Therapeutic Utility of Germline Variants Is an "Open Question"

Hannah Carter, PhD

Although heritable mutations have been implicated in cancer risk, the role that these aberrations play in the development of malignancies with acquired mutations is a question that will require studies of large data sets of patients, according to Hannah Carter, PhD.

“Several common germline variants have found their way to the clinic as biomarkers, but so far the utility of common germline variants in the clinic is an open question,” said Carter, a bioengineer at the University of California, San Diego (UCSD), whose laboratory uses computational modeling to study genetic mutations in cancer and identify molecular signatures that could lead to novel therapeutic strategies.

Carter, also an assistant professor in the Department of Medicine at UCSD, discussed the clinical impact of germline and somatic mutations in cancer in an interview with OncologyLive^®.

OncLive: What are the clinical implications of germline and somatic mutations in cancer at this time?

Carter: Somatic mutations are of interest because they are specific to the cancer cells. Sometimes these mutations can generate vulnerabilities that can be drugged to specifically kill tumor cells without damaging healthy cells without the mutation (so-called targeted therapies). Somatic mutations can also create neoantigens that the immune system can recognize. Usually tumors evolve mechanisms to evade the immune system, but if these evasive mechanisms can be suppressed (for example, using checkpoint inhibitor therapy), immune cells can attack tumor cells that express neoantigens.

Germline variants are usually divided into 2 categories: rare high-penetrance variants like BRCA1/2 mutations that are associated with cancer syndromes and early-onset disease, and common variants present in >1% of individuals in the population.

Rare high-penetrance variants can have implications for the type/subtype of cancer that will develop and the types of somatic mutations that will accumulate in cells. Many rare cancer syndrome variants influence the rate of accumulation of somatic mutations, for example, by interfering with DNA repair or sensitizing to ultraviolet radiation. These variants often travel in families, and if someone has a family history of cancer, they may receive carrier testing to see whether they have a rare germline variant in a cancer predisposition gene. Finding such a variant might indicate that a patient should be more closely monitored for developing malignancies, and there have been cases where patients opt to have prophylactic surgeries (for example, mastectomy with BRCA1/2 mutations).

Many common germline variants have been implicated in cancer risk, usually through genome-wide association studies [GWASs]. These studies compare groups of individuals with cancer with groups of healthy individuals and look for variants that are more frequent in the population with cancer. Common variants are often difficult to tie to cancer mechanistically because the markers studied are not necessarily the causal ones, but such markers can be used in aggregate to create genetic risk scores that can identify individuals at higher lifetime risk of developing cancer. These scores have not made their way to routine use in the clinic just yet, but investigators are beginning to evaluate them in clinical trials. Several common germline variants (also called single-nucleotide polymorphisms, or SNPs) have found their way to the clinic as biomarkers, but so far the utility of common germline variants in the clinic is an open question.

Please discuss recent studies suggesting a link between the 2 types of mutations.

The link is fairly obvious for rare germline variants that can modify somatic mutation rates to generate risk of early-onset disease. The link for common variants has been more tenuous, but there are increasing anecdotal reports that f ind SNPs that are associated with the presence of specific mutations or mutagenic processes in tumor cells.

For example, germline variants in the EGFR locus were found to be overrepresented in nonsmokers with EGFR-mutant lung cancer. This suggests a group of individuals who are predisposed to develop EGFR mutations and, consequently, lung cancer. SNPs have also been found to modify APOBEC-driven mutagenesis, where APOBEC is an enzyme that causes mutations at particular DNA sites and is often inappropriately activated in tumors.

Some SNPs also appear to be preferentially amplified by somatic DNA copy number changes in tumors. There was also a recent finding of a SNP associated with differences in immune cell infiltrates into tumors, suggesting the possibil-ity of effects on the tumor microenvironment as well as the somatic tumor genome. Results of such studies suggest direct links between the germline and the somatic tumor genome.^1-6

What are the implications for the development of cancer?

These findings suggest that tumor development is not completely random—that the mutations that get fixed in the developing tumor genome are influenced by an individual’s genetic back-ground. Depending on the strength of these relationships, it could be possible to predict aspects of tumor development from knowledge of the inherited genome.

How might this affect cancer management?

Because most common germline variants impli-cated so far have only a weak effect on risk, it is still unclear how useful germline—somatic inter-action information will ultimately be for clinical applications, such as assessing risk, prognosis, and potential to respond to therapies. However, some of the interactions detected so far have had stronger effects than the classic GWAS-risk SNPs. In addition, because germline–somatic interactions link germline markers to somatic events that are better studied and understood at the level of molecular mechanism, there is potential to gain new understanding of biology underlying cancer risk and progression.

Because somatic mutations are often targets for therapy, some germline—somatic interactions are likely to have implications for the potential to respond to therapies. There is already some indi-cation that the inherited genotype at the HLA [human leukocyte antigen] locus, which encodes a key component of the antigen presentation pathway, influences an individual’s potential to respond to immunotherapy.⁷

What are the most significant unanswered questions related to the roles of these 2 types of mutations in cancer?

Perhaps the biggest question is whether germ-line—somatic interactions will provide actionable information to guide risk-modifying lifestyle changes, screening, or treatment of tumors. Initial findings are suggestive that select interac-tions have relevant effects, but more studies are needed to identify and mechanistically characterize germline–somatic interactions in the context of clinical outcomes. This will require obtaining both germline and somatic genomes for tumors in large, clinically annotated patient cohorts.

References

1. Robles-Espinoza CD, Roberts ND, Chen S, et al. Germline MC1R status influences somatic mutation burden in melanoma. Nat Commun. 2016;7:12064. doi: 10.1038/ncomms12064.
2. Middlebrooks CD, Banday AR, Matsuda K, et al. Association of germline variants in the APOBEC3 region with cancer risk and enrichment with APOBEC-signature mutations in tumors. Nat Genet. 2016;48(11):1330-1338. doi: 10.1038/ng.3670.
3. Olcaydu D, Harutyunyan A, Jäger R, et al. A common JAK2 haplo-type confers susceptibility to myeloproliferative neoplasms. Nat Genet. 2009;41(4):450-454. doi: 10.1038/ng.341.
4. Liu W, He L, Ramirez J, 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(7):2423-2427. doi: 10.1158/0008-5472.CAN-10-2689.
5. Fleming JL, Dworkin AM, Allain DC, et al. Allele-specific imbal-ance mapping identifies HDAC9 as a candidate gene for cutane-ous squamous cell carcinoma. Int J Cancer. 2014;134(1):244-248. doi: 10.1002/ijc.28339.
6. Kogan D, Grabner A, Yanucil C, Faul C, Ulaganathan VK. STAT3-enhanc-ing germline mutations contribute to tumor-extrinsic immune evasion. J Clin Invest. 2018;128(5):1867-1872. doi: 10.1172/JCI96708.
7. Chowell D, Morris LG, Grigg CM, et al. Patient HLA class I genotype influences cancer response to checkpoint blockade immunotherapy. Science. 2018;359(6375):582-587. doi: 10.1126/science.aao4572.