From Metabolism to Genetics and Vice Versa: The Rising Role of Oncometabolites in Cancer Development and Therapy

Over the last decades, the study of cancer metabolism has returned to the forefront of cancer research and challenged the role of genetics in the understanding of cancer development. One of the major impulses of this new trend came from the discovery of oncometabolites, metabolic intermediates whose abnormal cellular accumulation triggers oncogenic signalling and tumorigenesis. These findings have led to reconsideration and support for the long-forgotten hypothesis of Warburg of altered metabolism as oncogenic driver of cancer and started a novel paradigm whereby mitochondrial metabolites play a pivotal role in malignant transformation. In this review, we describe the evolution of the cancer metabolism research from a historical perspective up to the oncometabolites discovery that spawned the new vision of cancer as a metabolic disease. The oncometabolites' mechanisms of cellular transformation and their contribution to the development of new targeted cancer therapies together with their drawbacks are further reviewed and discussed

the metabolomic scent of cancer disease progression in soft tissue sarcoma a case report

Background: The purpose of this case report is to describe the potential that metabolomics breath analysis may have in cancer disease monitoring. The advances in mass spectrometry instrumentation allow the accurate real-time analysis of volatile metabolites exhaled in the breath. The application of such non-invasive devices may provide innovative and complementary monitoring of the physio-pathological conditions of cancer patients. Case presentation: A 59-year-old Caucasian woman with spindle cell malignant mesenchymal sarcoma of the presacral region started a first-line therapy with non-pegylated liposomal doxorubicin and ifosfamide associated with pelvic radiant treatment. After two cycles of chemotherapy plus radiotherapy, a significant pulmonary disease progression was reported. Thus, a second-line therapy with trabectedin was administered. However, after only two cycles of treatment a re-staging computed tomography scan reported further cancer disease progression of the target pulmonary lesions as well as occurrence of new satellite bilateral nodules. Real-time analysis of breath exhaled volatile organic compounds, performed by select ion flow tube mass spectrometry (SIFT-MS) during the follow-up of the patient, showed a specific metabolic pattern not observed in the breath of other soft tissue sarcoma patients who achieved clinical benefit from the treatments. Conclusions: This case report revealed the importance of the non-invasive real-time volatile organic compounds breath analysis to distinguish individual specific chemo-resistance phenotypes among soft tissue sarcoma patients. Such observation seems to suggest that breath metabolomics may be particularly useful for monitoring cancer disease progression in soft tissue sarcoma patients where only cost-effective diagnostic tools, such as positron emission tomography and computed tomography, are available

Late tamoxifen in patients previously operated for breast cancer without postoperative tamoxifen: 5-year results of a single institution randomised study

BACKGROUND: A population of breast cancer patients exists who, for various reasons, never received adjuvant post-operative tamoxifen (TAM). This study was aimed to evaluate the role of late TAM in these patients. METHODS: From 1997 to 2003, patients aged 35 to 75 years, operated more than 2 years previously for monolateral breast cancer without adjuvant TAM, with no signs of metastases and no contraindication to TAM were randomized to TAM 20 mg/day orally for 2 years or follow-up alone. Events were categorized as locoregional relapse, distant metastases, metachronous breast cancer, tumours other than breast cancer and death from any causes, whichever occurred first. The sample size (197 patients per arm, plus 10% allowance) was based on the assumption of a 30% decrease in the number of events occurring at a rate of 5% annually in the 10 years following randomization. Four hundred and thirty-three patients were randomized in the study (TAM 217, follow-up 216). Patients characteristics (TAM/follow-up) included: median age 55/55 years, median time from surgery 25/25 months (range, 25-288/25-294), in situ carcinoma 18/24, oestrogen receptor (ER) positive in 75/68, negative in 70/57, unknown in 72/91 patients. Previous adjuvant treatment included chemotherapy in 131/120 and an LHRH analogue in 11/13 patients. RESULTS: Thirty-six patients prematurely discontinued TAM after a median of 1 month, mostly because of subjective intolerance. Eighty-three events (TAM 39, follow-up 44) occurred: locoregional relapse in 10/8, distant metastases in 14/16, metachronous breast cancer in 4/10, other tumours in 11/10 patients. Less ER-positive secondary breast cancers occurred in the TAM treated patients than in follow-up patients (1 vs 10, p = 0.005). Event-free survival was similar in both groups of patients. CONCLUSIONS: This 5-year analysis revealed significantly less metachronous ER-positive breast cancers in the TAM treated patients. No other statistically significant differences have emerged thus far

Association of the germline BRCA2 missense variation Glu2663Lys with high sensitivity to trabectedin-based treatment in soft tissue sarcoma

We report an interesting clinical case of a patient carrying a specific BRCA2 germline variant affected by bone and hepatic metastases from a high grade uterine stromal sarcoma who obtained a complete metabolic response after only 3 cycles of trabectedin treatment (1.5mg/m(2) given intravenously over 24hours every 21days). Molecular investigations linked this outstanding positive pharmacological response with the loss of heterozygosity (LOH) of the mutated BRCA2 gene. These data support the hypothesis that the response to trabectedin may be positively conditioned by the different DNA repair defects present in the neoplasm and that BRCAness tumor genotype is important in determining the efficacy of trabectedin-based chemotherapy

Carcinogenesis and Metastasis in Liver: Cell Physiological Basis

Hepatocellular carcinoma (HCC) incidence is rising. This paper summarises the current state of knowledge and recent discoveries in the cellular and physiological mechanisms leading to the development of liver cancer, especially HCC, and liver metastases. After reviewing normal hepatic cytoarchitecture and immunological characteristics, the paper addresses the pathophysiological factors that cause liver damage and predispose to neoplasia. Particular attention is given to chronic liver diseases, metabolic syndrome and the impact of altered gut microbiota, disrupted circadian rhythm and psychological stress. Improved knowledge of the multifactorial aetiology of HCC has important implications for the prevention and treatment of this cancer and of liver metastases in general

Tracking of the origin of recurrent mutations of the BRCA1 and BRCA2 genes in the North-East of Italy and improved mutation analysis strategy

14noopenopenCini, Giulia; Mezzavilla, Massimo; Della Puppa, Lara; Cupelli, Elisa; Fornasin, Alessio; D'Elia, Angela Valentina; Dolcetti, Riccardo; Damante, Giuseppe; Bertok, Sara; Miolo, Gianmaria; Maestro, Roberta; de Paoli, Paolo; Amoroso, Antonio; Viel, AlessandraCini, Giulia; Mezzavilla, Massimo; Della Puppa, Lara; Cupelli, Elisa; Fornasin, Alessio; D'Elia, Angela Valentina; Dolcetti, Riccardo; Damante, Giuseppe; Bertok, Sara; Miolo, Gianmaria; Maestro, Roberta; de Paoli, Paolo; Amoroso, Antonio; Viel, Alessandr

Monocyte-to-lymphocye ratio (MLR) and LDH level in metastatic colorectal cancer (mCRC) patients (pts)

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Selecting for BRCA1 testing using a combination of homogeneous selection criteria and immunohistochemical characteristics of breast cancers

<p>Abstract</p> <p>Background</p> <p>BRCA1 gene-related tumours are more frequently estrogen receptor (ER) and progesterone receptor (PR) negative with a lower prevalence of human epidermal growth factor receptor 2 (HER2) overexpression or amplification. We evaluated the effectiveness of a combination of homogeneously selected criteria and immunohistochemical (IHC) characteristics of Familial Breast Cancers (FBCs) in detecting BRCA1 mutation carriers.</p> <p>Methods</p> <p>Primary breast tumours from 93 FBC patients defined by specific eligibility criteria, based on personal and familial tumour history, were evaluated by Allred's method. The BRCA1 molecular analysis, including Multiplex Ligation-dependent Probe Amplification (MLPA), was considered as the gold standard assay.</p> <p>Results</p> <p>A total of 10 BRCA1 pathogenetic mutations was found. With the exclusion of the tumours characterized by double positive receptorial status and/or strong HER2 positivity (3+), we identified 22 patients, 10 of whom resulted as BRCA1 mutation carriers. The sensitivity, specificity, positive and negative predictive values were 100%, 83.3%, 45.4% and 100% respectively.</p> <p>Conclusion</p> <p>Our findings suggest that the IHC analysis by Allred's method improves our ability to select patients for BRCA1 testing.</p

Phenotypic features and genetic characterization of male breast cancer families: identification of two recurrent BRCA2 mutations in north-east of Italy

BACKGROUND: Breast cancer in men is an infrequent occurrence, accounting for ~1% of all breast tumors with an incidence of about 1:100,000. The relative rarity of male breast cancer (MBC) limits our understanding of the epidemiologic, genetic and clinical features of this tumor. METHODS: From 1997 to 2003, 10 MBC patients were referred to our Institute for genetic counselling and BRCA1/2 testing. Here we report on the genetic and phenotypic characterization of 10 families with MBC from the North East of Italy. In particular, we wished to assess the occurrence of specific cancer types in relatives of MBC probands in families with and without BRCA2 predisposing mutations. Moreover, families with recurrent BRCA2 mutations were also characterized by haplotype analysis using 5 BRCA2-linked dinucleotide repeat markers and 8 intragenic BRCA2 polymorphisms. RESULTS: Two pathogenic mutations in the BRCA2 gene were observed: the 9106C>T (Q2960X) and the IVS16-2A>G (splicing) mutations, each in 2 cases. A BRCA1 mutation of uncertain significance 4590C>G (P1491A) was also observed. In families with BRCA2 mutations, female breast cancer was more frequent in the first and second-degree relatives compared to the families with wild type BRCA1/2 (31.9% vs. 8.0% p = 0.001). Reconstruction of the chromosome phasing in three families and the analysis of three isolated cases with the IVS16-2A>G BRCA2 mutation identified the same haplotype associated with MBC, supporting the possibility that this founder mutation previously detected in Slovenian families is also present in the North East of our Country. Moreover, analysis of one family with the 9106C>T BRCA2 mutation allowed the identification of common haplotypes for both microsatellite and intragenic polymorphisms segregating with the mutation. Three isolated cases with the same mutation shared the same intragenic polymorphisms and three 5' microsatellite markers, but showed a different haplotype for 3' markers, which were common to all three cases. CONCLUSION: The 9106C>T and the IVS16-2A>G mutations constitute recurrent BRCA2 mutations in MBC cases from the North-East of Italy and may be associated with a founder effect. Knowledge of these two recurrent BRCA2 mutations predisposing to MBC may facilitate the analyses aimed at the identification of mutation carriers in our geographic area

A different immunologic profile characterizes patients with HER-2-overexpressing and HER-2-negative locally advanced breast cancer: implications for immune-based therapies

INTRODUCTION: The clinical efficacy of trastuzumab and taxanes is at least partly related to their ability to mediate or promote antitumor immune responses. On these grounds, a careful analysis of basal immune profile may be capital to dissect the heterogeneity of clinical responses to these drugs in patients with locally advanced breast cancer undergoing neoadjuvant chemotherapy. METHODS: Blood samples were collected from 61 locally advanced breast cancers (36 HER2- and 25 HER2+) at diagnosis and from 23 healthy women. Immunophenotypic profiling of circulating and intratumor immune cells, including regulatory T (Treg) cells, was assessed by flow cytometry and immunohistochemistry, respectively. Serum levels of 10 different cytokines were assessed by multiplex immunoassays. CD8+ T cell responses to multiple tumor-associated antigens (TAA) were evaluated by IFN-γ-enzyme-linked immunosorbent spot (ELISPOT). The Student's t test for two tailed distributions and the Wilcoxon two-sample test were used for the statistical analysis of the data. RESULTS: The proportion of circulating immune effectors was similar in HER2+ patients and healthy donors, whereas higher percentages of natural killer and Treg cells and a lower CD4+/CD8+ T cell ratio (with a prevalence of naïve and central memory CD8+ T cells) were observed in HER2- cases. Higher numbers of circulating CD8+ T cells specific for several HLA-A*0201-restricted TAA-derived peptides were observed in HER2+ cases, together with a higher prevalence of intratumor CD8+ T cells. Serum cytokine profile of HER2+ patients was similar to that of controls, whereas HER2- cases showed significantly lower cytokine amounts compared to healthy women (IL-2, IL-8, IL-6) and HER2+ cases (IL-2, IL-1β, IL-8, IL-6, IL-10). CONCLUSIONS: Compared to HER2- cases, patients with HER2-overexpressing locally advanced breast cancer show a more limited tumor-related immune suppression. This may account for the clinical benefit achieved in this subset of patients with the use of drugs acting through, but also promoting, immune-mediated effects