A Novel Genetic Signature For Predicting Breast Cancer / Una nuova firma genetica per prevedere il cancro al seno
A Novel Genetic Signature For Predicting Breast Cancer / Una nuova firma genetica per prevedere il cancro al seno
Segnalato dal Dott. Giuseppe Cotellessa / Reported by Dr. Giuseppe Cotellessa
Researchers have identified a genetic signature with prognostic value for certain kinds of breast cancer. The discovery also contributes to a better understanding of the molecular mechanisms of pathological angiogenesis, the aberrant proliferation of blood vessels that occurs during cancer and other diseases.
The research combined a study of the genes involved in retinopathy, as a model of angiogenesis, with analysis of transcriptomic gene expression profiles from public breast cancer databases. Conducted by researchers at the University of São Paulo’s Chemistry Institute (IQ-USP), in collaboration with the Ontario Institute for Cancer Research (OICR) in Toronto, Canada, the study was supported by FAPESP.
“We identified a set of genes whose expression in breast cancer correlates with the degree of pathological angiogenesis in the tumor, so that it serves as a genetic signature of angiogenesis that is prognostic and more robust than the signatures identified previously, given the correlation found between angiogenesis and tumors generally,” said Ricardo Giordano, a professor at IQ-USP, head of its Vascular Biology Laboratory and a co-author of the study.
In the study, the researchers identified 153 altered genes in both healthy and diseased retinas in mice. From this list they identified 149 equivalent human genes. The result served as the basis for a genetic signature study in partnership with the Canadian team, using a database with information on breast cancer patients. The conclusion was that 11 key genes involved in pathological angiogenesis performed best in terms of prognostic value.
Pathological angiogenesis is common to breast cancer and retinopathy. “The fact that these two diseases share this process and that angiogenesis is fundamental to the development of cancer in general led us to try to build a bridge between retinopathy and breast cancer,” said João Carlos Setubal, head of USP’s Bioinformatics Laboratory and also a co-author of the article.
According to the researchers, the study focused on breast cancer because of the large amount of data available on the disease. “We had to have access to a vast quantity of public data, given the considerable variation between one patient and another. This is the case for breast cancer. Genetic profiles are available for some 2,000 patients,” Setubal said.
Bioinformatics was crucial to finding the genetic signature, he added. The data generated in the laboratory was submitted to sophisticated computational processing in partnership with researchers at OICR in Canada. Another co-author of the study, Rodrigo Guarischi de Sousa, then a PhD student, wrote the program that tested the 149 human genes as possible components of the signature for breast cancer. In this part of the study he was supported by a scholarship from FAPESP for a research internship abroad supervised by Paul C. Boutros at OICR.
The researchers plan to find applications for this signature, especially in treatment for breast cancer. “Our next goal is to continue studying angiogenesis in cancer,” Giordano said. “We’re interested in identifying genes on this list that can be targets for the development of new drugs or new applications of existing drugs.”
From retinopathy to breast cancer
The discovery of the prognostic gene signature for breast cancer is the result of a long study supported by a research scholarship from the National Council for Scientific and Technological Development (CNPq) starting in 2010, when Giordano began studying the transcriptome (RNA expression) and proteome (protein expression) of pathological retinal angiogenesis.
“As a result of this study, our lab implemented a mouse model to research retinopathy. The murine model is important as it’s difficult to study blood vessel formation outside living tissue. This model enables us to induce retinopathy by modulating oxygen levels and study angiogenesis in the lab,” Giordano said.
The researchers took blood samples from mice to investigate the differences between physiological angiogenesis, which occurs in healthy individuals (in wound healing, ovulation and placental growth, for example) and pathological angiogenesis, which is part of disease (e.g. cancer or arthritis).
“We observed which genes were expressed by endothelial cells [the inner lining of blood vessels] in both kinds of angiogenesis, always looking for the genes that were more expressed in one kind than the other,” Giordano said.
A key element of the experiment was oxygen variation in the chambers containing newborn mouse pups. In chambers with oxygen at 75%, the mice became retinopathic, whereas in ambient air (oxygen at 20%) the retina developed normally.
The relationship between oxygen and cells has been in the news lately. William Kaelin, Peter Ratcliffe and Gregg Semenza won the 2019 Nobel Prize in Physiology or Medicine for discovering how cells sense and adapt to changing oxygen availability.
Gene expression-based prognostic signature
It is important to stress that clinical applications of the genetic signature for angiogenesis may differ from applications deriving from the marker gene BRCA1. The BRCA1 gene mutation became world-famous in 2013 when US actor Angelina Jolie underwent a preventive double mastectomy after genetic testing showed that she carried the mutation and hence ran an 87% risk of developing breast cancer.
“BRCA1 is a genomic gene,” Setubal said. “A woman with mutations in this gene faces a higher risk of developing breast cancer but won’t necessarily do so. The presence of mutations in this gene serves to help predict the appearance of the disease. The signature we describe in our study proved promising to predict the development of breast cancer after it actually appears.”
The research combined a study of the genes involved in retinopathy, as a model of angiogenesis, with analysis of transcriptomic gene expression profiles from public breast cancer databases. Conducted by researchers at the University of São Paulo’s Chemistry Institute (IQ-USP), in collaboration with the Ontario Institute for Cancer Research (OICR) in Toronto, Canada, the study was supported by FAPESP.
“We identified a set of genes whose expression in breast cancer correlates with the degree of pathological angiogenesis in the tumor, so that it serves as a genetic signature of angiogenesis that is prognostic and more robust than the signatures identified previously, given the correlation found between angiogenesis and tumors generally,” said Ricardo Giordano, a professor at IQ-USP, head of its Vascular Biology Laboratory and a co-author of the study.
In the study, the researchers identified 153 altered genes in both healthy and diseased retinas in mice. From this list they identified 149 equivalent human genes. The result served as the basis for a genetic signature study in partnership with the Canadian team, using a database with information on breast cancer patients. The conclusion was that 11 key genes involved in pathological angiogenesis performed best in terms of prognostic value.
Pathological angiogenesis is common to breast cancer and retinopathy. “The fact that these two diseases share this process and that angiogenesis is fundamental to the development of cancer in general led us to try to build a bridge between retinopathy and breast cancer,” said João Carlos Setubal, head of USP’s Bioinformatics Laboratory and also a co-author of the article.
According to the researchers, the study focused on breast cancer because of the large amount of data available on the disease. “We had to have access to a vast quantity of public data, given the considerable variation between one patient and another. This is the case for breast cancer. Genetic profiles are available for some 2,000 patients,” Setubal said.
Bioinformatics was crucial to finding the genetic signature, he added. The data generated in the laboratory was submitted to sophisticated computational processing in partnership with researchers at OICR in Canada. Another co-author of the study, Rodrigo Guarischi de Sousa, then a PhD student, wrote the program that tested the 149 human genes as possible components of the signature for breast cancer. In this part of the study he was supported by a scholarship from FAPESP for a research internship abroad supervised by Paul C. Boutros at OICR.
The researchers plan to find applications for this signature, especially in treatment for breast cancer. “Our next goal is to continue studying angiogenesis in cancer,” Giordano said. “We’re interested in identifying genes on this list that can be targets for the development of new drugs or new applications of existing drugs.”
From retinopathy to breast cancer
The discovery of the prognostic gene signature for breast cancer is the result of a long study supported by a research scholarship from the National Council for Scientific and Technological Development (CNPq) starting in 2010, when Giordano began studying the transcriptome (RNA expression) and proteome (protein expression) of pathological retinal angiogenesis.
“As a result of this study, our lab implemented a mouse model to research retinopathy. The murine model is important as it’s difficult to study blood vessel formation outside living tissue. This model enables us to induce retinopathy by modulating oxygen levels and study angiogenesis in the lab,” Giordano said.
The researchers took blood samples from mice to investigate the differences between physiological angiogenesis, which occurs in healthy individuals (in wound healing, ovulation and placental growth, for example) and pathological angiogenesis, which is part of disease (e.g. cancer or arthritis).
“We observed which genes were expressed by endothelial cells [the inner lining of blood vessels] in both kinds of angiogenesis, always looking for the genes that were more expressed in one kind than the other,” Giordano said.
A key element of the experiment was oxygen variation in the chambers containing newborn mouse pups. In chambers with oxygen at 75%, the mice became retinopathic, whereas in ambient air (oxygen at 20%) the retina developed normally.
The relationship between oxygen and cells has been in the news lately. William Kaelin, Peter Ratcliffe and Gregg Semenza won the 2019 Nobel Prize in Physiology or Medicine for discovering how cells sense and adapt to changing oxygen availability.
Gene expression-based prognostic signature
It is important to stress that clinical applications of the genetic signature for angiogenesis may differ from applications deriving from the marker gene BRCA1. The BRCA1 gene mutation became world-famous in 2013 when US actor Angelina Jolie underwent a preventive double mastectomy after genetic testing showed that she carried the mutation and hence ran an 87% risk of developing breast cancer.
“BRCA1 is a genomic gene,” Setubal said. “A woman with mutations in this gene faces a higher risk of developing breast cancer but won’t necessarily do so. The presence of mutations in this gene serves to help predict the appearance of the disease. The signature we describe in our study proved promising to predict the development of breast cancer after it actually appears.”
ITALIANO
I ricercatori hanno identificato una firma genetica con valore prognostico per alcuni tipi di carcinoma mammario. La scoperta contribuisce anche a una migliore comprensione dei meccanismi molecolari dell'angiogenesi patologica, la proliferazione aberrante dei vasi sanguigni che si verifica durante il cancro e altre malattie.
La ricerca ha combinato uno studio sui geni coinvolti nella retinopatia, come modello di angiogenesi, con l'analisi dei profili di espressione genica trascrittomica dai database pubblici sul carcinoma mammario. Condotto da ricercatori del Chemistry Institute (IQ-USP) dell'Università di San Paolo, in collaborazione con l'Ontario Institute for Cancer Research (OICR) di Toronto, in Canada, lo studio è stato sostenuto da FAPESP.
"Abbiamo identificato un insieme di geni la cui espressione nel carcinoma mammario è correlata al grado di angiogenesi patologica nel tumore, in modo che funga da firma genetica dell'angiogenesi che è prognostica e più robusta delle firme identificate in precedenza, data la correlazione trovata tra angiogenesi e tumori in generale ”, ha affermato Ricardo Giordano, professore presso il QI-USP, capo del suo laboratorio di biologia vascolare e coautore dello studio.
Nello studio, i ricercatori hanno identificato 153 geni alterati in retine sia sane che malate nei topi. Da questo elenco hanno identificato 149 geni umani equivalenti. Il risultato è servito come base per uno studio di firma genetica in collaborazione con il gruppo canadese, utilizzando un database con informazioni sui pazienti con carcinoma mammario. La conclusione è stata che 11 geni chiave coinvolti nell'angiogenesi patologica si sono comportati meglio in termini di valore prognostico.
L'angiogenesi patologica è comune al carcinoma mammario e alla retinopatia. "Il fatto che queste due malattie condividano questo processo e che l'angiogenesi sia fondamentale per lo sviluppo del cancro in generale ci ha portato a cercare di costruire un ponte tra retinopatia e carcinoma mammario", ha dichiarato João Carlos Setubal, capo del laboratorio di bioinformatica dell'USP e anche un coautore dell'articolo.
Secondo i ricercatori, lo studio si è concentrato sul cancro al seno a causa della grande quantità di dati disponibili sulla malattia. “Abbiamo dovuto avere accesso a una grande quantità di dati pubblici, data la notevole variazione tra un paziente e l'altro. Questo è il caso del cancro al seno. I profili genetici sono disponibili per circa 2.000 pazienti ", ha detto Setubal.
La bioinformatica è stata fondamentale per trovare la firma genetica, ha aggiunto. I dati generati in laboratorio sono stati sottoposti a sofisticate elaborazioni computazionali in collaborazione con ricercatori dell'OICR in Canada. Un altro coautore dello studio, Rodrigo Guarischi de Sousa, allora studente di dottorato, ha scritto il programma che ha testato i 149 geni umani come possibili componenti della firma per il cancro al seno. In questa parte dello studio è stato supportato da una borsa di studio della FAPESP per uno stage di ricerca all'estero supervisionato da Paul C. Boutros all'OICR.
I ricercatori hanno in programma di trovare applicazioni per questa firma, in particolare nel trattamento del cancro al seno. "Il nostro prossimo obiettivo è continuare a studiare l'angiogenesi nel cancro", ha detto Giordano. "Siamo interessati a identificare i geni in questo elenco che possono essere obiettivi per lo sviluppo di nuovi farmaci o nuove applicazioni di farmaci esistenti".
Dalla retinopatia al cancro al seno
La scoperta della firma del gene prognostico per il carcinoma mammario è il risultato di un lungo studio supportato da una borsa di studio del Consiglio nazionale per lo sviluppo scientifico e tecnologico (CNPq) a partire dal 2010, quando Giordano iniziò a studiare il trascrittoma (espressione di RNA) e il proteoma (espressione proteica) dell'angiogenesi retinica patologica.
“Come risultato di questo studio, il nostro laboratorio ha implementato un modello murino per ricercare la retinopatia. Il modello murino è importante in quanto è difficile studiare la formazione di vasi sanguigni al di fuori dei tessuti viventi. Questo modello ci consente di indurre la retinopatia modulando i livelli di ossigeno e studiando l'angiogenesi in laboratorio ", ha detto Giordano.
I ricercatori hanno prelevato campioni di sangue dai topi per studiare le differenze tra angiogenesi fisiologica, che si verifica in soggetti sani (ad esempio nella guarigione delle ferite, nell'ovulazione e nella crescita placentare) e nell'angiogenesi patologica, che fa parte della malattia (ad es. Cancro o artrite).
"Abbiamo osservato quali geni erano espressi dalle cellule endoteliali [il rivestimento interno dei vasi sanguigni] in entrambi i tipi di angiogenesi, cercando sempre i geni che erano più espressi in un tipo rispetto all'altro", ha detto Giordano.
Un elemento chiave dell'esperimento è stata la variazione di ossigeno nelle camere contenenti cuccioli di topo neonati. Nelle camere con ossigeno al 75%, i topi sono diventati retinopatici, mentre nell'aria ambiente (ossigeno al 20%) la retina si è sviluppata normalmente.
La relazione tra ossigeno e cellule è stata recentemente nelle notizie. William Kaelin, Peter Ratcliffe e Gregg Semenza hanno vinto il premio Nobel 2019 in fisiologia o medicina per scoprire come le cellule percepiscono e si adattano al cambiamento della disponibilità di ossigeno.
Firma prognostica basata sull'espressione genica
È importante sottolineare che le applicazioni cliniche della firma genetica per l'angiogenesi possono differire dalle applicazioni derivanti dal gene marcatore BRCA1. La mutazione del gene BRCA1 è diventata famosa nel mondo nel 2013, quando l'attore statunitense Angelina Jolie è stata sottoposta a una doppia mastectomia preventiva dopo che i test genetici hanno dimostrato che era portatrice della mutazione e quindi correva un rischio dell'87% di sviluppare il cancro al seno.
"BRCA1 è un gene genomico", ha detto Setubal. "Una donna con mutazioni di questo gene si trova ad affrontare un rischio più elevato di sviluppare il cancro al seno, ma non lo farà necessariamente. La presenza di mutazioni in questo gene serve per aiutare a prevedere la comparsa della malattia. La firma che descriviamo nel nostro studio si è rivelata promettente per prevedere lo sviluppo del carcinoma mammario dopo la sua effettiva comparsa. "
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