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Secondary Tumor Risk in Pediatric Cancer Survivors Linked to Germline Variants, Treatment Type

NEW YORK – Secondary cancer risk appears to jump in pediatric cancer patients carrying risky germline variants in DNA repair genes who are exposed to DNA-damaging treatments such as chemotherapy or radiotherapy as part of their original treatment, new research suggests.

For a study published in the Journal of Clinical Oncology on Thursday, a team led by investigators at St. Jude Children's Research Hospital did whole-genome sequencing on blood samples from 4,402 pediatric cancer survivors in the St. Jude Lifetime Cohort, including 495 individuals who went on to develop more than 1,200 secondary neoplasms, focusing on pathogenic germline alterations affecting more than 100 genes from half a dozen DNA repair pathways.

"[W]e hypothesized that pathogenic mutations in [DNA repair genes] of specific pathways … may lead to sub-optimal DNA repair proficiency resulting in the accumulation of specific DNA errors and contribute to the risk of [subsequent neoplasms] among childhood cancer survivors, especially those treated with high doses of certain radiotherapy and/or chemotherapeutic agents," St. Jude researchers Yutaka Yasui, Leslie Robison, and Jinghui Zhang, the study's co-senior authors, and their colleague explained.

More than 11 percent of the survivors carried pathogenic variants in one or more of the DNA repair genes profiled — alterations that together affected almost 100 different DNA repair genes, the researchers reported.

By bringing in available medial record information on the patients' past chemotherapy doses and radiotherapy exposures, they found ties between secondary breast cancer risk in women with pathogenic germline mutations in homologous recombination genes, particularly after some chest radiotherapy or anthracycline chemotherapy treatments.

The team's analysis also pointed to a rise in sarcoma risk after certain doses of alkylating chemotherapy in the past pediatric cancer patients with germline homologous recombination gene variants, while the cancer survivors with germline changes in genes from a nucleotide excision repair pathway appeared more prone to secondary thyroid cancer or non-melanoma skin cancer after earlier radiotherapy treatments.

"Collectively, our findings provide compelling evidence of increased [subsequent neoplasm] risk among childhood cancer survivors with [DNA repair gene] mutations and prior genotoxic treatment exposures," the authors wrote.

Together, they suggested, the new results "have the potential to facilitate identification of high-risk survivors who may benefit from genetic counseling and/or testing of [DNA repair genes], which may further inform personalized cancer surveillance and prevention strategies."

The work is the latest in a series of studies searching for genetic- or treatment-related contributors to secondary cancer or benign tumor development in individuals treated for cancer as children or young adults.

At the American Society of Clinical Oncology annual meeting in 2016, for example, Smita Bhatia, director of the University of Alabama at Birmingham's School of Medicine Institute for Cancer Outcomes and Survivorship, shared data from an array-based search for genetic contributors to secondary tumor risk in pediatric cancer survivors included in the St. Jude Lifetime Cohort or St. Jude's Childhood Cancer Survivor Study, focusing on meningioma tumors that are typically benign.

And in 2018, researchers from St. Jude and elsewhere described common and rare genetic contributors to breast cancer risk in Lifetime Cohort study participants. That Clinical Cancer Research study highlighted pathogenic or likely pathogenic variants in known breast cancer-related genes, along with a proposed polygenic risk score made up of common risk variants.

Sequencing data from the St. Jude Lifetime Cohort is part of the St. Jude Cloud, a dataset encompassing thousands of genome, exome, and RNA sequences that is open to other members of the research community that officially launched in 2018.