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Background <p>How germline and somatic alterations together contribute to alterations in cancer relevant pathways in individual cancers remains poorly understood. In this study, we provide a quantitative framework to characterize their contributions to pathway-level disturbances in individual cancers.</p> Methods <p>We mapped germline and somatic DNA alterations of individual cancer samples from The Cancer Genome Atlas (TCGA), the Breast Cancer Genome Guided Therapy Study (BEAUTY) and the East Asian-ancestry Lung Adenocarcinoma (EAS-LUAD) cohort onto Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. To quantify pathway-level disturbances from germline and somatic origins, we calculated gene-level impact scores by integrating the functional importance of a gene in sustaining cell survival with the predicted impact of its variants. These scores were then used to compute a pathway disturbance score (CanSys score), that quantified the combined effect of gene-level alterations across all pathway members.</p> Results <p>We found that more than 10% of TCGA cancers have rare protein function-altering germline alterations in cell cycle, telomere maintenance, and DNA repair hallmark pathways. At somatic mutation level, 12 pathways were altered in &gt; 75% of cancers corresponding to core cancer hallmarks, however different genes within the same pathway are affected in different individuals, illustrating phenotypic convergence. In addition, 404 pathways were affected in ≥ 25% but &lt; 50% of cancers which may contribute to the unique clinical course of each cancer. A freely available web tool (<a href="https://cansysplot.com">https://cansysplot.com</a>) developed for this study enables visualization of GO/KEGG pathway disturbances from germline and somatic origins at the individual sample level.</p> Conclusions <p>Our findings indicate that a substantial proportion of individuals with cancer harbor protein function-altering germline alterations in genes involved with cell cycle regulation, telomere maintenance, and DNA repair, whereas somatic mutations primarily affect pathways involved in cell adhesion, cell motility, metabolism, and a broad range of signal transduction processes. The unique combination of pathway alterations might explain the unique behavior of each cancer.</p>

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Functional germline variants together with somatic mutations alter the integrity of cancer hallmark regulatory networks

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月29日

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  • Jiawei Dai,
  • Mate Posta,
  • Michal Marczyk,
  • Tao Qing,
  • Balazs Gyorffy,
  • Lajos Pusztai

摘要

Background

How germline and somatic alterations together contribute to alterations in cancer relevant pathways in individual cancers remains poorly understood. In this study, we provide a quantitative framework to characterize their contributions to pathway-level disturbances in individual cancers.

Methods

We mapped germline and somatic DNA alterations of individual cancer samples from The Cancer Genome Atlas (TCGA), the Breast Cancer Genome Guided Therapy Study (BEAUTY) and the East Asian-ancestry Lung Adenocarcinoma (EAS-LUAD) cohort onto Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. To quantify pathway-level disturbances from germline and somatic origins, we calculated gene-level impact scores by integrating the functional importance of a gene in sustaining cell survival with the predicted impact of its variants. These scores were then used to compute a pathway disturbance score (CanSys score), that quantified the combined effect of gene-level alterations across all pathway members.

Results

We found that more than 10% of TCGA cancers have rare protein function-altering germline alterations in cell cycle, telomere maintenance, and DNA repair hallmark pathways. At somatic mutation level, 12 pathways were altered in > 75% of cancers corresponding to core cancer hallmarks, however different genes within the same pathway are affected in different individuals, illustrating phenotypic convergence. In addition, 404 pathways were affected in ≥ 25% but < 50% of cancers which may contribute to the unique clinical course of each cancer. A freely available web tool (https://cansysplot.com) developed for this study enables visualization of GO/KEGG pathway disturbances from germline and somatic origins at the individual sample level.

Conclusions

Our findings indicate that a substantial proportion of individuals with cancer harbor protein function-altering germline alterations in genes involved with cell cycle regulation, telomere maintenance, and DNA repair, whereas somatic mutations primarily affect pathways involved in cell adhesion, cell motility, metabolism, and a broad range of signal transduction processes. The unique combination of pathway alterations might explain the unique behavior of each cancer.