Germline Variants That Affect Tumor Progression

Abstract

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.

Keywords: cancer therapy; germline variants; personalized medicine; tumor progression.

Figure 1.

Molecular mechanisms by which germline variants may associate with outcome. (A) Germline variants increase the likelihood of a somatic mutation in the wild type allele of the same gene: a germline variant in RB1 increases the likelihood of a somatic mutation in the other allele of RB1 leading to retinoblastoma (shown here by the clinical sign of leukocoria). (B) Germline variants increase specific types of genome wide mutations: germline variants in MBD4 are associated with elevated C>T somatic mutations at CpG dinucleotides, consistent with the role of MBD4 in correcting G:T mismatches. (C) Germline variants are associated with specific transcriptome alterations: a germline variant in the Ras signaling gene GRB2 is associated with upregulation of Ras target genes. (D) Molecularly, germline variants may alter the function of tumor suppressor genes or oncogenes through amino acid changes. (E) Germline variants act as expression quantitative trait loci (eQTL) in cis: a germline variant in the putative regulatory element of the tumor suppressor gene CTSW is associated with increased expression of this tumor suppressor gene. (F) Germline variants increase the likelihood of additional somatic mutations in the same pathway: germline variants in GNA11, an activator of mTOR signaling, promote the acquisition of somatic mutations in PTEN, a tumor suppressor that suppresses mTOR signaling. (G) Germline variants perturb splicing machinery: germline variants in RBFOX1, an RNA binding protein involved in splicing, are associated with increased somatic mutations in SF3B1, another component of the spliceosome, leading to varied splicing patterns.

Figure 2.

A compilation of germline variants associated with outcome discussed in this review shows that the absolute value of the natural log of the hazard ratio (HR) (effect size) is negatively correlated with the frequency of the alternate allele in the population.

Figure 3.

The hallmarks of germline variants in cancer. The molecular mechanisms described in Figure 1 lead to larger phenotypic changes that drive the differences in clinical outcome.