Germline Variants That Affect Tumor Progression
Ajay Chatrath, Aakrosh Ratan, Anindya Dutta
Abstract
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. Cancer. 2017; 17: 692-704Crossref PubMed Scopus (171) Google Scholar, 6.Li M.M. et al.Standards and guidelines for the interpretation and reporting of sequence variants in cancer: a joint consensus recommendation of the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists.J. Mol. Diagn. 2017; 19: 4-23Abstract Full Text Full Text PDF PubMed Scopus (754) Google Scholar, 7.Zhang J. et al.Germline mutations in predisposition genes in pediatric cancer.N. Engl. J. Med. 2015; 373: 2336-2346Crossref PubMed Scopus (624) Google Scholar, 8.Bodmer W. Tomlinson I. Rare genetic variants and the risk of cancer.Curr. Opin. Genet. Dev. 2010; 20: 262-267Crossref PubMed Scopus (51) Google Scholar]. (i) The use of germline variants in managing cancer requires validation in large cohorts because variants with large effect sizes tend to be rare. 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]. (ii) While cancer risk is affected by germline variation, other clinical factors such as environmental exposure and age need to be considered to maximize their utility for prediction of cancer risk [10.Tomasetti C. Vogelstein B. Cancer etiology. Variation in cancer risk among tissues can be explained by the number of stem cell divisions.Science. 2015; 347: 78-81Crossref PubMed Scopus (1172) Google Scholar]. (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 in the molecular for the may be the of and or may be on environmental or may in genetic datasets with more detailed clinical of environmental and studies in and treatment or with the cancer with may treatment or may be with of detailed treatment datasets and in a suggest in this opinion that is use of germline variants in cancer tumor progression and The evidence suggesting that germline variation affects tumor progression from studies that germline variation can the landscape of somatic aberrations in cancer et landscape of with somatic in 2017; PubMed Scopus Google Scholar]. 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In with these a study germline variants in the tyrosine kinase associated with an increased risk for somatic mutations in W. et germline may risk for somatic mutations in non-small cell lung with a effect on PubMed Scopus Google Scholar]. large study by et the between and somatic aberrations in tumors across cancer et landscape of with somatic in 2017; PubMed Scopus Google Scholar]. and genetic between germline variants and somatic The somatic aberrations in genes that not the as the by the germline germline variants associated with increased risk for somatic mutations in other genes in the These findings suggest that more are to an understanding of the germline variants, that influence which somatic mutations or be in a tumor et landscape of with somatic in 2017; PubMed Scopus Google Scholar]. study of the between germline variation and somatic aberrations in cancer from patients across tumor by the of that germline variation is of somatic mutational processes across of of 2020; PubMed Scopus Google Scholar]. germline variants at the associated with in Rare variants in and associated with a of somatic variant and with a role of these in of Germline variants in a that for a that to and or in their associated with an rate of somatic mutations at germline that of somatic Overall, their also suggest that germline variation can somatic processes at a genome-wide of of 2020; PubMed Scopus Google Scholar]. studies have the between germline variation and somatic aberrations et the germline and somatic landscape in and Oncol. PubMed Scopus Google Scholar, et and of Mol. 2018; PubMed Scopus Google Scholar, et al.Germline variants somatic Genet. Full Text Full Text PDF PubMed Scopus Google Scholar]. study from et from patients with and a germline variant in an in the which associated with increased expression of genes in the The variant in also associated with a of somatic mutations in a tumor that which the genes and is in of A. et al.The germline variants and are of in Cancer 17: PubMed Scopus Google Scholar]. Understanding the between germline variation and somatic aberrations is from a clinical et the germline and somatic landscape in and Oncol. PubMed Scopus Google Scholar]. (i) between germline variation and somatic genetic suggests that the of a tumor can be based on the germline (ii) Germline variation has to be used to the selection of clinical as of this of personalized medicine in the 2015; PubMed Scopus Google Scholar, medicine and Clin. 2017; Full Text Full Text PDF PubMed Scopus Google Scholar, a general on to Med. 2017; Google Scholar, and study in Med. PubMed Scopus Google Scholar]. The of tumors and cancer cell has to identify the of M. et of the Cancer PubMed Scopus Google et the In PubMed Scopus Google Scholar]. The of an between germline variation and somatic aberrations suggests that can be the of germline variants. (iii) Germline variants in the genes instability, which the of and is associated with an improved response to immune et in cancer: of its clinical and Oncol. 2018; Google Scholar, J. for response to with immune in cancer PubMed Scopus Google Scholar, et and emerging for immune in PubMed Scopus Google Scholar]. 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Recent have also between patient outcome and germline variants in genes that not been previously to In patients with germline variants associated with in a of genes with effect sizes A. et al.The association of germline variants with outcome suggests the of genes and pathways in clinical Cancer. 19: PubMed Scopus Google Scholar]. study of patients with in and in to be associated with A. et variation in the and of J. 2018; PubMed Scopus (10) Google Scholar]. study by et of patients with germline variants associated with in the and the other in the tumor A. et al.The germline variants and are of in Cancer 17: PubMed Scopus Google Scholar]. study this to in The Cancer and the landscape of germline variants from patients A. et al.The landscape of germline variants in Med. 2020; PubMed Scopus Google Scholar]. 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(iii) The to development of adult is often than the to progression or to after a patient has a is of an opportunity for environmental factors to play a role in the progression of and may be to for factors in studies of tumor progression than studies of cancer risk. of the for germline variants cancer progression can be with a smaller number of the smaller to studies associating germline variants with cancer progression and patient Understanding the mechanisms by which germline variants are associated with patient outcome and tumor progression is challenging to factors and is to be a rich area of future datasets are to and germline variants in and this is variant that is associated with in these datasets may not be the variant for the effect on the could be in genetic with the variant that affects the In germline variants are in in the and could affect outcome through effects on such as through immune or in the tumor a which and which is for the has to the molecular mechanisms by which germline variants in this area has by which the variants may be such as through of and and modulation of expression C. et of with cancer and for and a and Oncol. 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