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Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
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Rare Variants Associated With Pediatric Cancer Treatment-Related Second Malignant Neoplasm Risk.
Claire Ducos1,2,3, Brice Fresneau1,2,3,4, Filippo Rosselli5
1Radiation Epidemiology Team, Center for Research in Epidemiology and Population Health, INSERM Unit 1018, Villejuif, France.
JCO Precision Oncology
|September 17, 2025
Summary
Genetic variations in RNASEL, APOBEC3F, and FANCM genes are linked to increased risk of second malignant neoplasms (SMNs) in childhood cancer survivors. These findings may help identify high-risk individuals for tailored follow-up care.
Area of Science:
- Oncology
- Genetics
- Cancer Epidemiology
Background:
- Childhood cancer survivors face an elevated risk of developing second malignant neoplasms (SMNs).
- Radiation therapy and chemotherapy are established risk factors, but genetic variations contribute to interindividual differences in SMN susceptibility.
- Understanding genetic predispositions is crucial for personalized risk assessment and management.
Purpose of the Study:
- To identify rare genetic variants associated with the risk of developing SMNs in childhood cancer survivors.
- To evaluate the influence of specific genetic variants on SMN risk, considering treatment exposures.
- To investigate genetic associations with specific SMNs, such as breast and thyroid cancers.
Main Methods:
- A nested case-control study using whole-exome sequencing was conducted on 450 childhood cancer survivors (163 cases, 287 controls).
- Rare variants within DNA replication, recombination, and repair pathways were analyzed using gene-based association tests.
- Logistic regression models assessed the association between genetic variants and SMN risk, adjusting for clinical factors and radiation doses.
Main Results:
- The study identified significant associations between rare variants in the RNASEL and APOBEC3F genes and an increased risk of SMNs.
- The FANCM gene was found to be associated with an elevated risk of developing breast SMNs.
- Specific odds ratios and p-values were reported for these genetic associations, highlighting their statistical significance.
Conclusions:
- This research provides novel evidence for the role of genetic variations in the development of SMNs among childhood cancer survivors.
- Further studies are warranted to validate these findings and elucidate the underlying biological mechanisms.
- Identifying high-risk survivors through genetic profiling could enable personalized treatment and surveillance strategies to mitigate SMN risk.
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