Decoding the genetic jigsaw: screening tests for cancer

“I would counsel the patient as they look at their report. It’s the start, but not the end of the story for that person.”

Following my recent article on breast cancer in India, I received many enquiries seeking more information on genetic screening tests. Especially from people with a family history of breast or ovarian cancer. The basic question: “should I get tested and how do I go about it.”

While genetic testing has become increasingly accessible, knowing when to get a test and choosing the right test is difficult. Interpreting results and understanding next steps is harder yet. To dig into this subject, I opted for a podcast format, teaming up with my collaborator, Dr. Jonathan Golob.

Dr. Golob and I plan a series of podcasts at increasing levels of depth.

1. Episode 1:Genetic screening tests for cancer (this episode).
2. Episode 2:Variants of Unknown Significance (VUS): Initial explorations.
3. Episode 3: Advanced bioinformatics approaches for re-classifying VUS.

A link to the full podcast, summary of what we discuss, as well as a transcript of highlights from the podcast follow.

What we discuss:

• The potential of genetic testing in providing personalized health information and risk assessment for a specific cancer.
• The concept of genetic variants and their significance.
• When and if a person with a family history of cancer should get tested and what to consider ahead of testing.
• The difference between diagnostic and screening genetic tests, targeted and non-targeted tests, direct-to-consumer (DTC) vs. tests that are prescribed by a physician.
• The distinction between pathogenic, benign and unknown variants (VUS).
• Next steps when a test result is inconclusive.

Highlights from the podcast:

On genetic tests:

“A genetic test at the end of the day is a test that tells you what genes a person has or what’s inside of their DNA. And the genes that we have can confer risks or protection from diseases, things like cancer. How well established those associations between the gene and an outcome varies quite a bit by disease to disease. Some genes are very very well described. Some we’re still working on it.”

Understanding genes:

“The way I could think about a genome or a collection of genes like a person has — they’re sort of addresses and in each address, kind of like a cookbook. You have a section for different recipes you want to make. The allele is the exact recipe that’s in there and maybe both you and another person will have a recipe here to say, make a biscuit but your biscuit recipe will be a little bit different than another person’s. It’s still biscuits.”

Alleles, variants and mutations:

“Variants are akin to alleles. So a gene has lots of variants. And we call in the specific case versions of a gene or variants of a gene as alleles, a mutation is by which the alleles exist.”

When to consider genetic testing:

“If the cancers are occurring younger than expected or you have multiple family members that have cancer, that’s when it starts to get concerning that there’s a component of genetics.”

On direct-to-consumer tests vs. tests prescribed by a physician:

“The hardest thing here is not identifying what genes a person has nowadays. The interpretation is the tricky part. And generally my advice to people is to find a doctor that you trust and you’ve worked with for years and have the conversation with them.”

Genetic tests targeted for a specific set of cancers vs. broader screening tests:

“I generally suggest, and I think it’s a better idea to do the targeted test.”

“Although it sounds great, like, well, ‘we’ll look at all of my genes, I want to look at everything’. It’s almost certain any random, perfectly healthy, person who will never go on to have a genetically related condition to find a couple variants or mutations that are that are associated with disease.”

You’re going to get genetic testing. What to do in the interim:

“The first thing to do even before genetics is get the screening done now and make sure you yourself do not have something early or brewing that is related to one of those cancers.”

What to expect in a test result:

“I would counsel the patient as they look at their report. It’s the start, but not the end of the story for that person.”

“I think what one wants from here is a very definitive answer, yes or no…You have no genetic risk for breast cancer. And that’s a very, very hard thing to say because it’s hard to prove a negative… More often it’s an increased risk in some degree.”

How variants get classified:

“All variants start out as a variant of unknown significance, and from here they can go one of two ways. As they’re studied further, they can become benign. In other words, a variant that seems to be associated with protection, or at least no increased risk in this case of cancer, or a pathologic variant. And then there’s sort of intermediate ways of likely pathologic or likely benign. And so you have that sort of grading scale, and most things end up right in the middle of unknown significance.”

If a result is positive:

“Having like a good physician partner to help walk through it is almost essential in a way, I think, that most physicians would want and be happy to be helping someone think through this very, very complicated decision. And BRCA mutations in some ways are easier in the sense that it’s a relatively clear answer. When one gets into the realm of possibly pathogenic or relatively lower penetrance less likely to result in cancer, the question gets harder and harder to answer, and sometimes requires an evolving discussion over time.”

An inconclusive result (variant of unknown significance) and what’s next:

“I think it’s critical to be an active participant. Unless you have a longitudinal relationship with the physician and have this on the agenda, I would not expect someone to go back to a previous genetic test results and revisit to see if these variants of unknown significance have since been identified as being at high risk or low risk.”

“Someone who has had multiple family members who have had cancer early in life : that prompted a genetic test that is targeted to a disease, and then the test comes back with variants of unknown significance or basically an indeterminate result. My interpretation of that whole picture is to still be quite concerned about that person’s risk for cancer. The original impulse for the test remains there, and we’ve gained no information that reduces our concern.”

In our next podcast, we discuss how clinical researchers, physicians and geneticists investigate a Variant of Unknown Significance — VUS. We talk about their approach and the tools that they use to help them understand the variant: we discuss genetic complexity, diversity, rarity of the variant and the role of population databases and functional studies in determining clinical significance.