Feature

Analysis emphasizes need for development of pediatric cancer-specific precision therapies

Photo of Jinghui Zhang
Jinghui Zhang
Photo Credit: St. Jude
Children’s Research Hospital

Researchers at St. Jude Children’s Research Hospital determined the genomic alterations that lead to cancer among children vary from those observed among adults.

The finding highlights the need to develop precision therapies for pediatric cancer, according to Jinghui Zhang, PhD, chair of St. Jude Children’s Research Hospital’s department of computational biology, and colleagues.

“This study shows for the first time that pediatric and adult cancers frequently arise from different genes with different mutations,” Zhang said in a press release.

For the pan-cancer analysis, Zhang and colleagues utilized three next-generation sequencing approaches to compare somatic genetic mutations and their impact on key biological processes in tumor and normal tissue among 1,699 pediatric patients with cancer.

Results showed only 45% of identified mutated genes were similar between children and adults.

“These results bring home the message that pediatric cancer patients are not small adults and their disease should not be treated as if that were the case,” Zhang said. “Better treatments and more sensitive diagnostic tests require understanding the biology driving pediatric cancer. These results provide a better roadmap for researchers working in the laboratory and the clinic.”

HemOnc Today spoke with Zhang about the study, how the results challenge conventional thinking, and how the findings support the need for more precise cancer treatments for younger patients.

 

Question: What prompted this study?

Answer: Cure rates for childhood cancers have increased to about 80%, but cancer is still the leading cause of death by disease in the developed world among children aged older than 1 year. A crucial step toward developing more specific and less damaging therapies is to better understand the complete genetic repertoire of childhood cancers. We presented a pan-cancer study of somatic alterations among 1,699 pediatric leukemia and solid tumors across six histotypes, with whole-genome, whole-exome and transcriptome sequencing data. This will enable us to identify novel genetic alterations that could be missed by analysis of a single histotype. Further, a comprehensive pediatric pan-cancer analysis would allow us to compare the genetic landscapes of pediatric cancer with those derived from adult pan-cancer analysis, so that we could gain insight into their similarities and differences. This information will help drive development of new therapies for pediatric cancers.

 

Q: How did you conduct the study?

A: The study is a collaboration with NCI. Patient genome data were generated by NCI’s Therapeutically Applicable Research to Generate Effective Treatments (TARGET) project. We developed a uniformed analysis pipeline to discover all types of somatic alterations, including single-nucleotide variants, small insertion/deletions, copy number alterations and structural variations across the entire cohort. We then applied statistical analysis to identify significantly mutated genes and evaluated mutation pathogenicity to identify driver mutations in this cohort.

 

Q: What did you find?

A: In the study, we identified 142 driver genes in pediatric cancers. Only 45% of those mutations matched those found in adult pan-cancer studies. The majority (62%) of the events were constituted by copy number alterations and structural variants. These data provided a comprehensive genomic architecture for pediatric cancers and emphasized the need for pediatric cancer-specific development of precision therapies. We also evaluated mutational signatures in pediatric cancer that revealed an unexpected UV-signature in eight patients with acute lymphoblastic leukemia that have aneuploidy genomic architecture.

Q: Do the results challenge conventional thinking?

A: Traditionally, there has not been a comprehensive analysis to compare the mutational landscape between pediatric and adult cancer. In that context, our discovery is new. However, the results are not completely surprising given that pediatric cancers commonly occur in developing mesodermic tissue, unlike adult epithelial tissues. Yet, without an in-depth analysis, people may not be able to appreciate the extent of the difference, as only 45% of driver genes in pediatric cancer overlap with those identified in adult cancers.

 

Q: What clinical implications do the findings have ?

A: We anticipate these complementary pan-cancer datasets will be an important resource for investigations of functional validation and implementation of precision oncology for pediatric cancers. For example, we may miss genomic abnormalities specific to pediatric cancers if a gene panel designed for adult cancer is used for screening pediatric patients with cancer. For genomic alterations that are present only in adult cancer, offering the same therapy for younger patients could turn out to be problematic.

 

Q: Is there anything else that you would like to mention ?

A: With this study, we have determined that children and adults with cancer usually have different mutated genes driving their disease. This suggests patients likely would benefit from different therapies. The findings underscore the need to develop precision medicines for pediatric cancer. – by Jennifer Southall

 

Reference:

Ma X, et al. Nature. 2018; doi:10.1038/nature25795.

 

For more information:

Jinghui Zhang, PhD, can be reached at St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105.

 

Disclosures: The NCI provided funding for this study. Zhang reports no relevant financial disclosures.

Photo of Jinghui Zhang
Jinghui Zhang
Photo Credit: St. Jude
Children’s Research Hospital

Researchers at St. Jude Children’s Research Hospital determined the genomic alterations that lead to cancer among children vary from those observed among adults.

The finding highlights the need to develop precision therapies for pediatric cancer, according to Jinghui Zhang, PhD, chair of St. Jude Children’s Research Hospital’s department of computational biology, and colleagues.

“This study shows for the first time that pediatric and adult cancers frequently arise from different genes with different mutations,” Zhang said in a press release.

For the pan-cancer analysis, Zhang and colleagues utilized three next-generation sequencing approaches to compare somatic genetic mutations and their impact on key biological processes in tumor and normal tissue among 1,699 pediatric patients with cancer.

Results showed only 45% of identified mutated genes were similar between children and adults.

“These results bring home the message that pediatric cancer patients are not small adults and their disease should not be treated as if that were the case,” Zhang said. “Better treatments and more sensitive diagnostic tests require understanding the biology driving pediatric cancer. These results provide a better roadmap for researchers working in the laboratory and the clinic.”

HemOnc Today spoke with Zhang about the study, how the results challenge conventional thinking, and how the findings support the need for more precise cancer treatments for younger patients.

 

Question: What prompted this study?

Answer: Cure rates for childhood cancers have increased to about 80%, but cancer is still the leading cause of death by disease in the developed world among children aged older than 1 year. A crucial step toward developing more specific and less damaging therapies is to better understand the complete genetic repertoire of childhood cancers. We presented a pan-cancer study of somatic alterations among 1,699 pediatric leukemia and solid tumors across six histotypes, with whole-genome, whole-exome and transcriptome sequencing data. This will enable us to identify novel genetic alterations that could be missed by analysis of a single histotype. Further, a comprehensive pediatric pan-cancer analysis would allow us to compare the genetic landscapes of pediatric cancer with those derived from adult pan-cancer analysis, so that we could gain insight into their similarities and differences. This information will help drive development of new therapies for pediatric cancers.

 

Q: How did you conduct the study?

A: The study is a collaboration with NCI. Patient genome data were generated by NCI’s Therapeutically Applicable Research to Generate Effective Treatments (TARGET) project. We developed a uniformed analysis pipeline to discover all types of somatic alterations, including single-nucleotide variants, small insertion/deletions, copy number alterations and structural variations across the entire cohort. We then applied statistical analysis to identify significantly mutated genes and evaluated mutation pathogenicity to identify driver mutations in this cohort.

 

Q: What did you find?

A: In the study, we identified 142 driver genes in pediatric cancers. Only 45% of those mutations matched those found in adult pan-cancer studies. The majority (62%) of the events were constituted by copy number alterations and structural variants. These data provided a comprehensive genomic architecture for pediatric cancers and emphasized the need for pediatric cancer-specific development of precision therapies. We also evaluated mutational signatures in pediatric cancer that revealed an unexpected UV-signature in eight patients with acute lymphoblastic leukemia that have aneuploidy genomic architecture.

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Q: Do the results challenge conventional thinking?

A: Traditionally, there has not been a comprehensive analysis to compare the mutational landscape between pediatric and adult cancer. In that context, our discovery is new. However, the results are not completely surprising given that pediatric cancers commonly occur in developing mesodermic tissue, unlike adult epithelial tissues. Yet, without an in-depth analysis, people may not be able to appreciate the extent of the difference, as only 45% of driver genes in pediatric cancer overlap with those identified in adult cancers.

 

Q: What clinical implications do the findings have ?

A: We anticipate these complementary pan-cancer datasets will be an important resource for investigations of functional validation and implementation of precision oncology for pediatric cancers. For example, we may miss genomic abnormalities specific to pediatric cancers if a gene panel designed for adult cancer is used for screening pediatric patients with cancer. For genomic alterations that are present only in adult cancer, offering the same therapy for younger patients could turn out to be problematic.

 

Q: Is there anything else that you would like to mention ?

A: With this study, we have determined that children and adults with cancer usually have different mutated genes driving their disease. This suggests patients likely would benefit from different therapies. The findings underscore the need to develop precision medicines for pediatric cancer. – by Jennifer Southall

 

Reference:

Ma X, et al. Nature. 2018; doi:10.1038/nature25795.

 

For more information:

Jinghui Zhang, PhD, can be reached at St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105.

 

Disclosures: The NCI provided funding for this study. Zhang reports no relevant financial disclosures.

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