Germline Variants That Affect Tumor Progression
Authors: Ajay Chatrath, Aakrosh Ratan, Anindya Dutta
Journal: Trends in Genetics (2020)

The differences in somatic aberrations between tumors can partially be explained by a patient's germline variants, suggesting that germline variants influence the somatic mutational landscape of cancer.Germline variants are associated with patient outcome across a large array of cancers. This suggests that germline variation is clinically relevant in the context of tumor progression.Molecularly, germline variants can affect tumor progression through amino acid changes, alteration of splicing patterns or expression of genes, influencing the selection for somatic mutations, and causing genome-wide mutational enrichment.Germline variants affect molecular and clinical phenotypes, such as genome instability, proliferative signaling, metastasis, alterations to the immune microenvironment, and modulation of therapeutic response and side effects.The smaller patient cohorts required to identify germline variants that affect tumor progression and patient outcome provide an outstanding opportunity to accelerate the identification and validation of clinically useful germline variants. 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. 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. Historically, the study of germline variation in cancer has focused on cancer risk [1.Lichtenstein P. et al.Environmental and heritable factors in the causation of cancer--analyses of cohorts of twins from Sweden, Denmark, and Finland.N. Engl. J. Med. 2000; 343: 78-85Crossref PubMed Scopus (3119) Google Scholar,2.Huang K.L. et al.Pathogenic germline variants in 10,389 adult cancers.Cell. 2018; 173: 355-370.e14Abstract Full Text Full Text PDF PubMed Scopus (341) Google Scholar]. The study of such germline variants (see Glossary) has improved our understanding of basic cellular processes, while also informing clinical screening and treatment guidelines. However, with a few exceptions, germline variants are not used widely for managing cancer after the diagnosis has been made. By contrast, tumor somatic mutations are widely used for cancer treatment decisions [3.Berger M.F. Mardis E.R. The emerging clinical relevance of genomics in cancer medicine.Nat. Rev. Clin. Oncol. 2018; 15: 353-365Crossref PubMed Scopus (178) Google Scholar]. Recent studies suggest that germline variation not only affects the risk of acquiring cancer but also affects the rate of tumor progression and therapeutic responsiveness. These findings suggest that the study of germline variants in the context of cancer progression could further the field's understanding of molecular processes and identify patients that may benefit from differential clinical management. In this opinion, we highlight these studies to draw attention to this relatively understudied area of oncology with the potential for improving patient care. While germline variants that increase cancer risk inform cancer screening and prevention guidelines, a broader utilization of germline variants for the management of cancer patients has been challenging (Table 1) [2.Huang K.L. et al.Pathogenic germline variants in 10,389 adult cancers.Cell. 2018; 173: 355-370.e14Abstract Full Text Full Text PDF PubMed Scopus (341) Google Scholar,4.Chirita-Emandi A. et al.Challenges in reporting pathogenic/potentially pathogenic variants in 94 cancer predisposing genes - in pediatric patients screened with NGS panels.Sci. Rep. 2020; 10: 223Crossref PubMed Scopus (10) Google Scholar, 5.Sud A. et al.Genome-wide association studies of cancer: current insights and future perspectives.Nat. Rev. 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These rare variants classically exhibit Mendelian inheritance patterns and may be associated with monogenic cancer syndromes. These variants can be studied in the context of familial syndromes. By contrast, common variants tend to have smaller effect sizes and thus still require large cohorts to validate. There seem to be many common variants that contribute to cancer development and progression and their effects tend to be fairly subtle. Therefore, the discovery of these common variants has shifted our understanding of cancer from monogenic diseases to multifactorial diseases. Common variants are not studied in the context of familial syndromes and are instead studied at the population level [9.Zhao M. et al.The Bim deletion polymorphism clinical profile and its relation with tyrosine kinase inhibitor resistance in Chinese patients with non-small cell lung cancer.Cancer. 2014; 120: 2299-2307Crossref PubMed Scopus (77) Google Scholar]. 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(iii) The effect sizes of the germline variants must be large enough to alter clinical decisions because of the increased cost and inconvenience to the patient to start screening for cancer earlier.Table 1Current Challenges and Opportunities for Further Study in Understanding How Germline Variants Play a Role in Shaping the Outcome of Patients with CancerCategoryChallengeExplanationPossible solutionsCancer risk, cancer progression, and general problems of germline variant cancer genomicsCohort sizeCommon variants typically have low effect sizes whereas variants with large effect sizes are often rare, thus requiring large cohortsBuilding large cohorts or tests involving groups of variantsIntegration with clinical phenotypesDatasets in genomics often have minimal clinical annotationBuilding datasets with more detailed clinical annotationEffect sizesThe effect sizes of individual germline variants must be large to motivate clinical useBuilding models with combinations of variants and incorporating variants with large effect sizes, such as pathogenic germline variantsEthnicity backgroundEffects of germline variants may differ based on ethnicityPerform analyses in ethnically diverse cohortsGermline–somatic interactionsUnderstanding the molecular basis for the interactionAssociations may be the result of several complex and indirect associations.Network-based computational approaches or experimental perturbationContext dependencyInteractions may be dependent on specific environmental exposures or may occur in certain genetic backgroundsBuilding datasets with more detailed clinical annotation of environmental exposures and performing studies in ethnically diverse cohortsDrug responsiveness and toxicityDiffering treatment regimens or differing dosagesPatients with the same cancer treated with chemotherapy may undergo different treatment regimens or may be treated with different dosages of chemotherapy drugsReport detailed treatment information when building genomic datasets and experimental perturbation Open table in a new tab We suggest in this opinion that there is another use of germline variants in cancer management: they predict tumor progression and outcome. The most compelling evidence suggesting that germline variation affects tumor progression initially stemmed from studies that showed germline variation can shape the landscape of somatic aberrations in cancer [11.Carter H. et al.Interaction landscape of inherited polymorphisms with somatic events in cancer.Cancer Discov. 2017; 7: 410-423Crossref PubMed Scopus (80) Google Scholar]. Germline variants can interact with somatic aberrations in cancer in multiple ways, such as increasing the likelihood of somatic mutations in the wild-type allele of the same gene or genes in the same pathway. Alfred Knudson's 'two-hit hypothesis' published in 1971 predicted this, as his hypothesis suggested that a germline variant that affected the function of RB1 (a tumor suppressor gene) could be followed by a somatic mutation that affected the other allele of that same tumor suppressor gene to cause tumorigenesis (Figure 1A , Key Figure) [12.Rahman N. 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In line with these findings, a previous study identified functional germline variants in the epidermal growth factor receptor (EGFR) tyrosine kinase associated with an increased risk for subsequent somatic mutations in EGFR [19.Liu W. et al.Functional EGFR germline polymorphisms may confer risk for EGFR somatic mutations in non-small cell lung cancer, with a predominant effect on exon 19 microdeletions.Cancer Res. 2011; 71: 2423-2427Crossref PubMed Scopus (41) Google Scholar]. A large study by Carter et al. analyzed the interaction between inherited polymorphisms and somatic aberrations in almost 6000 tumors across 22 different cancer types [11.Carter H. et al.Interaction landscape of inherited polymorphisms with somatic events in cancer.Cancer Discov. 2017; 7: 410-423Crossref PubMed Scopus (80) Google Scholar]. They identified and validated 412 genetic interactions between germline variants and somatic aberrations. The somatic aberrations were sometimes in genes that were not the same as the ones perturbed by the germline variant. For example, some germline variants were associated with increased risk for somatic mutations in other genes in the same pathway. These findings suggest that more complex computational methods are necessary to attain an integrated understanding of the varied factors, including germline variants, that influence which somatic mutations will occur, or be selected for, in a tumor [11.Carter H. et al.Interaction landscape of inherited polymorphisms with somatic events in cancer.Cancer Discov. 2017; 7: 410-423Crossref PubMed Scopus (80) Google Scholar]. A study of the interaction between germline variation and somatic aberrations in cancer using whole-genome sequencing data from 2658 patients across 38 tumor types by the Pan-Cancer Analysis of Whole Genomes Consortium found that germline variation is predictive of somatic mutational processes across cancers [20.The ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium Pan-cancer analysis of whole genomes.Nature. 2020; 578 (https://www.nature.com/articles/s41586-020-1969-6): 82-93Crossref PubMed Scopus (858) Google Scholar]. For example, germline variants at the 22q13.1 locus were associated with decreased APOBEC mutagenesis in cancer. Rare variants in BRCA1 and BRCA2 were associated with a higher abundance of small somatic structural variant deletions and tandem deletions, consistent with a role of these proteins in error-free homologous recombination directed repair of double-strand breaks. Germline variants in MBD4, a gene that codes for a protein that binds to methylated CpGsCPGs and corrects G:T or G:U mismatches in their vicinity, were associated with an elevated rate of C>T somatic mutations at CpG dinucleotides (Figure 1B). Finally, they identified 114 germline source L1 elements that were capable of active somatic retrotransposition. Overall, their results also suggest that germline variation can shape somatic processes at a genome-wide scale [20.The ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium Pan-cancer analysis of whole genomes.Nature. 2020; 578 (https://www.nature.com/articles/s41586-020-1969-6): 82-93Crossref PubMed Scopus (858) Google Scholar]. Numerous additional studies have explored the link between germline variation and somatic aberrations [21.Mamidi T.K.K. et al.Mapping the germline and somatic mutation interaction landscape in indolent and aggressive prostate cancers.J. 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The variant in GRB2 was also associated with a doubling of somatic mutations in CIC, a tumor suppressor gene that encodes Capicua transcriptional repressor, which negatively regulates the Ras target genes and is mutated in about 21.4% of LGGs (Figure 1C) [24.Chatrath A. et al.The germline variants rs61757955 and rs34988193 are predictive of survival in lower grade glioma patients.Mol. Cancer Res. 2019; 17: 1075-1086Crossref PubMed Scopus (7) Google Scholar]. Understanding the relationship between germline variation and somatic aberrations is particularly promising from a clinical perspective [21.Mamidi T.K.K. et al.Mapping the germline and somatic mutation interaction landscape in indolent and aggressive prostate cancers.J. Oncol. 2019; 2019: 4168784Crossref PubMed Scopus (3) Google Scholar]. (i) A relationship between germline variation and somatic genetic aberration suggests that the aggressiveness of a tumor can be predicted based on the germline status. 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Hematol. Oncol. 2018; 16: 735-745PubMed Google Scholar, 32.Duffy M.J. Crown J. Biomarkers for predicting response to immunotherapy with immune checkpoint inhibitors in cancer patients.Clin. Chem. 2019; 65: 1228-1238Crossref PubMed Scopus (95) Google Scholar, 33.Arora S. et al.Existing and emerging biomarkers for immune checkpoint immunotherapy in solid tumors.Adv. Ther. 2019; 36: 2638-2678Crossref PubMed Scopus (91) Google Scholar]. The idea that there is a link between germline variation and somatic events in cancer implies that germline variation may also affect tumor progression and could be used to predict the prognosis of patients with cancer. Studies in this area have identified germline variants predictive of patient outcome in genes with well-characterized driver roles in cancer. The SNP rs9939049 in the CDH1 gene has been associated with increased risk of colon cancer, along with poor outcome [hazard ratio (HR)_= 1.44] [34.Summers M.G. et al.Comprehensive analysis of colorectal cancer-risk loci and survival outcome: a prognostic role for CDH1 variants.Eur. J. Cancer. 2020; 124: 56-63Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar]. 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In patients with chronic lymphocytic leukemia (CLL), 12 germline variants associated with overall survival were discovered in a variety of genes with moderate-to-high effect sizes (HR = 3.97–43.14) [40.Mosquera Orgueira A. et al.The association of germline variants with chronic lymphocytic leukemia outcome suggests the implication of novel genes and pathways in clinical evolution.BMC Cancer. 2019; 19: 515Crossref PubMed Scopus (4) Google Scholar]. A study of 1365 patients with multiple myeloma found rs2235013 in ABCB1 (HR = 1.52) and rs4148388 in ABCC2 (HR = 2.15) to be associated with decreased overall survival [41.Macauda A. et al.Inherited variation in the xenobiotic transporter pathway and survival of multiple myeloma patients.Br. J. Haematol. 2018; 183: 375-384Crossref PubMed Scopus (10) Google Scholar]. A study by Chatrath et al. of patients with LGGs identified two germline variants associated with poor outcome, one in the oncogene GRB2 (HR = 20.4) and the other in the tumor suppressor gene ANKDD1a (HR = 1.73) [24.Chatrath A. et al.The germline variants rs61757955 and rs34988193 are predictive of survival in lower grade glioma patients.Mol. Cancer Res. 2019; 17: 1075-1086Crossref PubMed Scopus (7) Google Scholar]. A subsequent study extended this approach to all 33 cancers in The Cancer Genome Atlas and characterized the landscape of prognostic germline variants using genomic sequencing data from approximately 10 000 patients [42.Chatrath A. et al.The pan-cancer landscape of prognostic germline variants in 10,582 patients.Genome Med. 2020; 12: 15Crossref PubMed Scopus (12) Google Scholar]. The results suggest that germline variation is associated with patient outcome across all cancers and that germline variation affects tumor progression. Nearly half of the prognostic germline variants were in genes with previously reported roles as oncogenes or tumor suppressor genes. The other half of the genes with prognostic germline variants are of unknown function and require further study [42.Chatrath A. et al.The pan-cancer landscape of prognostic germline variants in 10,582 patients.Genome Med. 2020; 12: 15Crossref PubMed Scopus (12) Google Scholar]. Clinical criteria such as grade and stage of a tumor and selected molecular criteria [e.g., Isocitrate dehydrogenase (IDH) mutation in gliomas] are already being used to predict patient outcome. Such prognostication helps identify patients who are unlikely to respond well to current therapy and for whom newer therapies need to be devised. Adding the status of prognostic germline variants to current prognostic clinical and molecular criteria significantly improves outcome prediction and could therefore potentially be used for patient management decisions [24.Chatrath A. et al.The germline variants rs61757955 and rs34988193 are predictive of survival in lower grade glioma patients.Mol. Cancer Res. 2019; 17: 1075-1086Crossref PubMed Scopus (7) Google Scholar,42.Chatrath A. et al.The pan-cancer landscape of prognostic germline variants in 10,582 patients.Genome Med. 2020; 12: 15Crossref PubMed Scopus (12) Google Scholar]. Recent studies of the molecular functions of germline variants have suggested multiple mechanisms explaining how germline variants can affect tumorigenesis and progression, including some that have already been described (Figure 1A–C). In this section, we describe the intrinsic impact of germline variability on the tumor itself at the molecular level. Two types of genes, oncogenes and tumor suppressor genes, have been implicated in cancer development. Oncogenes are genes that have the potential to cause cancer when they acquire gain-of-function mutations or are highly expressed (e.g., RAS, MYC, and TRK). Gain-of-function mutations increase the activity of a protein or enable the protein to perform a novel function. Tumor suppressor genes normally prevent the development of cancer. Loss-of-function mutations or decreased expression of these genes can contribute to the development of cancer. Loss-of-function mutations alter the proteins coded for by tumor suppressor genes in such a way that they can no longer perform their normal cellular functions. Rare, pathogenic germline variants can result in amino acid changes in oncogenes or tumor suppressor genes resulting in dysfunction of these genes (Figure 1D). While the dysfunction of these genes was originally studied in the context of tumorigenesis, these same molecular mechanisms are likely contributing to differences in tumor progression as well [2.Huang K.L. et al.Pathogenic germline variants in 10,389 adult cancers.Cell. 2018; 173: 355-370.e14Abstract Full Text Full Text PDF PubMed Scopus (341) Google Scholar]. The effects of germline variants are frequently attributed to differences in the expression of nearby genes (expression quantitative trait loci, eQTLs, in cis) [43.Nat. Genet. 2013; 45: 580-585Crossref PubMed Scopus (3916) Google Scholar]. Germline variants can thus be associated with tumor progression because they are eQTLs for nearby genes. In fact, these differences in gene expression can occur in non-tumor cells and modulate tumor phenotypes. For example, the germline variant rs3903072 is associated with decreased risk of breast cancer and prolonged survival in patients with breast cancer. This germline variant is found in a putative regulatory element of the tumor suppressor gene CTSW and is associated with its increased expression. Although the function of CTSW is not entirely known, CTSW is specifically expressed in natural killer and T cells and is believed to play a role in T cell cytolytic activity. Therefore, this germline variant seems to be associated with differences in cell survival through its association with immune cell function (Figure 1E) [44.Zhang Y. et al.The cancer-associated genetic variant rs3903072 modulates immune cells in the tumor microenvironment.Front. Genet. 2019; 10: 754Crossref PubMed Scopus (9) Google Scholar]. We have described earlier that germline variants can affect tumor progression by increasing the incidence of somatic mutations elsewhere in the genome (Figure 1A,C). As another example, the germline variant rs25673 is associated with increased expression of GNA11, which activates mammalian target of rapamycin (mTOR) signaling. Patients with this germline variant are more likely to acquire somatic mutations in PTEN, a tumor suppressor gene, which suppresses mTOR signaling activity (Figure 1F) [11.Carter H. et al.Interaction landscape of inherited polymorphisms with somatic events in cancer.Cancer Discov. 2017; 7: 410-423Crossref PubMed Scopus (80) Google Scholar]. Germline variants can have effects on the transcriptome and splicing patterns independent of their roles as eQTLs. Some mechanisms involve selection for mutations elsewhere in the genome, as with CIC gene deletions in patients with germline variant rs25673 in the oncogene GRB2, an adaptor protein in the Ras signaling pathway, leading to upregulation of Ras target genes (Figure 1C) [24.Chatrath A. et al.The germline variants rs61757955 and rs34988193 are predi