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  • Clinical Research Article
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Germline mutations in cancer predisposition genes among pediatric patients with cancer and congenital anomalies

Pediatric Research volume 95, pages 1346–1355 (2024)Cite this article

Abstract

Background

Childhood cancer has a poorly known etiology, and investigating the underlying genetic background may provide novel insights. A recognized association exists between non-chromosomal birth defects and childhood cancer susceptibility.

Methods

We performed whole-exome sequencing and chromosomal microarray analysis in a cohort of childhood cancer (22 individuals, 50% with congenital anomalies) to unravel deleterious germline variants.

Results

A diagnostic yield of 14% was found, encompassing heterozygous variants in bona fide dominant Cancer Predisposition Genes (CPGs). Considering candidate and recessive CPGs harboring monoallelic variants, which were also deemed to play a role in the phenotype, the yield escalated to 45%. Most of the deleterious variants were mapped in genes not conventionally linked to the patient’s tumor type. Relevant findings were detected in 55% of the syndromic individuals, mostly variants potentially underlying both phenotypes.

Conclusion

We uncovered a remarkable prevalence of germline deleterious CPG variants, highlighting the significance of a comprehensive genetic analysis in pediatric cancer, especially when coupled with additional clinical signs. Moreover, our findings emphasized the potential for oligogenic inheritance, wherein multiple genes synergistically increase cancer risk. Lastly, our investigation unveiled potentially novel genotype-phenotype associations, such as SETD5 in neuroblastoma, KAT6A in gliomas, JAG1 in hepatoblastomas, and TNFRSF13B in Langerhans cell histiocytosis.

Impact

  • Novel gene-phenotype associations and candidate genes for pediatric cancer were unraveled, such as KAT6A in gliomas, SETD5 in neuroblastoma, JAG1 in hepatoblastomas, and TNFRSF13B in Langerhans cell histiocytosis.

  • Our analysis revealed a high frequency of deleterious germline variants, particularly in cases accompanied by additional clinical signs, highlighting the importance of a comprehensive genetic evaluation in childhood cancer.

  • Our findings also underscored the potential for oligogenic inheritance in pediatric cancer risk.

  • Understanding the cancer etiology is crucial for genetic counseling, often influencing therapeutic decisions and offering valuable insights into molecular targets for the development of oncological therapies.

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Fig. 1: Delineation of the experimental approach.
Fig. 2: Pediatric cancer cases, associated clinical phenotypes, and detection of pathogenic/likely pathogenic variants.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We would like to thank the patients and their families for participating in this study.

Funding

This research was carried out with financial support from CAPES (88887.606266/2021-00); FAPESP (2013/08028-1, 2018/21047-9, 2018/05961-2, 2022/03980-5); CNPq (grant number 305806/2019-0; 305101/2022-6). We are grateful for the confidence of these institutions in investing public funds in our research.

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Authors and Affiliations

  1. Human Genome and Stem Cell Research Center, Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, SP, Brazil

    Gustavo D. Dangoni, Anne Caroline B. Teixeira, Silvia S. da Costa, Marília O. Scliar, Laura M. L. Carvalho & Ana Cristina V. Krepischi

  2. Department of Pediatrics, Instituto de Tratamento do Câncer Infantil (ITACI), Faculty of Medicine, University of São Paulo, São Paulo, SP, Brazil

    Luciana N. Silva, Estela M. Novak, Sofia M. M. Sugayama & Vicente Odone-Filho

  3. Hospital Israelita Albert Einstein, São Paulo, SP, Brazil

    Carolina S. C. Vince

  4. Research Center, Boldrini Children’s Hospital, Campinas, SP, Brazil

    Mariana C. Maschietto

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  1. Gustavo D. Dangoni
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  2. Anne Caroline B. Teixeira
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Contributions

A.C.V.K: study design. G.D.D., L.N.S., E.M.N., C.S.C.V., S.M.M.S., V.O.F. participant enrollment and data collection. G.D.D., A.C.B.T., S.S.C., A.C.V.K.: data analysis and interpretation. G.D.D., A.C.V.K.: manuscript writing. G.D.D., A.C.B.T., L.M.L.C., M.C.M., A.C.V.K. manuscript revision. All authors contributed to the article and approved the submitted version.

Corresponding author

Correspondence to Ana Cristina V. Krepischi.

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The authors declare no competing interests.

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The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national guidelines on human experimentation (Resolution 466/12) and with the Helsinki Declaration of 1975, as revised in 2008. The project was approved by the Research Ethics Committee of the Clinical Hospital - Faculty of Medicine of the University of São Paulo (CAAE 47277115.0.0000.0068), and Institute of Biosciences (University of São Paulo, São Paulo, Brazil) (CAAE 09163818.4.0000.5464). Informed consent was obtained from all study participants.

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Dangoni, G.D., Teixeira, A.C.B., da Costa, S.S. et al. Germline mutations in cancer predisposition genes among pediatric patients with cancer and congenital anomalies. Pediatr Res 95, 1346–1355 (2024). https://doi.org/10.1038/s41390-023-03000-7

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