La chemioterapia infantile lascia danni permanenti al DNA nei tessuti sani. / Childhood Chemotherapy Leaves Lasting DNA Damage in Healthy Tissues

La chemioterapia infantile lascia danni permanenti al DNA nei tessuti sani. / Childhood Chemotherapy Leaves Lasting DNA Damage in Healthy Tissues

Segnalato dal Dott. Giuseppe Cotellessa / Reported by Dr. Giuseppe Cotellessa

Gli scienziati hanno scoperto che alcuni farmaci chemioterapici possono invecchiare le cellule sane dei bambini, causando in un breve periodo la stessa quantità di danni al DNA che normalmente si accumulerebbe in decenni negli adulti di mezza età. 

I risultati pubblicati oggi su Science rivelano l'entità del danno al DNA causato dalla chemioterapia a base di platino nei bambini trattati per il cancro, incluso un modello di danno al fegato finora sconosciuto che potrebbe contribuire a spiegare alcuni dei problemi di salute a lungo termine riscontrati nei sopravvissuti. 

"Il nostro studio rappresenta una pietra miliare nella comprensione dei danni al DNA causati dalla chemioterapia nei tessuti normali", ha affermato Anna Wenger, PhD, ricercatrice post-dottorato presso il Wellcome Sanger Institute e l'Università di Göteborg. "Abbiamo esplorato le possibili implicazioni per i bambini che si sottopongono a questo trattamento salvavita in giovane età, poiché gli effetti collaterali a lungo termine spesso si manifestano nel corso della vita."

I ricercatori sottolineano che questi risultati non dovrebbero scoraggiare l'uso della chemioterapia, che rimane essenziale per il trattamento dei tumori infantili. Al contrario, comprendere come il trattamento influisce sui tessuti sani potrebbe in futuro aiutare gli scienziati a sviluppare metodi per ridurre i rischi per la salute in età adulta. "La nostra scoperta ci permette di iniziare a pensare a come proteggere i tessuti sani dai danni al DNA", ha affermato Wenger.

La chemioterapia uccide le cellule tumorali danneggiandone il DNA durante la loro rapida divisione. Mentre le cellule sane possono sopravvivere a questo danno, il trattamento può lasciare tracce mutazionali con effetti sconosciuti sulla salute a lungo termine dei pazienti sopravvissuti. 

Per comprendere questi cambiamenti, il gruppo di Wenger ha utilizzato un metodo di sequenziamento genomico sviluppato presso il Wellcome Sanger Institute, noto come sequenziamento a nanorate (NanoSeq), che sequenzia entrambi i filamenti di DNA in modo indipendente e confronta i risultati per ottenere un'elevata risoluzione. Questa tecnica è particolarmente utile per il sequenziamento dei tumori infantili, poiché questi presentano un minor numero di mutazioni condivise con i tessuti sani, che potrebbero sfuggire ai metodi di sequenziamento di massa convenzionali. 

I ricercatori hanno analizzato 186 campioni, comprendenti un'ampia gamma di tessuti, prelevati da nove bambini affetti da tumore al fegato, dopo un trattamento chemioterapico a base di platino. Altri 77 campioni sono stati raccolti da bambini con altre forme di cancro, da bambini sottoposti a trattamenti non a base di platino o da bambini che non avevano ricevuto alcun trattamento. 

L'analisi ha rivelato un numero significativamente maggiore di alterazioni del DNA nelle cellule sane in seguito alla chemioterapia a base di platino, con alcuni bambini che presentavano livelli di danno genetico paragonabili a quelli riscontrati nei tessuti degli adulti. Alcune di queste mutazioni sono considerate fattori scatenanti del cancro, ovvero possono potenzialmente contribuire allo sviluppo della malattia, sebbene i tumori secondari successivi al trattamento del cancro infantile rimangano rari.

È importante sottolineare che i risultati hanno rivelato un modello distintivo di danno al DNA nel tessuto epatico, mai osservato prima. Tale modello non è stato riscontrato in altri tessuti e sembra essere specificamente associato alla chemioterapia a base di platino. Poiché i farmaci a base di platino vengono metabolizzati nel fegato, quest'organo potrebbe essere particolarmente esposto ai processi responsabili di questo tipo di danno al DNA.

"Le nostre scoperte hanno portato alla luce qualcosa di assolutamente senza precedenti riguardo alla chemioterapia ed al danno al DNA: lo stesso farmaco chemioterapico può causare diversi tipi di danno al DNA in tessuti differenti", ha affermato Foad J. Rouhani, MD, PhD, responsabile del gruppo presso il Francis Crick Institute e chirurgo consulente onorario per i trapianti al King's College Hospital. "Si tratta di un'osservazione fondamentale che mette in discussione la nostra ipotesi secondo cui la chemioterapia causi lo stesso danno al DNA in tutti i tessuti. Nel caso del fegato, abbiamo osservato che la chemioterapia può causare danni al DNA specifici che potrebbero plausibilmente contribuire allo sviluppo di patologie epatiche in età adulta in questi pazienti."

I risultati potrebbero in parte spiegare perché i sopravvissuti al cancro infantile si trovino spesso ad affrontare problemi di salute legati all'invecchiamento precoce. Tuttavia, saranno necessarie ulteriori ricerche per comprendere esattamente in che modo queste mutazioni influenzino la salute a lungo termine dei sopravvissuti e se i danni possano essere prevenuti o ridotti. 

"La chemioterapia è fondamentale per curare il cancro nei bambini e non ci sono alternative", ha affermato Sam Behjati, MD, PhD, primario di pediatria all'Università di Cambridge e direttore del Cambridge Children's Research Institute. "Il nostro lavoro rivela ora un plausibile meccanismo, il danno al DNA nei tessuti normali, attraverso il quale la chemioterapia in età pediatrica può causare effetti collaterali a lungo termine. Il prossimo passo sarà quello di acquisire una comprensione più approfondita di questo danno, che potrebbe consentirci di sviluppare trattamenti protettivi per ridurre i rischi per la salute a lungo termine dei bambini sopravvissuti al cancro".

ENGLISH

Scientists have found that certain chemotherapy drugs can age children’s healthy cells, causing the same amount of DNA damage in a short period that would normally accumulate over decades in middle-aged adults. 

Results published today in Science uncover the extent of DNA damage caused by platinum-based chemotherapy in children treated for cancer, including a previously unseen pattern of damage in the liver that could help explain some of the long-term health problems experienced by survivors. 

“Our study represents a milestone in revealing the DNA damage that chemotherapy causes in normal tissues,” said Anna Wenger, PhD, postdoctoral fellow at the Wellcome Sanger Institute and the University of Gothenburg. “We explored what this might mean for children who undergo this life-saving treatment at a young age, as delayed side effects from treatment often unfold over a lifetime.”

The researchers stress that these findings should not discourage the use of chemotherapy, which remains essential for treating childhood cancer. Instead, understanding how treatment affects healthy tissues could eventually help scientists develop ways to reduce health risks later in life. “Our finding enables us to begin to think about ways in which we could protect healthy tissues from DNA damage,” said Wenger.

Chemotherapy kills cancer cells by damaging their DNA as they rapidly divide. While healthy cells can survive this damage, the treatment can leave mutational signatures with unknown effects on the long-term health of survivors. 

To understand these changes, Wenger’s team used a genomic sequencing method developed at the Wellcome Sanger institute known as nanorate sequencing (NanoSeq), which sequences both strands of DNA independently and compares results to achieve high resolution. The technique is especially useful when sequencing childhood tumors, as these have fewer shared mutations with healthy tissues that can be missed by conventional bulk sequencing methods. 

The researchers analyzed 186 samples covering a wide range of tissues from nine children with liver cancer, collected after treatment with platinum-based chemotherapy. Another 77 samples were collected from children with either other forms of cancer, who had received non-platinum treatment, or who had not undergone treatment at all. 

The analysis revealed substantially more DNA changes in healthy cells following platinum-based chemotherapy, with some children showing levels of genetic damage comparable to those found in adult tissues. Some of these mutations are considered cancer drivers, meaning they can potentially contribute to the development of cancer, although secondary cancers following childhood cancer treatment remain rare.

Importantly, results unveiled a distinctive pattern of DNA damage in liver tissue that had not previously been observed. The signature was not found in other tissues and appeared to be specifically associated with platinum-based chemotherapy. Because platinum-based drugs are broken down in the liver, the organ may be particularly exposed to the processes responsible for this type of DNA damage.

“Our findings have unearthed something quite unprecedented about chemotherapy and DNA damage: The same chemotherapy drug can cause different types of DNA damage across tissues,” said Foad J. Rouhani, MD, PhD, group leader at the Francis Crick Institute and honorary consultant transplant surgeon at King’s College Hospital. “This is a fundamental observation that questions our assumption that chemotherapy causes the same DNA damage in all tissues. In the case of the liver, we have seen that chemotherapy can cause distinctive DNA damage which may plausibly be the contributor to liver disease in adult life in these patients.”

The findings may partly explain why childhood cancer survivors commonly face health issues related to premature aging. However, further research will be needed to understand exactly how these mutations affect the long-term health of survivors and whether the damage can be prevented or reduced. 

“Chemotherapy is the key to curing cancer in children, and there is no alternative,” said Sam Behjati, MD, PhD, head of pediatrics at the University of Cambridge and director of the Cambridge Children’s Research Institute. “Our work now reveals a plausible mechanism, DNA damage in normal tissues, through which chemotherapy in childhood may cause late adverse effects. The next step will be to gain a deeper understanding of this damage which may enable us to develop protective treatments to reduce long-term health risks for childhood cancer survivors.”

ENGLISH

Scientists have found that certain chemotherapy drugs can age children’s healthy cells, causing the same amount of DNA damage in a short period that would normally accumulate over decades in middle-aged adults. 

Results published today in Science uncover the extent of DNA damage caused by platinum-based chemotherapy in children treated for cancer, including a previously unseen pattern of damage in the liver that could help explain some of the long-term health problems experienced by survivors. 

“Our study represents a milestone in revealing the DNA damage that chemotherapy causes in normal tissues,” said Anna Wenger, PhD, postdoctoral fellow at the Wellcome Sanger Institute and the University of Gothenburg. “We explored what this might mean for children who undergo this life-saving treatment at a young age, as delayed side effects from treatment often unfold over a lifetime.”

The researchers stress that these findings should not discourage the use of chemotherapy, which remains essential for treating childhood cancer. Instead, understanding how treatment affects healthy tissues could eventually help scientists develop ways to reduce health risks later in life. “Our finding enables us to begin to think about ways in which we could protect healthy tissues from DNA damage,” said Wenger.

Chemotherapy kills cancer cells by damaging their DNA as they rapidly divide. While healthy cells can survive this damage, the treatment can leave mutational signatures with unknown effects on the long-term health of survivors. 

To understand these changes, Wenger’s team used a genomic sequencing method developed at the Wellcome Sanger institute known as nanorate sequencing (NanoSeq), which sequences both strands of DNA independently and compares results to achieve high resolution. The technique is especially useful when sequencing childhood tumors, as these have fewer shared mutations with healthy tissues that can be missed by conventional bulk sequencing methods. 

The researchers analyzed 186 samples covering a wide range of tissues from nine children with liver cancer, collected after treatment with platinum-based chemotherapy. Another 77 samples were collected from children with either other forms of cancer, who had received non-platinum treatment, or who had not undergone treatment at all. 

The analysis revealed substantially more DNA changes in healthy cells following platinum-based chemotherapy, with some children showing levels of genetic damage comparable to those found in adult tissues. Some of these mutations are considered cancer drivers, meaning they can potentially contribute to the development of cancer, although secondary cancers following childhood cancer treatment remain rare.

Importantly, results unveiled a distinctive pattern of DNA damage in liver tissue that had not previously been observed. The signature was not found in other tissues and appeared to be specifically associated with platinum-based chemotherapy. Because platinum-based drugs are broken down in the liver, the organ may be particularly exposed to the processes responsible for this type of DNA damage.

“Our findings have unearthed something quite unprecedented about chemotherapy and DNA damage: The same chemotherapy drug can cause different types of DNA damage across tissues,” said Foad J. Rouhani, MD, PhD, group leader at the Francis Crick Institute and honorary consultant transplant surgeon at King’s College Hospital. “This is a fundamental observation that questions our assumption that chemotherapy causes the same DNA damage in all tissues. In the case of the liver, we have seen that chemotherapy can cause distinctive DNA damage which may plausibly be the contributor to liver disease in adult life in these patients.”

The findings may partly explain why childhood cancer survivors commonly face health issues related to premature aging. However, further research will be needed to understand exactly how these mutations affect the long-term health of survivors and whether the damage can be prevented or reduced. 

“Chemotherapy is the key to curing cancer in children, and there is no alternative,” said Sam Behjati, MD, PhD, head of pediatrics at the University of Cambridge and director of the Cambridge Children’s Research Institute. “Our work now reveals a plausible mechanism, DNA damage in normal tissues, through which chemotherapy in childhood may cause late adverse effects. The next step will be to gain a deeper understanding of this damage which may enable us to develop protective treatments to reduce long-term health risks for childhood cancer survivors.”

Da:

https://www.insideprecisionmedicine.com/topics/oncology/childhood-chemotherapy-leaves-lasting-dna-damage-in-healthy-tissues/