Molecular aspects involved in the development and progression of breast ductal carcinoma: investigation of carcinoma in situ progression and the role of BRCA1 mutation in the triple negative tumor

• Grant number: 13/23277-8
• Support Opportunities: Research Projects - Thematic Grants
• Start date: February 01, 2014
• End date: April 30, 2018
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Dirce Maria Carraro
• Grantee: Dirce Maria Carraro
• Host Institution: A C Camargo Cancer Center. Fundação Antonio Prudente (FAP). São Paulo , SP, Brazil
• Associated researchers: Adriana Miti Nakahata ; Cynthia Aparecida Bueno de Toledo Osorio ; Eliana Vanina Elias ; Elisa Napolitano e Ferreira ; Felipe Cavalcanti Carneiro da Silva ; Jorge Estefano Santana de Souza ; Maria Isabel Alves de Souza Waddington Achatz ; Sandro José de Souza ; Tiago Góss dos Santos ; Victor Piana de Andrade ; Vilma Regina Martins ; Vladmir Cláudio Cordeiro de Lima
• Associated research grant(s): 14/00917-4 - 105th AACR Annual Meeting 2014, AR.EXT
• Associated scholarship(s): 14/03681-1 - Computational analysis of the role of exonic variations in breast cancer genesis and progression, BP.PD; 12/11842-0 - Study of the role of myoepitelial and stromal cells in the progression of in situ ductal carcinoma of the breast: toward novel prognostic markers, BP.PD

Abstract

This proposal encompasses the molecular aspects involved in risk, development and progression of breast cancer using next generation sequencing as the main approach. Mutation in the susceptibility genes, BRCA1/BRCA2, is one of the most important risk factors of developing breast cancer. The identification of the genetic cause that leads to higher risk of developing breast cancer is crucial for properly assisting women and inserting them into screening programs and also for adopting proper preventive measures. Our group has been working hereditary breast cancer syndrome and previous results based on more than 200 patients showed that 20% of patients had pathogenic mutations, and 80% did not harbored any known pathogenic alterations in these genes. By careful analysis of the pedigrees of these patients, it is clear that there is a major genetic factor that leads to increased risk, and that needs to be identified, being this one of the goals of this proposal. Other important aspect of breast cancer is the characterization of the molecular changes that occur during the progression of breast cancer, an issue that the group has been contributing. The search for more accurate and detailed information about the molecular alterations involved in the progression of ductal carcinoma in situ (DCIS) of the breast using more sensitive approaches for analysis of pre-invasive stages of BC are promising for the identification of genetic and molecular events involved in the earliest steps of the invasion process of epithelial tumor cells into the surrounding tissue. It is well known the participation of the tumor and microenviromental cells in the invasion to adjacent tissue. Thus, one of the objectives of this proposal is to investigate the changes in the gene expression profile of epithelial tumor cells and in the microenvironment, the myoepithelial cells and fibroblasts, of the two types of pre-invasive lesions with different malignant potential: pure DCIS and in situ DCIS component coexisting with invasive carcinoma (DCIS - IDC). Furthermore, we propose the identification of the somatic mutational pattern of the epithelial cells of these two pre-invasive lesions. The idea is to find biomarkers associated with a risk of progression of DCIS to invasive disease. Another study considered in this proposal, which integrates data from germline mutation and their respective tumor, is the molecular alterations in TN tumor mediated by BRCA1-germline mutation. It is well known that women with BRCA2-germline mutations preferentially develop tumors that are hormone receptor positive (ER and / or PR), and women with BRCA1-germline mutations develop hormone receptor-negative tumors, especially those TN, characterized by the lack of expression of hormone receptors, ER and PR, and no amplification and/or overexpression of HER2. TN tumors are more aggressive and have a poorer prognosis, and for which there is no targeted therapy available for the patient's treatment. In this context, we aim in this project to characterize the prevalence of BRCA1 mutations in TN tumors, and also to classify them as somatic or germline mutation. We also plan to investigate the role of the germline mutation in the development of TN tumors by the investigation of the global transcriptional and mutational profile of TN-associated or -negative to BRCA1 germline mutation. All data obtained will be correlated with clinical and pathologic features of patients being the idea to properly and detailed classify the heterogeneous group of TN. Additionally, in an exploratory way, we intend to be able to detect tumor DNA in plasma of patients with breast cancer, using tools of high sensitivity in combination with information generated by massively parallel sequencing. Our interest in this regard is to establish a sensitive and accurate method for monitoring disease progression to be inserted in clinical practice, particularly for tumor types involved in this proposal. (AU)

Scientific publications

(14)

(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)

FERREIRA, ELISA NAPOLITANO; FIGUEIREDO BARROS, BRUNA DURAES; DE SOUZA, JORGE ESTEFANO; ALMEIDA, RENAN VALIERIS; TORREZAN, GIOVANA TARDIN; GARCIA, SHEILA; VICTORINO KREPISCHI, ANA CRISTINA; LOPES DE MELLO, CELSO ABDON; DA CUNHA, ISABELA WERNECK; LOPES PINTO, CLOVIS ANTONIO; et al. A genomic case study of desmoplastic small round cell tumor: comprehensive analysis reveals insights into potential therapeutic targets and development of a monitoring tool for a rare and aggressive disease. HUMAN GENOMICS, v. 10, NOV 18 2016. (13/23277-8)

VILLACIS, ROLANDO A. R.; BASSO, TATIANE R.; CANTO, LUISA M.; PINHEIRO, MAISA; SANTIAGO, KARINA M.; GIACOMAZZI, JULIANA; DE PAULA, CLAUDIA A. A.; CARRARO, DIRCE M.; ASHTON-PROLLA, PATRICIA; ACHATZ, MARIA I.; et al. Rare germline alterations in cancer-related genes associated with the risk of multiple primary tumor development. JOURNAL OF MOLECULAR MEDICINE-JMM, v. 95, n. 5, p. 523-533, MAY 2017. (13/23277-8, 08/57887-9)

FERREIRA, ELISA NAPOLITANO; MOLINA, GUSTAVO DE CAMPOS; PUGA, RENATO DAVID; NAGAI, MARIA APARECIDA; FROES MARQUES CAMPOS, ANTONIO HUGO JOSE; GUIMARAES, GUSTAVO CARDOSO; NUNES, DIANA NORONHA; PASQUALINI, RENATA; ARAP, WADIH; BRENTANI, HELENA; et al. Linear mRNA amplification approach for RNAseq from limited amount of RNA. Gene, v. 564, n. 2, p. 220-227, JUN 15 2015. (13/23277-8)

MORENO, MARCELO; OLIVEIRA, JULIA SALLES; BRIANESE, RAFAEL CANFIELD; DE CASTRO, DOUGLAS GUEDES; SANCHES, SOLANGE MORAES; TORREZAN, GIOVANA TARDIN; SANTIAGO, KARINA MIRANDA; DE BROT, MARINA; CORDEIRO DE LIMA, VLADMIR CLAUDIO; ALVES MAKDISSI, FABIANA BARONI; et al. Risk of metastasis in BRCA2 carriers diagnosed with triple-negative breast cancer. CANCER MEDICINE, v. N/A, p. 13-pg., 2023-07-23. (13/23277-8, 14/50943-1)

TORRES, JACQUELINE APARECIDA; BRITO, ANGELO BORSARELLI CARVALHO; SILVA, VIRGILIO SOUZA E; MESSIAS, IARA MONIQUE; BRAUN, ALEXCIA CAMILA; RUANO, ANNA PAULA CARRETA; BUIM, MARCILEI E. C.; CARRARO, DIRCE MARIA; CHINEN, LUDMILLA THOME DOMINGOS. CD47 Expression in Circulating Tumor Cells and Circulating Tumor Microemboli from Non-Small Cell Lung Cancer Patients Is a Poor Prognosis Factor. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 24, n. 15, p. 16-pg., 2023-08-01. (13/23277-8, 14/50943-1, 21/04920-3, 19/18100-8)

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)

BARBOSA, MALU VITER R.; CORDEIRO DE LIMA, VLADMIR C.; FORMIGA, MARIA NIRVANA; ANDRADE DE PAULA, CLAUDIA A.; TORREZAN, GIOVANA T.; CARRARO, DIRCE M.. High Prevalence of EGFR Mutations in Lung Adenocarcinomas From Brazilian Patients Harboring the TP53 p.R337H Variant. CLINICAL LUNG CANCER, v. 21, n. 2, p. E37-E44, MAR 2020. (13/23277-8)

FERREIRA, ELISA NAPOLITANO; BRIANESE, RAFAEL CANFIELD; BUENO DE ALMEIDA, RENAN VALIERIS; DRUMMOND, RODRIGO DUARTE; DE SOUZA, JORGE ESTEFANO; DA SILVA, ISRAEL TOJAL; DE SOUZA, SANDRO JOSE; CARRARO, DIRCE MARIA. Influence of BRCA1 Germline Mutations in the Somatic Mutational Burden of Triple-Negative Breast Cancer. TRANSLATIONAL ONCOLOGY, v. 12, n. 11, p. 1453-1460, NOV 2019. (13/23277-8)

TAKENAKA, ISABELLA KUNIKO T. M.; BARTELLI, THAIS F.; DEFELICIBUS, ALEXANDRE; SENDOYA, JUAN M.; GOLUBICKI, MARIANO; ROBBIO, JUAN; SERPA, MARIANNA S.; BRANCO, GABRIELA P.; SANTOS, LUANA B. C.; CLARO, LAURA C. L.; et al. Exome and Tissue-Associated Microbiota as Predictive Markers of Response to Neoadjuvant Treatment in Locally Advanced Rectal Cancer. FRONTIERS IN ONCOLOGY, v. 12, p. 16-pg., 2022-03-22. (14/50943-1, 13/23277-8)

SOARES DE SA, BIANCA COSTA; DE MACEDO, MARIANA PETACCIA; TORREZAN, GIOVANA TARDIN; TAVOLONI BRAGA, JULIANA CASAGRANDE; FIDALGO, FELIPE; MOREDO, LUCIANA FACURE; LELLIS, RUTE; DUPRAT, JOAO PEREIRA; CARRARO, DIRCE MARIA. BAP1 tumor predisposition syndrome case report: pathological and clinical aspects of BAP1-inactivated melanocytic tumors (BIMTs), including dermoscopy and confocal microscopy. BMC CANCER, v. 19, n. 1, NOV 9 2019. (13/23277-8)

DE FIGUEIREDO BARROS, BRUNA D.; KUPPER, BRUNA E. C.; AGUIAR JUNIOR, SAMUEL; DE MELLO, CELSO A. L.; BEGNAMI, MARIA D.; CHOJNIAK, RUBENS; DE SOUZA, SANDRO J.; TORREZAN, GIOVANA T.; CARRARO, DIRCE M.. Mutation Detection in Tumor-Derived Cell Free DNA Anticipates Progression in a Patient With Metastatic Colorectal Cancer. FRONTIERS IN ONCOLOGY, v. 8, AUG 10 2018. (13/23277-8)

SILVA, FELIPE CARNEIRO; TORREZAN, GIOVANA TARDIN; BRIANESE, RAFAEL CANFIELD; STABELLINI, RAQUEL; CARRARO, DIRCE MARIA. Pitfalls in genetic testing: a case of a SNP in primer-annealing region leading to allele dropout in BRCA1. MOLECULAR GENETICS & GENOMIC MEDICINE, v. 5, n. 4, p. 443-447, JUL 2017. (13/23277-8)

DE GREGORIIS, GIULIANA; RAMOS, JULIENE ANTONIO; FERNANDES, PRISCILA VALVERDE; VIGNAL, GISELLE MARIA; BRIANESE, RAFAEL CANFIELD; CARRARO, DIRCE MARIA; MONTEIRO, ALVARO N.; STRUCHINER, CLAUDIO JOSE; SUAREZ-KURTZ, GUILHERME; VIANNA-JORGE, ROSANE; et al. DNA repair genes PAXIP1 and TP53BP1 expression is associated with breast cancer prognosis. CANCER BIOLOGY & THERAPY, v. 18, n. 6, p. 439-449, 2017. (13/23277-8)

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)