Brazil. SCIENTIFIC REPORTS, v. 8, JUN 15 2018. (13/24633-2)

FELICIO, PAULA SILVA; MELENDEZ, MATIAS ELISEO; REBOLHO BATISTA ARANTES, LIDIA MARIA; KERR, LIGIA MARIA; CARRARO, DIRCE MARIA; GRASEL, REBECA SILVEIRA; CAMPACCI, NATALIA; SCAPULATEMPO-NETO, CRISTOVAM; FERNANDES, GABRIELA CARVALHO; DE CARVALHO, ANA CAROLINA; et al. Genetic and epigenetic characterization of the BRCA1 gene in Brazilian women at-risk for hereditary breast cancer. ONCOTARGET, v. 8, n. 2, p. 2850-2862, JAN 10 2017. (13/24633-2, 13/23277-8)

GRASEL, REBECA SILVEIRA; FELICIO, PAULA SILVA; DE PAULA, ANDRE ESCREMIM; CAMPACCI, NATALIA; DE OLIVEIRA GARCIA, FELIPE ANTONIO; DE ANDRADE, EDILENE SANTOS; EVANGELISTA, ADRIANE FEIJO; FERNANDES, GABRIELA CARVALHO; SABATO, CRISTINA DA SILVA; DE MARCHI, PEDRO; et al. Using Co-segregation and Loss of Heterozygosity Analysis to Define the Pathogenicity of Unclassified Variants in Hereditary Breast Cancer Patients. FRONTIERS IN ONCOLOGY, v. 10, p. 10-pg., 2020-10-02. (13/24633-2)