| 1. |
- Gatto, Francesco, 1987, et al.
(författare)
-
Glycosaminoglycan Profiling in Patients' Plasma and Urine Predicts the Occurrence of Metastatic Clear Cell Renal Cell Carcinoma
- 2016
-
Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 15:8, s. 1822-1836
-
Tidskriftsartikel (refereegranskat)abstract
- Metabolic reprogramming is a hallmark of clear cell renal cell carcinoma (ccRCC) progression. Here, we used genome-scale metabolic modeling to elucidate metabolic reprogramming in 481 ccRCC samples and discovered strongly coordinated regulation of glycosaminoglycan (GAG) biosynthesis at the transcript and protein levels. Extracellular GAGs are implicated in metastasis, so we speculated that such regulation might translate into a non-invasive biomarker for metastatic ccRCC (mccRCC). We measured 18 GAG properties in 34 mccRCC samples versus 16 healthy plasma and/or urine samples. The GAG profiles were distinctively altered in mccRCC. We derived three GAG scores that distinguished mccRCC patients with 93.1%-100% accuracy. We validated the score accuracies in an independent cohort (up to 18 mccRCC versus nine healthy) and verified that the scores normalized in eight patients with no evidence of disease. In conclusion, coordinated regulation of GAG biosynthesis occurs in ccRCC, and non-invasive GAG profiling is suitable for mccRCC diagnosis.
|
|
| 2. |
|
|
| 3. |
- Gatto, Francesco, 1987, et al.
(författare)
-
In search for symmetries in the metabolism of cancer
- 2016
-
Ingår i: Wiley Interdisciplinary Reviews: Systems Biology and Medicine. - : Wiley. - 1939-5094 .- 1939-005X. ; 8:1, s. 23-35
-
Forskningsöversikt (refereegranskat)abstract
- Even though aerobic glycolysis, or the Warburg effect, is arguably the most common trait of metabolic reprogramming in cancer, it is unobserved in certain tumor types. Systems biology advocates a global view on metabolism to dissect which traits are consistently reprogrammed in cancer, and hence likely to constitute an obligate step for the evolution of cancer cells. We refer to such traits as symmetric. Here, we review early systems biology studies that attempted to reveal symmetric traits in the metabolic reprogramming of cancer, discuss the symmetry of reprogramming of nucleotide metabolism, and outline the current limitations that, if unlocked, could elucidate whether symmetries in cancer metabolism may be claimed.
|
|
| 4. |
- Gatto, Francesco, 1987, et al.
(författare)
-
Prognostic Value of Plasma and Urine glycosaminoglycan scores in clear cell renal cell carcinoma
- 2016
-
Ingår i: Frontiers in Oncology. - : Frontiers Media SA. - 2234-943X. ; 6:NOV, s. Art. no. 253-
-
Tidskriftsartikel (refereegranskat)abstract
- Background: The prognosis of metastatic clear cell renal cell carcinoma (ccRCC) vastly improved since the introduction of antiangiogenic-targeted therapy. However, it is still unclear which biological processes underlie ccRCC aggressiveness and affect prognosis. Here, we checked whether a recently discovered systems biomarker based on plasmatic or urinary measurements of glycosaminoglycans (GAGs) aggregated into diagnostic scores correlated with ccRCC prognosis. Methods: Thirty-one patients with a diagnosis of ccRCC (23 metastatic) were prospectively enrolled, and their urine and plasma biomarker scores were correlated to progression-free survival (PFS) and overall survival (OS) as either a dichotomous ("Low" vs. "High") or a continuous variable in a multivariate survival analysis. Results: The survival difference between "High"-vs. "Low"-scored patients was significant in the case of urine scores (2-year PFS rate = 53.3 vs. 100%, p = 3 x 10(-4) and 2-year OS rate = 73.3 vs. 100%, p = 0.0078) and in the case of OS for plasma scores (2-year PFS rate = 60 vs. 84%, p = 0.0591 and 2-year OS rate = 66.7 vs. 90%, p = 0.0206). In multivariate analysis, the urine biomarker score as a continuous variable was an independent predictor of PFS [hazard ratio (HR): 4.62, 95% CI: 1.66-12.83, p = 0.003] and OS (HR: 10.13, 95% CI: 1.80-57.04, p = 0.009). Conclusion: This is the first report on an association between plasma or urine GAG scores and the prognosis of ccRCC patients. Prospective trials validating the prognostic and predictive role of this novel systems biomarker are warranted.
|
|
| 5. |
- Gatto, Francesco, 1987, et al.
(författare)
-
Systematic analysis of overall survival and interactions between tumor mutations and drug treatment
- 2016
-
Ingår i: Journal of Hematology and Oncology. - : Springer Science and Business Media LLC. - 1756-8722. ; 9:1
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Few exceptional responses in cancer treatment were attributed to a genetic predisposition of the tumor. Methods: We analyzed a cohort of 3105 patients from 12 different cancer types and systematically sought the existence of a correlation between overall survival and the interaction of 21 antineoplastic treatments with 6 tumor mutations. Results: We identified a single significant correlation resulting in increased overall survival from temozolomide in lower-grade glioma with IDH1 R132H mutations. The trend could not be attributed to either the treatment or the mutation alone. Univariate and multivariate Cox regression demonstrated that this interaction stood as an independent prognostic predictor of survival. Conclusion: Our results suggest infrequent instances of exceptional responses ascribable to tumor genomics yet corroborate the existence of an interaction of temozolomide with IDH1 mutations in lower-grade glioma.
|
|
| 6. |
- Gatto, Francesco, 1987, et al.
(författare)
-
Systematic Analysis Reveals that Cancer Mutations Converge on Deregulated Metabolism of Arachidonate and Xenobiotics
- 2016
-
Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 16:3, s. 878-895
-
Tidskriftsartikel (refereegranskat)abstract
- Mutations are the basis of the clonal evolution of most cancers. Nevertheless, a systematic analysis of whether mutations are selected in cancer because they lead to the deregulation of specific biological processes independent of the type of cancer is still lacking. In this study, we correlated the genome and transcriptome of 1,082 tumors. We found that nine commonly mutated genes correlated with substantial changes in gene expression, which primarily converged on metabolism. Further network analyses circumscribed the convergence to a network of reactions, termed AraX, that involves the glutathione- and oxygen-mediated metabolism of arachidonic acid and xenobiotics. In an independent cohort of 4,462 samples, all nine mutated genes were consistently correlated with the deregulation of AraX. Among all of the metabolic pathways, AraX deregulation represented the strongest predictor of patient survival. These findings suggest that oncogenic mutations drive a selection process that converges on the deregulation of the AraX network.
|
|
