Germline variants have a rich history of being studied in the context of cancer risk. Emerging studies now suggest that germline variants contribute not only to cancer risk but to tumor progression as well. In this opinion article, we discuss the initial discoveries associating germline variants with patient outcome and the mechanisms by which germline variants affect molecular pathways. Germline variants affect molecular pathways through amino acid changes, alteration of splicing patterns or expression of genes, influencing the selection for somatic mutations, and causing genome-wide mutational enrichment. These molecular alterations can lead to tumor phenotypes that become clinically apparent such as metastasis, alterations to the immune microenvironment, and modulation of therapeutic response. Overall, the growing body of evidence suggests that germline variants play a larger role in tumor progression than has been previously appreciated and that germline variation holds substantial potential for improving personalized medicine and patient outcomes.

生殖系变异在癌症风险背景下的研究历史悠久。新兴研究现在表明，种系变异不仅会导致癌症风险，还会导致肿瘤进展。在这篇观点文章中，我们讨论了将种系变异与患者结果相关联的初步发现以及种系变异影响分子途径的机制。种系变异通过氨基酸变化、剪接模式或基因表达的改变、影响体细胞突变的选择以及导致全基因组突变富集来影响分子途径。这些分子改变可导致临床上明显的肿瘤表型，例如转移、免疫微环境的改变和治疗反应的调节。总体，