Germline variant burden in cancer genes correlates with age at diagnosis and somatic mutation burden

Cancers harbor many somatic mutations and germline variants, we hypothesized that the combined effect of germline variants that alter the structure, expression, or function of protein-coding regions of cancer-biology related genes (gHFI) determines which and how many somatic mutations (sM) must occur for malignant transformation. We show that gHFI and sM affect overlapping genes and the average number of gHFI in cancer hallmark genes is higher in patients who develop cancer at a younger age ( r = −0.77, P = 0.0051), while the average number of sM increases in increasing age groups ( r = 0.92, P = 0.000073). A strong negative correlation exists between average gHFI and average sM burden in increasing age groups ( r = −0.70, P = 0.017). In early-onset cancers, the larger gHFI burden in cancer genes suggests a greater contribution of germline alterations to the transformation process while late-onset cancers are more driven by somatic mutations. Germline variants that affect the expression or function of protein-coding regions of cancer genes are associated with cancer susceptibility. Here, the authors show that a larger number of germline variants are present in early-onset cancers, while acquired somatic mutations are prevalent in cancers that develop at older age.