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Background <p>Adolescents and young adults (AYA) aged 15 to 39&#xa0;years with cancer have a higher prevalence of germline pathogenic variants than older patients. This study characterized the prevalence and distribution of germline pathogenic/likely pathogenic variants (GPVs) in Japanese AYA with advanced solid tumors using nationwide real-world paired tumor and normal sequencing data.</p> Methods <p>This retrospective study was conducted using a nationwide cancer genomics database in Japan. In total, 359 AYA with solid tumors who underwent comprehensive genomic profiling with a paired tumor and normal samples between June 2019 and December 2023 were included. The analyses were restricted to 39 genes for which germline findings, defined as variants detected in the matched normal sample within genes eligible for germline disclosure in Japan, are clinically reportable.</p> Results <p>Among 359 patients with advanced solid tumors, GPVs were identified in 32 patients, corresponding to a prevalence of 8.9%. Variants in the <i>TP53</i> and <i>BRCA2</i> genes were the most frequently identified. Notably, 13 of 32 cases were identified in an off-tumor context. In lung cancer, GPVs were identified in <i>TP53</i> and <i>BRCA2</i>, indicating that GPVs in established cancer-predisposition genes can also be detected in tumor types not classically associated with these hereditary cancer genes. In univariable analysis, a family history of cancer and double cancer were associated with GPV positivity.</p> Conclusions <p>This national paired tumor and normal sequencing study in Japanese AYA with cancer, identified GPVs including those detected in off-tumor contexts. Germline findings may warrant consideration beyond conventional approaches based on tumor type.</p>

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Germline pathogenic variants in Japanese adolescents and young adults with advanced solid tumors: a nationwide tumor–normal paired sequencing study

  • 期刊论文

  • 发表日期：

    2026年7月27日

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  • Kota Ishioka,
  • Naomi Hayashi,
  • Naoki Miyazaki,
  • Akito Dobashi,
  • Eri Habano,
  • Asami Kuga,
  • Keika Kaneko,
  • Hiromi Arakawa,
  • Yuko Minoura,
  • Ippei Fukada,
  • Masumi Yamazaki,
  • Naoki Fukuda,
  • Akemi Kataoka,
  • Toshimi Takano,
  • Masayuki Watanabe,
  • Shunji Takahashi,
  • Arisa Ueki,
  • Makiko Ono

摘要

Background

Adolescents and young adults (AYA) aged 15 to 39 years with cancer have a higher prevalence of germline pathogenic variants than older patients. This study characterized the prevalence and distribution of germline pathogenic/likely pathogenic variants (GPVs) in Japanese AYA with advanced solid tumors using nationwide real-world paired tumor and normal sequencing data.

Methods

This retrospective study was conducted using a nationwide cancer genomics database in Japan. In total, 359 AYA with solid tumors who underwent comprehensive genomic profiling with a paired tumor and normal samples between June 2019 and December 2023 were included. The analyses were restricted to 39 genes for which germline findings, defined as variants detected in the matched normal sample within genes eligible for germline disclosure in Japan, are clinically reportable.

Results

Among 359 patients with advanced solid tumors, GPVs were identified in 32 patients, corresponding to a prevalence of 8.9%. Variants in the TP53 and BRCA2 genes were the most frequently identified. Notably, 13 of 32 cases were identified in an off-tumor context. In lung cancer, GPVs were identified in TP53 and BRCA2, indicating that GPVs in established cancer-predisposition genes can also be detected in tumor types not classically associated with these hereditary cancer genes. In univariable analysis, a family history of cancer and double cancer were associated with GPV positivity.

Conclusions

This national paired tumor and normal sequencing study in Japanese AYA with cancer, identified GPVs including those detected in off-tumor contexts. Germline findings may warrant consideration beyond conventional approaches based on tumor type.