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Inborn-like errors of metabolism are determinants of breast cancer risk, clinical response and survival: a study of human biochemical individuality

2018; Impact Journals LLC; Volume: 9; Issue: 60 Linguagem: Inglês

10.18632/oncotarget.25839

1949-2553

Ismael da Silva, Rene da Costa Vieira, C Stella, Edson Guimarães Loturco, André Lopes Carvalho, Carlos Augusto Rodrigues Véo, Cristovam Scapulatempo‐Neto, Sandra Monteiro Silva, Paulo D’Amora, Márcia Batista Salzgeber, Délcio Matos, Celso R. Silva, José Renato Assis Lemos Marques de Oliveira, Iara Baldim Rabelo, Patrícia Eiko Yamakawa, Rui M. B. Maciel, Rosa Paula M. Biscolla, Maria Izabel Chiamolera, Renato Fraietta, Felipe C.G. Reis, Marcelo A. Mori, Dirce Maria Lobo Marchioni, Antônio Augusto Ferreira Carioca, Gustavo Arantes Rosa Maciel, Renato Tomioka, Edmund Chada Baracat, Clóvis A. Silva, Celso Granato, R. S. Díaz, Bruno Scarpellini, Daniel Egle, Heidi Fiegl, Irmgard Himmel, Christina Troi, Robert A. Nagourney,

Epigenetics and DNA Methylation

// Ismael da Silva 1, 2, 8 , Rene da Costa Vieira 8 , Carolina Stella 1 , Edson Loturco 6 , André Lopes Carvalho 8 , Carlos Veo 8 , Cristovam Neto 8 , Sandra M. Silva 8 , Paulo D'Amora 1 , Marcia Salzgeber 1 , Delcio Matos 3 , Celso R. Silva 4 , Jose R. Oliveira 4 , Iara Rabelo 4 , Patricia Yamakawa 4 , Rui Maciel 2, 5 , Rosa Biscolla 5 , Maria Chiamolera 5 , Renato Fraietta 6 , Felipe Reis 7 , Marcelo Mori 9 , Dirce Marchioni 10 , Antonio Carioca 10 , Gustavo Maciel 2, 11 , Renato Tomioka 11 , Edmund Baracat 11 , Clovis Silva 12 , Celso Granato 2, 13 , Ricardo Diaz 13 , Bruno Scarpellini 2, 13 , Daniel Egle 14 , Heidi Fiegl 15 , Irmgard Himmel 15 , Christina Troi 16 and Robert Nagourney 17 1 Gynecology Department, College of Medicine of the Federal University of São Paulo (EPM-UNIFESP), São Paulo, Brazil 2 Fleury Laboratories, São Paulo, Brazil 3 Department of Surgery, Surgical Gastroenterology Division, College of Medicine of the Federal University of São Paulo (EPM-UNIFESP), São Paulo, Brazil 4 Clinical and Experimental Oncology Department, Hematology and Hemotherapy Division, College of Medicine of the Federal University of São Paulo (EPM-UNIFESP), São Paulo, Brazil 5 Department of Medicine, Endocrinology Division, College of Medicine of the Federal University of São Paulo (EPM-UNIFESP), São Paulo, Brazil 6 Department of Surgery, Urology Unit, Human Reproduction Division, College of Medicine of the Federal University of São Paulo (EPM-UNIFESP), São Paulo, Brazil 7 Biophysics Department, College of Medicine of the Federal University of São Paulo (EPM-UNIFESP), São Paulo, Brazil 8 Barretos Cancer Hospital (HCB), Barretos, Brazil 9 Department of Biochemistry and Tissue Biology, State University of Campinas (UNICAMP), Campinas, Brazil 10 Nutrition Department, School of Public Health, University of São Paulo School of Medicine (FMUSP), São Paulo, Brazil 11 Department of Obstetrics and Gynecology, University of São Paulo School of Medicine (HCFMUSP), São Paulo, Brazil 12 Department of Pediatrics, Children’s Hospital, University of São Paulo School of Medicine (HCFMUSP), São Paulo, Brazil 13 Retrovirology Laboratory, Infectious Diseases Unit, Medicine Department, College of Medicine of the Federal University of São Paulo (EPM-UNIFESP), São Paulo, Brazil 14 Department of Obstetrics and Gynecology, Medical University of Innsbruck, Innsbruck, Austria 15 Department of Gynecology, Meran Hospital, Meran, Italy 16 Department of Gynecology, Brixen Hospital, Brixen, Italy 17 Department of Obstetrics and Gynecology, Gynecological Oncology Unit, University of California Irvine (UCI), California, USA Correspondence to: Robert Nagourney, email: rnagourney@nagourneyci.com Keywords: breast cancer; metabolism; prognosis; response; survival Received: May 31, 2018 Accepted: July 12, 2018 Published: August 03, 2018 ABSTRACT Breast cancer remains a leading cause of morbidity and mortality worldwide yet methods for early detection remain elusive. We describe the discovery and validation of biochemical signatures measured by mass spectrometry, performed upon blood samples from patients and controls that accurately identify (>95%) the presence of clinical breast cancer. Targeted quantitative MS/MS conducted upon 1225 individuals, including patients with breast and other cancers, normal controls as well as individuals with a variety of metabolic disorders provide a biochemical phenotype that accurately identifies the presence of breast cancer and predicts response and survival following the administration of neoadjuvant chemotherapy. The metabolic changes identified are consistent with inborn-like errors of metabolism and define a continuum from normal controls to elevated risk to invasive breast cancer. Similar results were observed in other adenocarcinomas but were not found in squamous cell cancers or hematologic neoplasms. The findings describe a new early detection platform for breast cancer and support a role for pre-existing, inborn-like errors of metabolism in the process of breast carcinogenesis that may also extend to other glandular malignancies. Statement of Significance: Findings provide a powerful tool for early detection and the assessment of prognosis in breast cancer and define a novel concept of breast carcinogenesis that characterizes malignant transformation as the clinical manifestation of underlying metabolic insufficiencies.