{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T20:35:11Z","timestamp":1785530111575,"version":"3.56.0"},"reference-count":74,"publisher":"Korean Neurosurgical Society","issue":"3","license":[{"start":{"date-parts":[[2025,2,17]],"date-time":"2025-02-17T00:00:00Z","timestamp":1739750400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/3.0\/"}],"funder":[{"DOI":"10.13039\/501100004332","name":"Seoul National University Hospital","doi-asserted-by":"publisher","award":["22A-017-0100"],"award-info":[{"award-number":["22A-017-0100"]}],"id":[{"id":"10.13039\/501100004332","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["jkns.or.kr"],"crossmark-restriction":true},"short-container-title":["J Korean Neurosurg Soc"],"published-print":{"date-parts":[[2025,5,1]]},"abstract":"<jats:p>Pathogenic germline variants (PGVs) are increasingly recognized as critical elements in pediatric cancer predisposition. Determining the pathogenicity of germline variants is a dynamic process, with advancements in next-generation sequencing and expanding genome databases reshaping our understanding of cancer genomics. This article reviews the role of PGVs in key oncogenic pathways, including RTK (receptor tyrosine kinase)\/RAS\/MAPK (mitogen-activated protein kinase), PI3K (phosphatidylinositol 3-kinase)\/AKT (v-akt murine thymoma viral oncogene homolog 1), WNT (wingless-type), and Hedgehog signaling, highlighting their associations with specific cancer predisposition syndromes and neurosurgical implications. Most PGVs are inherited in an autosomal dominant pattern and are frequent in tumor suppressor genes, while autosomal recessive conditions like Ataxia-telangiectasia and Fanconi anemia are less common. Germline variants in proto-oncogenes such as &lt;i&gt;PTPN11, KRAS&lt;\/i&gt;, and &lt;i&gt;HRAS&lt;\/i&gt; are associated with RASopathies, including Noonan and Costello syndromes, which show variable cancer risks. Similarly, &lt;i&gt;PTEN PGVs&lt;\/i&gt;, linked to Cowden syndrome, and &lt;i&gt;DICER1&lt;\/i&gt; PGVs, responsible for DICER1 syndrome, exemplify the diverse clinical presentations and risks of pediatric cancer predisposition syndromes. Medulloblastoma, a pediatric-specific brain tumor, shows an increasing proportion of PGVs, with approximately 12% of all medulloblastomas harboring PGVs in &lt;i&gt;APC, PTCH1, SUFU&lt;\/i&gt;, and &lt;i&gt;ELP1&lt;\/i&gt; in the WNT-activated and sonic hedgehog-activated subtypes. Emerging evidence suggests that approximately 8.5\u201320% of pediatric cancer patients harbor PGVs, with a substantial proportion arising &lt;i&gt;de novo&lt;\/i&gt;. Routine germline screening for pediatric cancer patients is increasingly recommended, as many PGVs lack family history. Programs like STREAM (Solid Tumor REsearch And Magic) in Korea underscore the importance of comprehensive pediatric genome databases for personalized precision medicine. As neurosurgeons are frequently the first to encounter central nervous system tumor manifestations, a robust understanding of genomic medicine is essential. This review emphasizes the need for international collaboration to develop actionable insights into pediatric cancer genomics, ultimately improving diagnostic, therapeutic, and preventive strategies.<\/jats:p>","DOI":"10.3340\/jkns.2025.0011","type":"journal-article","created":{"date-parts":[[2025,2,18]],"date-time":"2025-02-18T00:40:07Z","timestamp":1739839207000},"page":"350-359","update-policy":"https:\/\/doi.org\/10.3340\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Germline Variants in Pediatric Cancer : Based on Oncogenic Pathways"],"prefix":"10.3340","volume":"68","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2286-3301","authenticated-orcid":true,"given":"Joo Whan","family":"Kim","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1892","reference":[{"key":"ref1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-16067-1"},{"key":"ref2","doi-asserted-by":"publisher","DOI":"10.1111\/ahg.12502"},{"key":"ref3","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.11537"},{"key":"ref4","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2019.01.066"},{"key":"ref5","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ejhg.5201088"},{"key":"ref6","doi-asserted-by":"publisher","DOI":"10.1038\/s41416-023-02229-7"},{"key":"ref7","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.22475"},{"key":"ref8","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpeds.2020.01.048"},{"key":"ref9","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.23358"},{"key":"ref10","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2009.067751"},{"key":"ref11","first-page":"eabc9207","volume-title":"Histone H3.3 beyond cancer: germline mutations in histone 3 family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients","author":"Bryant","year":"2020"},{"key":"ref12","first-page":"166","volume-title":"Diagnosis of PTEN mosaicism: the relevance of additional tumor DNA sequencing. 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