Suchergebnisse

Triple-Negative Breast Cancer (TNBC) has poor prognosis and no approved targeted therapy. We previously showed that the enzyme fatty acid synthase (FASN) was largely expressed in a small TNBC patients' cohort and its inhibition synergized with cetuximab in TNBC preclinical mouse models. Here, we evaluated FASN and EGFR expression in a cohort of TNBC patients and we study their prognostic role and their association with clinico-histopathological features, intrinsic TNBC subtypes and survival. FASN, EGFR, CK5/6 and vimentin expression were retrospective evaluated by Immunohistochemistry in 100 primary TNBC tumors. FASN expression was classified into high and low FASN groups. EGFR, CK5/6 and vimentin expression were used in TNBC intrinsic subtypes classification. FASN was expressed in most of the TNBC patients but did not correlate with overall survival or disease-free survival in this cohort. High FASN group was significantly associated with positive node status. FASN expression was significantly higher in Basal-Like patients than in Mesenchymal-Like ones. EGFR expression was positive in 50% of the tumors, and those patients showed poorer DFS. Altogether, our findings provide a rationale for further investigation the prognostic role of FASN and EGFR expression in a larger cohort of TNBC patients ; This work was supported in part by the Spanish Instituto de Salud Carlos III (ISCIII) (FIS PI11/00692; TP and PI14/00329; TP), Fundación Ramón Areces (TP), the Catalonian Government (2014SGR00868) and the University of Girona (MPCUdG2016/036 and predoctoral grant to AG-P)

Somatic epigenetic inactivation of the DNA repair protein O6-methylguanine DNA methyltransferase (MGMT) is frequent in colorectal cancer (CRC); however, its involvement in CRC predisposition remains unexplored. We assessed the role and relevance of MGMT germline mutations and epimutations in familial and early-onset CRC. Mutation and promoter methylation screenings were performed in 473 familial and/or early-onset mismatch repair-proficient nonpolyposis CRC cases. No constitutional MGMT inactivation by promoter methylation was observed. Of six rare heterozygous germline variants identified, c.346C > T (p.H116Y) and c.476G > A (p.R159Q), detected in three and one families respectively, affected highly conserved residues and showed segregation with cancer in available family members. In vitro, neither p.H116Y nor p.R159Q caused statistically significant reduction of MGMT repair activity. No evidence of somatic second hits was found in the studied tumors. Case-control data showed over-representation of c.346C > T (p.H116Y) in familial CRC compared to controls, but no overall association of MGMT mutations with CRC predisposition. In conclusion, germline mutations and constitutional epimutations in MGMT are not major players in hereditary CRC. Nevertheless, the over-representation of c.346C > T (p.H116Y) in our familial CRC cohort warrants further research ; This work was funded by the Spanish Ministry of Science, Innovation and Universities, co-funded by FEDER funds -a way to build Europe- [SAF2016-80888-R (LV), SAF2014-55000-R (ME), SAF2015- 68016-R (GC/MP), Juan de la Cierva and Sara Borrell postdoctoral contracts (PM)]; Instituto de Salud Carlos III [DTS16/00153 (ME) and CIBERONC CB16/12/00234]; the Government of Catalonia [Pla Estratègic de Recerca i Innovació en Salut SLT002/16/0037, 2017SGR1282, 2017SGR1080, 2014SGR633 and 2009SGR1315]; and Fundación Olga Torres. We thank the CERCA/Generalitat de Catalunya Program for institutional support. This study has been enabled by COST Action CA17118

The cancer-predisposing syndrome caused by biallelic mutations in NTHL1 may not be a solely colorectal cancer (CRC) and polyposis syndrome but rather a multi-tumor recessive disease. The presence of ≤10 adenomas in several mutation carriers suggests a possible causal role of NTHL1 in hereditary or early-onset nonpolyposis CRC. The involvement of NTHL1 in serrated/hyperplastic polyposis remains unexplored. The aim of our study is to elucidate the role of NTHL1 in the predisposition to personal or familial history of multiple tumor types, familial/early-onset nonpolyposis CRC, and serrated polyposis. NTHL1 mutational screening was performed in 312 cancer patients with personal or family history of multiple tumor types, 488 with hereditary nonpolyposis CRC, and 96 with serrated/hyperplastic polyposis. While no biallelic mutation carriers were identified in patients with personal and/or family history of multiple tumor types or with serrated polyposis, one was identified among the 488 nonpolyposis CRC patients. The carrier of c.268C>T (p.Q90*) and 550-1G>A was diagnosed with CRC and meningioma at ages 37 and 45 respectively, being reclassified as attenuated adenomatous polyposis after the cumulative detection of 26 adenomas. Our findings suggest that biallelic mutations in NTHL1 rarely cause CRC, a personal/familial multi-tumor history, or serrated polyposis, in absence of adenomas ; Tis study was funded by the Spanish Ministry of Science, Innovation and Universities, co-funded by FEDER funds- a way to build Europe, [SAF2016-80888-R (LV), SAF2015-68016-R (GC), Formación de Personal Investigador (IQ)]; Instituto de Salud Carlos III [CIBERONC CB16/12/00234, PI16/00563 (CL), Sara Borrell postdoctoral contract (PM)], the Government of Catalonia [Department of Health PERIS SLT002/16/0037, SLT002/16/00164 "Acció instrumental d'incorporació de científcs i tecnòlegs" (MT)], AGAUR 2017SGR1282 and CERCA Program] and Fundación Olga Torres. Tis study has been enabled by COST Action CA17118

Constitutional MLH1 methylation (epimutation) is a rare cause of Lynch syndrome. Low-level methylation (≤ 10%) has occasionally been described. This study aimed to identify low-level constitutional MLH1 epimutations and determine its causal role in patients with MLH1-hypermethylated colorectal cancer. Eighteen patients with MLH1-hypermethylated colorectal tumors in whom MLH1 methylation was previously undetected in blood by methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) were screened for MLH1 methylation using highly sensitive MS-melting curve analysis (MS-MCA). Constitutional methylation was characterized by different approaches. MS-MCA identified one patient (5.6%) with low-level MLH1 methylation (~ 1%) in blood and other normal tissues, which was confirmed by clonal bisulfite sequencing in blood. The patient had developed three clonally related gastrointestinal MLH1-methylated tumor lesions at 22, 24, and 25 years of age. The methylated region in normal tissues overlapped with that reported for other carriers of constitutional MLH1 epimutations. Low-level MLH1 methylation and reduced allelic expression were linked to the same genetic haplotype, whereas the opposite allele was lost in patient's tumors. Mutation screening of MLH1 and other hereditary cancer genes was negative. Herein, a highly sensitive MS-MCA-based approach has demonstrated its utility for the identification of low-level constitutional MLH1 epigenetic mosaicism. The eventual identification and characterization of additional cases will be critical to ascertain the cancer risks associated with constitutional MLH1 epigenetic mosaicism ; This work was funded by the Spanish Ministry of Economy and Competitiveness, which is part of Agencia Estatal de Investigación (AEI), and co-funded by FEDER funds—a way to build Europe—(grant SAF2012-33636 and SAF2015-68016-R), CIBERONC, the Spanish Association Against Cancer (080253), and the Government of Catalonia (grants 2014SGR338, 2017SGR1282, and PERIS SLT002/16/0037). ED ...

Mitochondrial metabolism and the generation of reactive oxygen species (ROS) contribute to the acquisition of DNA mutations and genomic instability in cancer. How genomic instability influences the metabolic capacity of cancer cells is nevertheless poorly understood. Here, we show that homologous recombination‐defective (HRD) cancers rely on oxidative metabolism to supply NAD+ and ATP for poly(ADP‐ribose) polymerase (PARP)‐dependent DNA repair mechanisms. Studies in breast and ovarian cancer HRD models depict a metabolic shift that includes enhanced expression of the oxidative phosphorylation (OXPHOS) pathway and its key components and a decline in the glycolytic Warburg phenotype. Hence, HRD cells are more sensitive to metformin and NAD+ concentration changes. On the other hand, shifting from an OXPHOS to a highly glycolytic metabolism interferes with the sensitivity to PARP inhibitors (PARPi) in these HRD cells. This feature is associated with a weak response to PARP inhibition in patient‐derived xenografts, emerging as a new mechanism to determine PARPi sensitivity. This study shows a mechanistic link between two major cancer hallmarks, which in turn suggests novel possibilities for specifically treating HRD cancers with OXPHOS inhibitors ; This study has been funded by the Ministerio de Ciencia, Innovación y Universidades, which is part of the Agencia Estatal de Investigación (AEI), through the project SAF2017-85869-R (cofunded by the European Regional Development Fund (ERDF), a way to build Europe) to FV and BFU2015-66030-R to JCP; by the FIS PI15/00854 and FIS PI16/01898 (Instituto Carlos III, cofunded by FEDER funds/European Regional Development Fund (ERDF), a way to build Europe) to MAP and AVillanueva and with the support of the Secretariat for Universities and Research of the Department of Business and Knowledge of the Government of Catalonia (2017SGR449) to FV. We thank the CERCA Program/Generalitat de Catalunya for their institutional support. We particularly wish to acknowledge the collaboration of ...