Genetics and genomics are both important concepts in biology, and have become household terms to some extent—but what do they mean? And how are technologies associated with genetics and genomics helping to improve care for patients today, including those with cancer?
To discuss these questions and more, CRI spoke with Corrie Painter, Ph.D., of the Broad Institute of MIT and Harvard as well as the Angiosarcoma Project, and Eliezer Van Allen, M.D., of Harvard Medical School and Dana-Farber Cancer Institute, as part of the Cancer Research Institute (CRI) “Cancer Immunotherapy and You” patient education webinar series.
One point that was made abundantly clear is that this topic is confusing and complicated and that the terms used are not always well understood.
In general, genetics is used to describe the genes you’re born with, the ones you’ve inherited from your parents. This is also called the germline, and every cell in the body starts out with essentially the same exact copy.
Over time, genes within certain cells can change from random DNA repair mistakes or exposure to things that can mutate DNA, like ultraviolet (UV) radiation, cigarette smoke, and other carcinogens.
The study of changes that occur in the genes of living cells is called genomics. In the context of cancer, that is the analysis of the mutated genomes of tumor cells. (These changes in living cells are also known as somatic mutations.) Thus, genomic testing, or genome sequencing, has the potential to provide important information to doctors and enable them to provide better care for their patients.
With genomic testing, doctors can find out how many mutations a tumor has. This is known as tumor mutational burden, or TMB. Doctors can also tell if a tumor has become unstable based on the presence of high microsatellite instability, or have “MSI-H” status, meaning they have clusters of genetic errors.
Both TMB-H and MSI-H tumors are more likely to respond to immunotherapy, and the FDA has already issued two immunotherapy approvals for people with all types of advanced cancers with these genetic markers, regardless of which organ they originated from. The reason immunotherapy works better against these tumors is they typically appear more “foreign” to the immune system due to their mutations.
Importantly, as Van Allen noted, just because a patient’s tumor doesn’t have either of these biomarkers—TMB-H or MSI-H—doesn’t mean they won’t respond to immunotherapy. These aren’t perfect biomarkers, and there is still a lot we don’t know, and that’s why continued clinical research is so crucial.
Scientists are busy looking for other meaning genetic clues beyond TMB-H and MSI-H status. There are many different mutations seen in different patients, and little remains known about which are important, either for driving the tumor’s growth and survival or providing targets for the immune system, or knowing which mutations are just bystanders.
It’s clear that some genomic changes—known as “events”—can occur after treatment, and those changes might be important for the next treatment decision. And there are now enough drugs related to specific genomic changes—that can theoretically be found in any and all cancers—to suggest they can provide clinical value.
Additionally, these tools can also enable the identification of specific mutations for emerging cell therapies and vaccines that can be personalized for individual patients. New tools are also being developed to improve the way tumor genomes are analyzed.
Liquid biopsies are a promising approach, which Painter explained is “just a fancy way to say blood draw.” Both normal cells and tumor cells can “shed” DNA that can end up circulating in the blood, and this material can be analyzed via blood-based biopsies. Cell-free DNA, or cfDNA, refers to all of this DNA, whereas cancer-related DNA is called circulating tumor DNA, or ctDNA.
This noninvasive biopsy method, as it becomes validated, may enable doctors to monitor patients tumors’ more quickly and easily, and without actually having to perform a surgical biopsy. It could also make it easier to do multiple tests over time in patients with advanced, treatment-resistant cancers. Lastly, liquid biopsies offer the ability to analyze DNA from tumors at different sites in people with metastatic disease.
Both Drs. Painter and Van Allen also emphasized that more data will be needed to further optimize these approaches as well as our understanding of genomic testing in general, and stressed that the patient community has a chance to help drive significant progress here.
In contrast to tumor genomics, genetics—which focuses on the genes that you inherited from your parents—can help patients better understand their potential risk of developing cancer, and can be particularly informative in people whose families have a history of cancer or may have other known genetic risk factors.
Certain inherited genetic factors, such as certain versions of the BRCA gene or those associated with Lynch syndrome, have been linked to a higher risk of developing cancer throughout one’s life. The presence of some of these can also suggest whether a person is likely to respond to a certain therapeutic intervention if and when they do develop cancer.
Painter—who herself has had a brush with cancer—also addressed the very real concerns that some patients have had with respect to consumer testing kits—and perhaps just the concept of letting someone else have access to information about their DNA in general.
In particular, she discussed concerns about privacy and the anxiety that can result. Ultimately, she emphasized the importance of people talking to—and really digging down deep with—their medical team about which tests might be appropriate for them. She also encouraged patients to speak with genetic counselors if at all possible. Trained genetics professionals can be incredibly helpful when navigating and attempting to understand the risks of different options available to someone. These decisions, after all, are of a very individual and absolutely personal nature.
For more information on genomic sequencing for patients, check out Sequence Me. More information about genetic testing and counseling can be found through the National Society of Genetic Counselors.
CRI's "Cancer Immunotherapy and You" webinar series is produced by the Cancer Research Institute and was hosted by Arthur Brodsky, Ph.D.. Sponsorship for this webinar was generously provided by Bristol-Myers Squibb, Alkermes, and Foundation Medicine. Sponsorship does not influence editorial decisions or content. Browse our Cancer Immunotherapy and You Webinar Series playlist on YouTube or visit the Webinars page on our website to see other webinars in this series.