Host genetics helps explain childhood cancer survivors’ mortality risk from second cancers

(MEMPHIS, Tenn. – October 02, 2023) The population of childhood cancer survivors in the U.S. is increasing, with an overall childhood cancer survival rate greater than 85% five years after diagnosis. However, survivors can still be at increased risk of various health conditions, including second cancers. Using data from the Childhood Cancer Survivor Study (CCSS) and the St. Jude Lifetime Cohort Study (St. Jude Life), scientists at St. Jude Children’s Research Hospital have identified a genetic explanation for why a small proportion of survivors are more likely to develop second cancers and why they may be more severe or deadly. The findings, which will inform genetic counseling, testing and adoption of personalized cancer screening and prevention strategies, were published today in The Lancet Oncology. 

The St. Jude group showed that survivors with pathogenic (damaging) genetic variants in specific genes, called cancer-predisposing variants, are at an increased risk of developing second, or subsequent, cancers as adults, and those cancers are more likely to be severe and deadly. The scientists had previously identified that survivors with pathogenic variants in one of 60 different cancer-predisposing genes or 127 DNA damage repair genes were more likely to experience a second or subsequent cancer. This study extends that research to show a direct connection between cancer-predisposing variants and increased second-cancer-related mortality. 

Many of these genetic variants are known to be causally linked to cancers. For example, the tumor suppressor gene TP53 is one of the 60 genes included in the analysis. The key to the discovery’s utility is that these variants are present in the DNA of patients when diagnosed with cancer as children, allowing for an individualized medicine approach to be developed early in life for each survivor. By better understanding the effect such genes can have on future cancer risk and its outcome beyond the primary childhood cancer, the study will help inform efforts to prevent second cancers and improve the outcomes in these individuals. 

“Our study pinpoints that clinical genetic testing to screen for and identify if survivors are carriers of these pathogenic variants could lead to screening and early interventions for those at higher risk to develop deadly second cancers, potentially saving their lives,” said senior corresponding author Zhaoming Wang, Ph.D., St. Jude Department of Epidemiology and Cancer Control. 

Cancer prevention in adult childhood cancer survivors 

The total number of childhood cancer survivors who develop second or subsequent cancers is small (

“This is the first comprehensive study looking for the genetic reason for late mortality — specifically late mortality due to second cancers,” Wang said. “Now we know that cancer-predisposing variants contribute to the risk of death from second cancer.” 

Increased surveillance may help limit the impact of these cancer-predisposing variants as childhood cancer survivors grow into adulthood. By knowing which survivors are at greater risk, health care providers may be able to recommend personalized cancer screening, which may lead to the detection of additional cancers at their earliest and most treatable stage.  

These variants are part of the inherited, or germline, DNA that people are born with. This means they can be detected in children when they are first diagnosed with childhood cancers, arming survivors with the knowledge they need to lower their risk later in life. 

“Even before finishing childhood cancer treatment, clinicians can recommend referral to do genetic counseling so that survivors with these variants can seek cancer prevention strategies later on,” Wang said. “Depending on the gene harboring the variant, survivors that are carriers may be able to implement prevention strategies to safeguard their long-term health.” 

Authors and funding 

The study’s co-first authors are Cheng Chen, of Shanghai Jiao Tong University School of Medicine; Na Qin, of Nanjing Medical University; and Mingjuan Wang, of St. Jude. The other co-senior authors are Hui Wang, Shanghai Jiao Tong University School of Medicine; Deo Kumar Srivastava and Leslie L. Robison (Emeritus Faculty), St. Jude. The study’s other authors are Qian Dong, Saima Sultana Tithi, Yawei Hui, Wenan Chen, Gang Wu, Dennis Kennetz, Michael Edmonson, Michael Rusch, Andrew Thrasher, John Easton, Heather Mulder, Noel-Marie Plonski, Kyla Shelton, Matthew Ehrhardt, Kim E. Nichols, Yutaka Yasui, Gregory Armstrong, Kirsten Ness, Melissa Hudson and Jinghui Zhang, St. Jude; Nan Song, Chungbuk National University; Cindy Im, University of Minnesota; Wendy Leisenring and Kayla Stratton, Fred Hutchinson Cancer Research Center; Rebecca Howell, The University of Texas MD Anderson Cancer Center; Smita Bhatia, University of Alabama at Birmingham. 

The study was supported by grants from the National Institutes of Health (CA195547, CA55727 and CA021765) and ALSAC, the fundraising and awareness organization of St. Jude. 

St. Jude Media Relations Contacts 

Chelsea Bryant 

Desk: (901) 595-0564 

chelsea.bryant@stjude.org 

media@stjude.org 

Rae Lyn Rushing 

Cell: (901) 686-2597 

raelyn.rushing@stjude.org 

media@stjude.org 

St. Jude Children’s Research Hospital 

St. Jude Children’s Research Hospital is leading the way the world understands, treats and cures childhood cancer, sickle cell disease and other life-threatening disorders. It is the only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children. Treatments developed at St. Jude have helped push the overall childhood cancer survival rate from 20% to 80% since the hospital opened more than 60 years ago. St. Jude shares the breakthroughs it makes to help doctors and researchers at local hospitals and cancer centers around the world improve the quality of treatment and care for even more children. To learn more, visit stjude.org, read St. Jude Progress blog, and follow St. Jude on social media at @stjuderesearch.