Nearly half\u00a0of childhood\u00a0tumors\u00a0treated with common\u00a0types of\u00a0chemotherapy\u00a0showed detectable\u00a0DNA changes linked to\u00a0treatment within\u00a018 months, according to a\u00a0new\u00a0international\u00a0study led by The Hospital for Sick Children (SickKids).\u00a0Researchers say these changes could eventually help clinicians spot\u00a0treatment\u00a0resistance\u00a0earlier,\u00a0before cancer returns or spreads, opening the door to a more precise\u00a0use of chemotherapy.\u00a0<\/p>\n
Published in\u00a0Nature, researchers\u00a0analyzed\u00a0more than\u00a0600\u00a0tumors\u00a0from 544 patients in Canada,\u00a0Australia\u00a0and the United States.\u00a0By\u00a0combining whole\u00a0genome\u00a0sequencing\u00a0with detailed\u00a0medical records\u00a0and\u00a0advanced\u00a0computational methods\u00a0developed\u00a0at SickKids,\u00a0the team found\u00a0distinct\u00a0genomic\u00a0signatures\u00a0of DNA changes left behind by different chemotherapies.\u00a0Some of\u00a0these patterns\u00a0appeared\u00a0as early as\u00a091\u00a0days\u00a0after\u00a0treatment\u00a0began.\u00a0<\/p>\n
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There’s a long-standing belief that\u00a0paediatric\u00a0cancers are genetically quiet because they haven’t had much time to\u00a0mutate. Instead,\u00a0it was\u00a0mind-blowing\u00a0to see\u00a0how many mutations\u00a0found\u00a0in tumors that\u00a0had\u00a0relapsed\u00a0or spread were\u00a0linked to\u00a0the\u00a0chemotherapy used to treat\u00a0the cancer\u00a0in the first place.”\u00a0<\/p>\n
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Dr. Adam Shlien, Lead Author, Senior Scientist, Genetics & Genome Biology and Lab Director in Genome Diagnostics at SickKids<\/p>\n
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Among the most striking findings was the impact of platinum-based chemotherapy,\u00a0which\u00a0is administered to\u00a0nearly half\u00a0of all treated cancer patients.\u00a0Within\u00a018 months\u00a0of treatment,\u00a048 per cent of\u00a0tumors\u00a0had a detectable platinum-related\u00a0“signature”\u00a0on surviving cancer cells.\u00a0<\/p>\n
Can we\u00a0reduce the risk\u00a0of late effects?\u00a0<\/p>\n
Over the past 50 years,\u00a0outcomes in\u00a0childhood cancer\u00a0have vastly\u00a0improved, with more than\u00a085 per cent\u00a0of\u00a0young patients\u00a0surviving.\u00a0Still,\u00a0chemotherapy’s toxic effects mean\u00a0it\u00a0can\u00a0damage healthy cells and\u00a0cause\u00a0lifelong\u00a0health consequences,\u00a0including\u00a0the risk of\u00a0heart damage or\u00a0another\u00a0cancer\u00a0years later.\u00a0<\/p>\n
Such\u00a0‘late\u00a0effects’\u00a0are\u00a0uniquely impactful\u00a0for\u00a0children.\u00a0<\/p>\n
“For a\u00a0young patient\u00a0with their whole life ahead of them,\u00a0developing\u00a0a secondary\u00a0cancer or cardiac\u00a0issue a decade\u00a0later means\u00a0confronting a new, life-altering crisis\u00a0in their\u00a0teens or\u00a0twenties,” says\u00a0first author\u00a0Dr.\u00a0Mehdi Layeghifard,\u00a0Senior Research Associate\u00a0in the\u00a0Shlien Lab.\u00a0<\/p>\n
Until now,\u00a0researchers\u00a0have not known how much DNA damage is linked to chemotherapy exposure\u00a0or\u00a0when\u00a0and\u00a0how\u00a0treatment-resistant\u00a0tumors\u00a0emerge\u00a0in childhood cancer.\u00a0Genomic signatures, or fingerprints, are records of how cancer cells responded to therapy and\u00a0now that researchers have recorded these unique signatures, clinicians can track them and\u00a0identify cancers that are evolving in ways that make them more likely to resist treatment, spread or return later.\u00a0<\/p>\n
Study required new levels of computational analysis\u00a0<\/p>\n
In\u00a0the study, researchers performed\u00a0the kind of deeply\u00a0intricate computational genomics\u00a0needed to\u00a0both interpret and translate\u00a0the\u00a0signatures\u00a0that\u00a0each cancer drug\u00a0had left in\u00a0the genome.\u00a0<\/p>\n
“We spent years\u00a0analyzing the data and developing new computational methods\u00a0to\u00a0pinpoint\u00a0these\u00a0subtle patterns and connect them to specific therapies,”\u00a0says\u00a0Shlien, who\u00a0says\u00a0he\u00a0believes\u00a0this is\u00a0the world’s largest exploration of therapy signatures in childhood cancer using whole genome sequencing.\u00a0<\/p>\n
The\u00a0work was made\u00a0possible because researchers had\u00a0access to detailed\u00a0chemotherapy exposure\u00a0information, such as\u00a0therapy type,\u00a0dose\u00a0and timing, from\u00a0so many families, the majority of whom\u00a0engaged in\u00a0the SickKids\u00a0Kids Cancer Sequencing\u00a0(KiCS)\u00a0program.\u00a0<\/p>\n
One such family\u00a0is\u00a0the\u00a0Gublers\u00a0of Oshawa, Ont.,\u00a0who were shocked\u00a0when their\u00a0son Roman was\u00a0diagnosed with lymphoma\u00a0after visiting the\u00a0SickKids\u00a0emergency department\u00a0last spring\u00a0with\u00a0an unrelenting\u00a0fever.\u00a0He was treated from May to September,\u00a0successfully, and his lymphoma has been in remission ever since.\u00a0<\/p>\n
“When we understood what it meant to be part of\u00a0KiCS, to help hunt for new treatments,\u00a0we were totally on board,” says\u00a0Nicole,\u00a0Roman’s mom.\u00a0“Despite what he went through,\u00a0Roman told me\u00a0he’s\u00a0so proud to contribute to helping other kids.\u00a0If\u00a0my little nine-year-old\u00a0boy\u00a0can\u00a0be part of such important research,\u00a0then\u00a0that’s\u00a0pretty wonderful.”\u00a0<\/p>\n
A potential early warning system\u00a0<\/p>\n
The\u00a0Nature\u00a0study\u00a0exemplifies\u00a0Precision Child Health,\u00a0combining\u00a0genomic information with treatment\u00a0history to\u00a0better\u00a0understand\u00a0how\u00a0a therapy\u00a0could\u00a0affect\u00a0a\u00a0patient’s\u00a0cancer over time and adjust treatment\u00a0to\u00a0potentially\u00a0reduce toxic effects.\u00a0<\/p>\n
The findings are in fact a\u00a0rare case of multiple levels of precision.\u00a0<\/p>\n
“Every\u00a0tumor\u00a0is\u00a0unique and is driven\u00a0by\u00a0its own biology based on where it originated and how it evolved,”\u00a0Shlien\u00a0says.\u00a0“When\u00a0we treat it with chemotherapy, the interaction between\u00a0tumor\u00a0and treatment\u00a0changes its makeup and evolutionary pathway.\u00a0Defining\u00a0that interaction\u00a0could\u00a0help clinicians detect\u00a0important\u00a0signals of future outcomes long before they become\u00a0clinically\u00a0visible.”\u00a0<\/p>\n
Researchers say\u00a0the\u00a0genomic\u00a0signatures\u00a0identified\u00a0in the study\u00a0may, in the future,\u00a0act as\u00a0biomarkers to create a\u00a0potential\u00a0early warning system\u00a0for children undergoing cancer treatment.\u00a0<\/p>\n
“Ultimately the goal is\u00a0for\u00a0clinicians\u00a0to\u00a0use\u00a0these to\u00a0identify\u00a0those\u00a0patients\u00a0where\u00a0they could\u00a0de-escalate\u00a0chemotherapy\u00a0and intervene as early as three months\u00a0if they see\u00a0concerning\u00a0genomic\u00a0signatures,”\u00a0Layeghifard\u00a0says.\u00a0<\/p>\n
In the future, that could\u00a0mean\u00a0a blood test\u00a0for\u00a0patients of any age\u00a0who face\u00a0the need for chemotherapy.\u00a0Importantly, the\u00a0research\u00a0team\u00a0validated\u00a0their findings in\u00a0independent datasets,\u00a0which included\u00a0adult patients.\u00a0<\/p>\n
“We\u00a0ultimately\u00a0believe these findings will have\u00a0tremendous clinical\u00a0value for adult cancers treated with similar drugs,”\u00a0Shlien says.\u00a0<\/p>\n
Source:<\/p>\n
The Hospital for Sick Children<\/a><\/p>\n Journal reference:<\/p>\n