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

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.

Platinum resistance in gynecologic malignancies: Response, disease free and overall survival are predicted by biochemical signature: A metabolomic analysis

“…4A-B). The Valine/Phenylalanine ratio reflects Fisher's quotient [19] an established measure of liver health and function, that we previously applied in a metabolomic analysis of breast cancer [20] while the lipid and Tryptophan ratios reflect altered bio-energetic and immune signatures. The analyses that examined specific lipid species and ratios with a focus upon acyl-carnitines, phosphatidylcholines and sphingomyelins that were used to define the shift in mitochondrial function from structural lipids to inflammation and energy production are provided in Supplementary Figs.…”

Distinct pattern of one-carbon metabolism, a nutrient-sensitive pathway, in invasive breast cancer: A metabolomic study

“…These are defined by genetic changes that result in the overexpression of oncogenes and downregulation of tumor suppressor genes, generating different malignant phenotypes [8][9][10]. Several oncogenes (i. e., RAS, PI3K, TP53 and MYC) can regulate metabolic pathways that are critical for cell survival in the inhospitable tumor microenvironment, where oxygen and nutrients sources are highly limited [11,12].…”

Biochemical phenotyping of multiple myeloma patients at diagnosis reveals a disorder of mitochondrial complexes I and II and a Hartnup-like disturbance as underlying conditions, also influencing different stages of the disease

“…Additionally, groups of AAs were computed by summing the levels of amino acids (AA) belonging to certain families or chemical structures depending on their functions such as the sum of: 1. branched-chain (Leu + Ile + Val) amino acids (BCAA), 2 tryptophan/phenylalanine ratio (Trp/Phe) 56 3. levels of methionine sulphoxide (Met-SO) alone or in 4. combination to unmodified methionine (Met-SO/Met) as well as 5. symmetric (SDMA), 6. asymmetric (ADMA) and 7. total dimethylation of arginine residues (Total DMA) were quantified to gain access to insulin resistance, activity of the Melatonin Receptor 1B (MTNR1B) 56 , ROS-mediated protein modifications as well as to systemic arginine methylation status respectively 67 .…”