Genetic testing is just as important to a healthy patient having a mammogram as it is to a patient who has multiple types of cancer in her family, according to Sandra Brown, MS, LCGC, Manager of the Cancer Genetics Program at the Center for Cancer Prevention and Treatment at St. Joseph Hospital, Orange, CA.
At the AONN+ 10th Annual Navigation & Survivorship Conference, Ms Brown discussed the importance of understanding the role of genetic testing in the cancer realm, and took an in-depth look into the science that backs it.
“Genetics counselors are your partners in patient healthcare, navigation, and survivorship,” she said. “They’re also your partners in understanding targeted therapies, and in understanding and helping patients to interpret their experience with genetics and genomics.”
“Tissue Is the Issue”
Understanding the functions of different tissues in the body is paramount to understanding genetics and genomics.
Each cell type in the body uses only the specific genes that provide the functions for that particular cell to be healthy. A mutation occurs when a gene undergoes a change that alters the sequence of DNA, and thereby alters the function of the gene.
“Genes are like instructions, so they do say something,” she explained. “If a gene is supposed to say ‘time to dream,’ and there’s a single letter change in the DNA, it changes the meaning of the sentence (eg, ‘tame to dream’).” A translocation (when letters are reversed), a deletion, or an insertion would also change the meaning of the “sentence” and would in turn alter the function of the protein the gene has created. “A lot of what we do in genetics is to try to understand the consequence of having a change in an amino acid and an alteration in the protein,” she added.
“Not All Cancers Are Inherited, But All Cancer Is Genetic”
Most cancers are not inherited: about 60% are sporadic, 30% are familial (likely caused by a combination of genetic and environmental risk factors), and the remaining 5% to 10% are hereditary (high risk).
“Cancer itself is a function of an accumulation of mutations, and those mutations lead to the progression of tumorigenesis,” she said.
A person might be more likely to develop that accumulation of mutations when a cancer is inherited, but the same process occurs with cancers that are not inherited.
“Inherited mutations occur and exist in every cell in the body, but some cell types don’t really care,” she explained. For example, the consequence of a BRCA mutation is not significant to the bones or muscles, but it is significant to the breast tissue.
However, not all inherited mutations lead to cancer. The development of cancer is still partially due to the accumulation of mutations as a natural function of aging (in addition to having that inherited mutation that created the initial susceptibility). Sporadic mutations also develop with age, and although some may never lead to cancer, others may accumulate and create a tumor.
But as these mutations occur throughout a person’s life, tumor suppressor genes act like “brakes” against cancer and save cells by fixing mutations, telling bad cells to go kill themselves, and telling good cells to copy themselves. But cancer resists cell death and proliferates when tumor suppressor genes lose their function. When a person has a mutation, some of the protective functioning of tumor suppressive genes ceases to occur, and that person’s tumor mutational burden starts to accumulate.
Cancer Genetic Counseling and Risk Assessment
According to Ms Brown, a number of issues should be addressed in a patient’s first genetic counseling appointment. Start by collecting a 4-generation family history (including ages, cancer diagnoses, polyps, tumors, excisions, surgeries, and pathology), and making sure the patient understands the difference between sporadic, familial, and inherited patterns of cancer risk (understanding inheritance and germline vs somatic [noninherited] genetic findings).
She noted that about 5 years ago, patients were only tested for 5 to 8 genes, but now they are routinely tested for anywhere between 80 and 100 genes. “The cancers that trigger us to test patients are not rare, and the biggest trigger is breast cancer,” she added, noting that the American Society of Breast Surgeons now recommends genetic testing for every new diagnosis of breast cancer.
Once genetic testing is done, it is important to be able to accurately interpret the results. “If a patient has a variant of unknown significance, if we’re suspicious and think it should be reclassified as a deleterious mutation, we have to do a lot of work to gather more information from the family,” she said. “We also have to talk with the lab about increasing the quality of the evidence so we can work on advancing the knowledge about that particular mutation.”
An important facet of interpreting risk comes down to understanding that the less risky a mutation is and the less risk a gene has, the more commonly it will be carried in the population. Conversely, the higher the risk of a mutation or gene, the rarer it is in the population. For example, inheriting a TP53 mutation has very high risk, and it is the least identified in genetic testing, she noted.
Although a mutation in a tumor might have been inherited (the National Comprehensive Cancer Network recommends confirmatory testing if a mutation is found to have reasonable clinical suspicion of being of germline origin), the lack of a mutation in a tumor is not enough evidence to rule out the chance that a cancer was hereditary. “Tumors can get rid of evidence of inheritance, but they can also show us evidence of inheritance,” she said. “So it’s important to look at the tumor at your next NGS [next-generation sequencing] tumor profiling with an eye of caution.”
The American College of Medical Genetics and Genomics now lists 55 specific genes that should be acted on when seen in a tumor. “And typically, we’re doing NGS testing on higher-stage cancers, regardless of the tumor type,” she said. “If it’s a metastatic cancer, in our cancer centers they’re all having next-generation sequencing and profiling.”
Future Directions
According to Ms Brown, genetic testing improves physician and patient satisfaction while also increasing patient access to cutting-edge genetic research.
“People wonder what is the most efficient way to screen patients, and I think what’s important is to know that there are limits to what’s out there,” she said. For example, one study showed that popular direct-to-consumer genetic tests like 23andMe have about a 40% false-positive rate.
“I think people are overly trusting and confident that a 23andMe result is a clinical result,” she cautioned. “This is important in large part because a 40% false-positive rate is obviously intolerable, but what we don’t know is the false-negative rate, and that’s likely to be much higher.” She also pointed out the recent uptick in genetic testing scams and fraudulent providers who target patients. If a test is not connected to a legitimate genetics provider, she urges patients and providers to be dubious.
According to Ms Brown, future directions in genetics will focus on things like CRISPR (clustered regularly interspaced short palindromic repeats), tumor gene editing, developing genetic therapies to reinstate loss of function, improving toxicities (particularly off-target toxicities), and increasing the predictive reliability of response to therapy, including more specific tumor profiling mutations.
“One of the most common things we hear in our molecular tumor board is a desire to better understand,” she said. “We think we might have a drug target, and then the patient either doesn’t respond or becomes refractory right away. We want to better understand how to create a permanent response and a permanent benefit to these patients.”