Human mutation · 2026
Integrated Mutation Profiling and Prognostic Genomic Signature in Pediatric Testicular and Ovarian Germ Cell Tumors.
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Xuan Xiaoqi, Yang Yue, Li Yongle, Yang Jinlong, Wu Hang, Gong Yulong, Li Guogen, Pu Xiao
Аннотация
BACKGROUND: Pediatric testicular and ovarian germ cell tumors generally have favorable outcomes, but a subset of patients experience relapse, progression, or persistent disease. Conventional risk assessment is based primarily on stage, histology, primary site, serum tumor markers, and treatment response; the incremental prognostic value of genomic profiling remains uncertain.
METHODS: This retrospective molecular clinicopathological study included 72 patients younger than 18 years with primary testicular or ovarian germ cell tumors diagnosed from January 2014 to December 2023. Pretreatment formalin-fixed paraffin-embedded (FFPE) tumor specimens underwent targeted next-generation sequencing with a custom 89-gene hybrid-capture panel. One qualifying feature was counted for each pathogenic or likely pathogenic TP53 mutation, chromosome 12p gain, KRAS amplification, and each additional pathogenic or likely pathogenic oncogenic alteration retained after annotation; tumors with two or more qualifying features were classified as signature-positive. Event-free survival (EFS) was the primary endpoint, and overall survival (OS) was secondary.
RESULTS: The cohort comprised 45 ovarian and 27 testicular tumors. Recurrent alterations included chromosome 12p gain; KRAS, TP53, KIT, and NRAS mutations; and KRAS amplification. Twenty tumors were signature-positive, and 52 were signature-negative. Events occurred in 35.0% versus 17.3%, and 3-year EFS was 65.0% versus 88.5% (log-rank p = 0.019). The stage-adjusted hazard ratio for EFS was 2.74 (95% confidence interval, 1.01-7.43; p = 0.048). Three-year OS was 85.0% versus 98.1% and did not differ significantly (p = 0.087).
CONCLUSION: Targeted sequencing identified recurrent mutations and copy-number alterations in pediatric gonadal germ cell tumors. The exploratory adverse genomic signature was associated with EFS but not OS. This hypothesis-generating finding requires independent validation and does not establish mandatory testing, treatment escalation, or modification of first-line therapy.
METHODS: This retrospective molecular clinicopathological study included 72 patients younger than 18 years with primary testicular or ovarian germ cell tumors diagnosed from January 2014 to December 2023. Pretreatment formalin-fixed paraffin-embedded (FFPE) tumor specimens underwent targeted next-generation sequencing with a custom 89-gene hybrid-capture panel. One qualifying feature was counted for each pathogenic or likely pathogenic TP53 mutation, chromosome 12p gain, KRAS amplification, and each additional pathogenic or likely pathogenic oncogenic alteration retained after annotation; tumors with two or more qualifying features were classified as signature-positive. Event-free survival (EFS) was the primary endpoint, and overall survival (OS) was secondary.
RESULTS: The cohort comprised 45 ovarian and 27 testicular tumors. Recurrent alterations included chromosome 12p gain; KRAS, TP53, KIT, and NRAS mutations; and KRAS amplification. Twenty tumors were signature-positive, and 52 were signature-negative. Events occurred in 35.0% versus 17.3%, and 3-year EFS was 65.0% versus 88.5% (log-rank p = 0.019). The stage-adjusted hazard ratio for EFS was 2.74 (95% confidence interval, 1.01-7.43; p = 0.048). Three-year OS was 85.0% versus 98.1% and did not differ significantly (p = 0.087).
CONCLUSION: Targeted sequencing identified recurrent mutations and copy-number alterations in pediatric gonadal germ cell tumors. The exploratory adverse genomic signature was associated with EFS but not OS. This hypothesis-generating finding requires independent validation and does not establish mandatory testing, treatment escalation, or modification of first-line therapy.