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Article ; Online: hacksig: a unified and tidy R framework to easily compute gene expression signature scores.

Carenzo, Andrea / Pistore, Federico / Serafini, Mara S / Lenoci, Deborah / Licata, Armando G / De Cecco, Loris

2022 Volume 38, Issue 10, Page(s) 2940–2942

Abstract: Summary: Hundreds of gene expression signatures have been developed during the last two decades. However, due to the multitude of development procedures and sometimes a lack of explanation for their implementation, it can become challenging to apply the ...

Abstract	Summary: Hundreds of gene expression signatures have been developed during the last two decades. However, due to the multitude of development procedures and sometimes a lack of explanation for their implementation, it can become challenging to apply the original method on custom data. Moreover, at present, there is no unified and tidy interface to compute signature scores with different single sample enrichment methods. For these reasons, we developed hacksig, an R package intended as a unified framework to obtain single sample scores with a tidy output as well as a collection of manually curated gene signatures and methods from cancer transcriptomics literature. Availability and implementation: The hacksig R package is freely available on CRAN (https://CRAN.R-project.org/package=hacksig) under the MIT license. The source code can be found on GitHub at https://github.com/Acare/hacksig. Supplementary information: Supplementary data are available at Bioinformatics online.
MeSH term(s)	Humans ; Neoplasms/genetics ; Software ; Transcriptome
Language	English
Publishing date	2022-05-12
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1422668-6
ISSN	1367-4811 ; 1367-4803
ISSN (online)	1367-4811
ISSN	1367-4803
DOI	10.1093/bioinformatics/btac161
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Article ; Online: A pilot exome sequencing study suggests that germline variants influence methotrexate-induced toxicities in pediatric patients with localized osteosarcoma.

Minnai, Francesca / Noci, Sara / Mangano, Nunzia / De Cecco, Loris / Meazza, Cristina / Terenziani, Monica / Massimino, Maura / Colombo, Francesca

Pediatric blood & cancer

2023 , Page(s) e30501

Abstract: Introduction: Osteosarcoma (OS) is a rare pediatric cancer for which therapeutic approaches, including chemotherapy and surgery, show a wide interindividual variability in patient response, both in terms of adverse events and therapy efficacy. There is ... ...

Abstract	Introduction: Osteosarcoma (OS) is a rare pediatric cancer for which therapeutic approaches, including chemotherapy and surgery, show a wide interindividual variability in patient response, both in terms of adverse events and therapy efficacy. There is growing evidence that this individual variable response to therapies is also influenced by inherited genetic variations. However, the results obtained to date in these pediatric cancers have been contradictory and often lack validation in independent series. Additionally, these studies frequently focused only on a limited number of polymorphisms in candidate genes. Methods: In order to identify germline coding variations associated with individual differences in adverse events occurrence in pediatric patients affected by localized OS, we carried out an exome-wide association study in 24 OS patients treated with methotrexate, cisplatin, and doxorubicin, using the SNP-Set (Sequence) Kernel Association Test (SKAT), optimized for small sample size. Results: Gene sets significantly associated (FDR < .05) with neutropenia and hepatotoxicity induced by methotrexate were identified. Some of the identified genes map in loci previously associated with similar phenotypes (e.g., leukocyte count, alkaline phosphatase levels). Conclusion: Further studies in larger series and with functional characterization of the identified associations are needed; nonetheless, this pilot study prompts the relevance of broadly investigating variants along the whole genome, to identify new potential pharmacogenes, beyond drug metabolism, transport, and receptor candidate genes.
Language	English
Publishing date	2023-06-20
Publishing country	United States
Document type	Journal Article
ZDB-ID	2131448-2
ISSN	1545-5017 ; 1545-5009
ISSN (online)	1545-5017
ISSN	1545-5009
DOI	10.1002/pbc.30501
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Article ; Online: SAA1-dependent reprogramming of adipocytes by tumor cells is associated with triple negative breast cancer aggressiveness.

Rybinska, Ilona / Mangano, Nunzia / Romero-Cordoba, Sandra L / Regondi, Viola / Ciravolo, Valentina / De Cecco, Loris / Maffioli, Elisa / Paolini, Biagio / Bianchi, Francesca / Sfondrini, Lucia / Tedeschi, Gabriella / Agresti, Roberto / Tagliabue, Elda / Triulzi, Tiziana

International journal of cancer

2024 Volume 154, Issue 10, Page(s) 1842–1856

Abstract: Triple negative breast cancers (TNBC) are characterized by a poor prognosis and a lack of targeted treatments. Their progression depends on tumor cell intrinsic factors, the tumor microenvironment and host characteristics. Although adipocytes, the ... ...

Abstract	Triple negative breast cancers (TNBC) are characterized by a poor prognosis and a lack of targeted treatments. Their progression depends on tumor cell intrinsic factors, the tumor microenvironment and host characteristics. Although adipocytes, the primary stromal cells of the breast, have been determined to be plastic in physiology and cancer, the tumor-derived molecular mediators of tumor-adipocyte crosstalk have not been identified yet. In this study, we report that the crosstalk between TNBC cells and adipocytes in vitro beyond adipocyte dedifferentiation, induces a unique transcriptional profile that is characterized by inflammation and pathways that are related to interaction with the tumor microenvironment. Accordingly, increased cancer stem-like features and recruitment of pro-tumorigenic immune cells are induced by this crosstalk through CXCL5 and IL-8 production. We identified serum amyloid A1 (SAA1) as a regulator of the adipocyte reprogramming through CD36 and P2XR7 signaling. In human TNBC, SAA1 expression was associated with cancer-associated adipocyte infiltration, inflammation, stimulated lipolysis, stem-like properties, and a distinct tumor immune microenvironment. Our findings constitute evidence that the interaction between tumor cells and adipocytes through the release of SAA1 is relevant to the aggressiveness of TNBC.
MeSH term(s)	Humans ; Triple Negative Breast Neoplasms/pathology ; Signal Transduction ; Stromal Cells/pathology ; Adipocytes/metabolism ; Inflammation/pathology ; Tumor Microenvironment ; Serum Amyloid A Protein/metabolism
Chemical Substances	SAA1 protein, human ; Serum Amyloid A Protein
Language	English
Publishing date	2024-01-30
Publishing country	United States
Document type	Journal Article
ZDB-ID	218257-9
ISSN	1097-0215 ; 0020-7136
ISSN (online)	1097-0215
ISSN	0020-7136
DOI	10.1002/ijc.34859
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Zs.A 478: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article: Prognostic Evidence of the miRNA-Based Ovarian Cancer Signature MiROvaR in Independent Datasets.

De Cecco, Loris / Bagnoli, Marina / Chiodini, Paolo / Pignata, Sandro / Mezzanzanica, Delia

Cancers

2021 Volume 13, Issue 7

Abstract: Epithelial ovarian cancer (EOC) remains the second most common cause of gynecological cancer deaths. To improve patients' outcomes, we still need reliable biomarkers of early relapse, of which external independent validation is a crucial process. Our ... ...

Abstract	Epithelial ovarian cancer (EOC) remains the second most common cause of gynecological cancer deaths. To improve patients' outcomes, we still need reliable biomarkers of early relapse, of which external independent validation is a crucial process. Our previously established prognostic signature, MiROvaR, including 35 microRNAs (miRNA) able to stratify EOC patients for their risk of relapse, was challenged on a new independent cohort of 197 EOC patients included in the Pelvic Mass Study whose miRNA profile was made publically available, thus resulting in the only accessible database aside from the EOC TCGA collection. Following accurate data matrix adjustment to account for the use of different miRNA platforms, MiROvaR confirmed its ability to discriminate early relapsing patients. The model's original cutoff separated 156 (79.2%) high- and 41 (20.8%) low-risk patients with median progression free survival (PFS) of 16.3 months and not yet reached (NYR), respectively (hazard ratio (HR): 2.42-95% Confidence Interval (CI) 1.49-3.93; Log-rank
Language	English
Publishing date	2021-03-27
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers13071544
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Article: Medullary Thyroid Carcinoma Mutational Spectrum Update and Signaling-Type Inference by Transcriptional Profiles: Literature Meta-Analysis and Study of Tumor Samples.

Minna, Emanuela / Romeo, Paola / Dugo, Matteo / De Cecco, Loris / Aiello, Antonella / Pistore, Federico / Carenzo, Andrea / Greco, Angela / Borrello, Maria Grazia

Cancers

2022 Volume 14, Issue 8

Abstract: Medullary thyroid carcinoma (MTC) is a rare but aggressive tumor. ... ...

Abstract	Medullary thyroid carcinoma (MTC) is a rare but aggressive tumor. Although
Language	English
Publishing date	2022-04-13
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers14081951
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Article ; Online: A gene expression-based classifier for HER2-low breast cancer.

Di Cosimo, Serena / Pizzamiglio, Sara / Ciniselli, Chiara Maura / Duroni, Valeria / Cappelletti, Vera / De Cecco, Loris / De Marco, Cinzia / Silvestri, Marco / De Santis, Maria Carmen / Vingiani, Andrea / Paolini, Biagio / Orlandi, Rosaria / Iorio, Marilena Valeria / Pruneri, Giancarlo / Verderio, Paolo

Scientific reports

2024 Volume 14, Issue 1, Page(s) 2628

Abstract: In clinical trials evaluating antibody-conjugated drugs (ADCs), HER2-low breast cancer is defined through protein immunohistochemistry scoring (IHC) 1+ or 2+ without gene amplification. However, in daily practice, the accuracy of IHC is compromised by ... ...

Abstract	In clinical trials evaluating antibody-conjugated drugs (ADCs), HER2-low breast cancer is defined through protein immunohistochemistry scoring (IHC) 1+ or 2+ without gene amplification. However, in daily practice, the accuracy of IHC is compromised by inter-observer variability. Herein, we aimed to identify HER2-low breast cancer primary tumors by leveraging gene expression profiling. A discovery approach was applied to gene expression profile of institutional INT1 (n = 125) and INT2 (n = 84) datasets. We identified differentially expressed genes (DEGs) in each specific HER2 IHC category 0, 1+, 2+ and 3+. Principal Component Analysis was used to generate a HER2-low signature whose performance was evaluated in the independent INT3 (n = 95), and in the publicly available TCGA and GSE81538 datasets. The association between the HER2-low signature and HER2 IHC categories was evaluated by Kruskal-Wallis test with post hoc pair-wise comparisons. The HER2-low signature discriminatory capability was assessed by estimating the area under the receiver operating characteristic curve (AUC). Gene Ontology and KEGG analyses were performed to evaluate the HER2-low signature genes functional enrichment. A HER2-low signature was computed based on HER2 IHC category-specific DEGs. The twenty genes included in the signature were significantly enriched with lipid and steroid metabolism pathways, peptidase regulation, and humoral immune response. The HER2-low signature values showed a bell-shaped distribution across IHC categories (low values in 0 and 3+; high values in 1+ and 2+), effectively distinguishing HER2-low from 0 (p < 0.001) to 3+ (p < 0.001). Notably, the signature values were higher in tumors scored with 1+ as compared to 0. The HER2-low signature association with IHC categories and its bell-shaped distribution was confirmed in the independent INT3, TCGA and GSE81538 datasets. In the combined INT1 and INT3 datasets, the HER2-low signature achieved an AUC value of 0.74 (95% confidence interval, CI 0.67-0.81) in distinguishing HER2-low vs. the other categories, outperforming the individual ERBB2 mRNA AUC value of 0.52 (95% CI 0.43-0.60). These results represent a proof-of-concept for an observer-independent gene-expression-based classifier of HER2-low status. The herein identified 20-gene signature shows promise in distinguishing between HER2 0 and HER2-low expressing tumors, including those scored as 1+ at IHC, and in developing a selection approach for ADCs candidates.
MeSH term(s)	Humans ; Female ; Breast Neoplasms/genetics ; Receptor, ErbB-2/metabolism ; Genes, erbB-2 ; Immunohistochemistry ; Gene Expression ; Biomarkers, Tumor/genetics ; Biomarkers, Tumor/metabolism
Chemical Substances	Receptor, ErbB-2 (EC 2.7.10.1) ; Biomarkers, Tumor
Language	English
Publishing date	2024-02-01
Publishing country	England
Document type	Journal Article
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-024-52148-7
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Article ; Online: Multistep tumor genetic evolution and changes in immunogenicity trigger immune-mediated disease eradication in stage IV melanoma: lessons from a single case.

Vallacchi, Viviana / Vergani, Elisabetta / Cossa, Mara / Gargiuli, Chiara / Busico, Adele / Devecchi, Andrea / Dugo, Matteo / Bergamaschi, Laura / De Cecco, Loris / Cavalieri, Stefano / Valeri, Barbara / Tamborini, Elena / Gallino, Gianfrancesco / Del Vecchio, Michele / Santinami, Mario / Sensi, Marialuisa / Rivoltini, Licia / Di Guardo, Lorenza / Rodolfo, Monica

Journal for immunotherapy of cancer

2024 Volume 12, Issue 1

Abstract: Durable remissions are observed in 10%-20% of treated patients with advanced metastatic melanoma but the factors associated with long-term complete clinical responses are largely unknown. Here, we report the molecular characteristics of tumor evolution ... ...

Abstract	Durable remissions are observed in 10%-20% of treated patients with advanced metastatic melanoma but the factors associated with long-term complete clinical responses are largely unknown. Here, we report the molecular characteristics of tumor evolution during disease progression along a 9-year clinical course in a patient with advanced disseminated melanoma who received different treatments, including trametinib, ipilimumab, radiation, vemurafenib, surgical tumor debulking and a second ipilimumab course, ultimately achieving complete long-term disease remission.Longitudinal analyses of therapies-resistant metastatic tumors revealed the effects of different treatments on tumor's microenvironment and immunogenicity, ultimately creating a milieu favorable to immunotherapy response. Monitoring of the temporal dynamics of T cells by analysis of the T cell receptor (TCR) repertoire in the tumor and peripheral blood during disease evolution indicated that T-cell clones with common TCR rearrangements, present at low levels at baseline, were maintained and expanded after immunotherapy, and that TCR diversity increased. Analysis of genetic, molecular, and cellular components of the tumor depicted a multistep process in which treatment with kinase inhibitors strongly conditioned the immune microenvironment creating an inflamed milieu converting cold into hot tumors, while ipilimumab impacted and increased the TCR repertoire, a requirement for tumor rejection.Since the optimal sequencing of treatment with antibodies targeting immune checkpoints and kinase inhibitors for advanced melanoma is still clinically debated, this case indicates that immunotherapy success is possible even after progression on targeted therapy.
MeSH term(s)	Humans ; Melanoma/drug therapy ; Melanoma/genetics ; Melanoma/pathology ; Ipilimumab/therapeutic use ; Vemurafenib ; T-Lymphocytes/pathology ; Receptors, Antigen, T-Cell/therapeutic use ; Tumor Microenvironment
Chemical Substances	Ipilimumab ; Vemurafenib (207SMY3FQT) ; Receptors, Antigen, T-Cell
Language	English
Publishing date	2024-01-04
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2719863-7
ISSN	2051-1426 ; 2051-1426
ISSN (online)	2051-1426
ISSN	2051-1426
DOI	10.1136/jitc-2023-007612
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Article: Genomic and transcriptomic analyses of thyroid cancers identify DICER1 somatic mutations in adult follicular-patterned RAS-like tumors.

Minna, Emanuela / Devecchi, Andrea / Pistore, Federico / Paolini, Biagio / Mauro, Giuseppe / Penso, Donata Alda / Pagliardini, Sonia / Busico, Adele / Pruneri, Giancarlo / De Cecco, Loris / Borrello, Maria Grazia / Sensi, Marialuisa / Greco, Angela

Frontiers in endocrinology

2023 Volume 14, Page(s) 1267499

Abstract: Background: Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer (TC). Several genomic and transcriptomic studies explored the molecular landscape of follicular cell-derived TCs, and : Methods: Here, we report the molecular ... ...

Abstract	Background: Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer (TC). Several genomic and transcriptomic studies explored the molecular landscape of follicular cell-derived TCs, and Methods: Here, we report the molecular characterization of 30 retrospective follicular cell-derived thyroid tumors, comprising PTCs (90%) and poorly differentiated TCs (10%), collected at our Institute. We performed DNA whole-exome sequencing using patient-matched control for somatic mutation calling, and targeted RNA-seq for gene fusion detection. Transcriptional profiles established in the same cohort by microarray were investigated using three signaling-related gene signatures derived from The Cancer Genome Atlas (TCGA). Results: The occurrence of Conclusion: Even though small, our series recapitulates the genetic background of PTC. Furthermore, we identified
MeSH term(s)	Humans ; Adult ; Transcriptome ; Retrospective Studies ; Protein-Tyrosine Kinases ; Proto-Oncogene Proteins/genetics ; Thyroid Neoplasms/genetics ; Thyroid Neoplasms/pathology ; Thyroid Cancer, Papillary/genetics ; Thyroid Cancer, Papillary/pathology ; Mutation ; Genomics ; Ribonuclease III/genetics ; DEAD-box RNA Helicases/genetics
Chemical Substances	Protein-Tyrosine Kinases (EC 2.7.10.1) ; Proto-Oncogene Proteins ; DICER1 protein, human (EC 3.1.26.3) ; Ribonuclease III (EC 3.1.26.3) ; DEAD-box RNA Helicases (EC 3.6.4.13)
Language	English
Publishing date	2023-10-05
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2592084-4
ISSN	1664-2392
ISSN	1664-2392
DOI	10.3389/fendo.2023.1267499
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Article ; Online: JMJD6 Shapes a Pro-tumor Microenvironment via ANXA1-Dependent Macrophage Polarization in Breast Cancer.

Cioni, Bianca / Ratti, Silvia / Piva, Annamaria / Tripodi, Irene / Milani, Matteo / Menichetti, Francesca / Langella, Tiziana / Botti, Laura / De Cecco, Loris / Chiodoni, Claudia / Lecis, Daniele / Colombo, Mario P

Molecular cancer research : MCR

2023 Volume 21, Issue 6, Page(s) 614–627

Abstract: Breast cancer is the most common type of cancer in women worldwide, with the luminal subtype being the most widespread. Although characterized by better prognosis compared with other subtypes, luminal breast cancer is still considered a threatening ... ...

Abstract	Breast cancer is the most common type of cancer in women worldwide, with the luminal subtype being the most widespread. Although characterized by better prognosis compared with other subtypes, luminal breast cancer is still considered a threatening disease due to therapy resistance, which occurs via both cell- and non-cell-autonomous mechanisms. Jumonji domain-containing 6, arginine demethylase and lysine hydroxylase (JMJD6) is endowed with a negative prognostic value in luminal breast cancer and, via its epigenetic activity, it is known to regulate many intrinsic cancer cell pathways. So far, the effect of JMJD6 in molding the surrounding microenvironment has not been explored.Here, we describe a novel function of JMJD6 showing that its genetic inhibition in breast cancer cells suppresses lipid droplet formation and ANXA1 expression, via estrogen receptor alpha and PPARα modulation. Reduction of intracellular ANXA1 results in decreased release in the tumor microenvironment (TME), ultimately preventing M2-type macrophage polarization and tumor aggressiveness. Implications: Our findings identify JMJD6 as a determinant of breast cancer aggressiveness and provide the rationale for the development of inhibitory molecules to reduce disease progression also through the remodeling of TME composition.
MeSH term(s)	Humans ; Female ; Breast Neoplasms/pathology ; Tumor Microenvironment ; Jumonji Domain-Containing Histone Demethylases/genetics ; Macrophages/pathology
Chemical Substances	Jumonji Domain-Containing Histone Demethylases (EC 1.14.11.-) ; JMJD6 protein, human (EC 1.14.11.-)
Language	English
Publishing date	2023-03-28
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2098788-2
ISSN	1557-3125 ; 1541-7786
ISSN (online)	1557-3125
ISSN	1541-7786
DOI	10.1158/1541-7786.MCR-22-0370
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Article ; Online: Peritoneal fluid COVID-19 testing in patients with a negative nasopharyngeal swab: prospective study.

Licata, Armando G / Ciniselli, Chiara M / Sorrentino, Luca / Micali, Arianna / Daidone, Maria Grazia / Guaglio, Marcello / Gariboldi, Manuela / Verderio, Paolo / De Cecco, Loris / Cosimelli, Maurizio

The British journal of surgery

2023 Volume 110, Issue 4, Page(s) 504–505

MeSH term(s)	Humans ; COVID-19 Testing ; COVID-19/diagnosis ; Prospective Studies ; Ascitic Fluid ; Nasopharynx ; Specimen Handling
Language	English
Publishing date	2023-02-01
Publishing country	England
Document type	Journal Article
ZDB-ID	2985-3
ISSN	1365-2168 ; 0263-1202 ; 0007-1323 ; 1355-7688
ISSN (online)	1365-2168
ISSN	0263-1202 ; 0007-1323 ; 1355-7688
DOI	10.1093/bjs/znad019
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