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BRCA Mutations Investigated in Colorectal Cancer

Greg Kennelty
Published Online:3:56 PM, Tue July 5, 2016

Matthew B. Yurgelun, MD

A recent study uncovered BRCA1 and BRCA2 mutations as possible risk markers for colorectal cancer, according to Matthew B. Yurgelun, MD.

In an interview with Targeted Oncology, Yurgelun, Instructor in Medicine, Harvard Medical School, discusses a possible link between BRCA1 and BRCA2 mutations and colorectal cancer, as well as other genetic markers that have yet to be defined.

TARGETED ONCOLOGY: Can you tell us about your recent study into colorectal cancer risk?

Yurgelun: We examined over 1000 individuals with colorectal cancer who were seen at the Dana Farber Cancer Institute, and who ultimately consented to participation in a sample registry. We were really looking to try to understand what the prevalence of hereditary cancer susceptibility syndromes is in this patient population. Data that are out there suggest that there's probably about a 3% prevalence of Lynch syndrome in colorectal cancer patients, but these data have been primarily ascertained from looking for specific high-risk features in the colorectal cancer patients themselves. These features include tumor testing for mismatch repair deficiency and high-level microsatellite instability.

We were really trying to go into this looking at patients without any sort of pre-selection, and to test them beyond just Lynch syndrome. We wanted to test them for Lynch syndrome, but also for mutations linked to other hereditary colorectal cancer syndromes, as well as other hereditary cancer syndromes that are not necessarily linked to other colorectal cancer risks.

We took about 1059 patients with colorectal cancer seen at the Dana Farber Cancer Institute, all of whom had germline DNA collected and all of whom had clinical data available based on their clinical care, and we performed germline genetic testing to evaluate for pathogenic mutations in 25 cancer susceptibility genes.

TARGETED ONCOLOGY: What were the most significant findings?

Yurgelun: Ultimately, we found that 10% of patients in our cohort had pathogenic mutations in one or more cancer susceptibility genes. We found a 3.1% prevalence of Lynch syndrome, which fits with what's seen in the established literature. Reassuringly, virtually all of these patients who had Lynch syndrome had tumors with high-level microsatellite instability and mismatch repair deficiency, more or less illustrating that our current processes for identifying Lynch syndrome among colorectal cancer patients seems to work. If you do universal tumor testing, which is endorsed by the NCCN right now, you really should pick up the majority of patients with Lynch syndrome.

What was novel about our study however, was that we found 7.1% of patients with colorectal cancer actually had a mutation in the non-Lynch syndrome cancer susceptibility gene. These are patients who wouldn't be picked up by typical tumor testing, because tumor testing really just looks for evidence of Lynch syndrome. The most common high-penetrance finding that we found in this cohort beyond Lynch syndrome were surprisingly mutations in BRCA1 and BRCA2. These are genes that are not traditionally linked to risks of colorectal cancer, so we need some more information to help us understand what to do with these types of results and whether or not a germline BRCA mutation found in a colorectal cancer patient has the same significance as one found in a breast or ovarian cancer patient.

I think what it shows to the community oncologist is that tumor testing for Lynch syndrome seems to work well, but we really can't stop there and we need to think beyond Lynch syndrome when we're looking at colorectal cancer patients.

TARGETED ONCOLOGY: What are the steps you should take in addressing this for patients?

Yurgelun: There's a lot of interest right now in testing tumor specimens to look for mutations that are driving somebody's tumor and to try to pick out new targeted therapies to help treat their cancer. At the same time we can't forget about the germline DNA because it helps us understand what's going on in the tumor, but just as importantly or perhaps more importantly, it helps us understand why the patient got cancer in the first place. Are they at risk for more cancers? Is their family at risk? These are things that a lot of patients do want to know. They might not think they're at risk for these things, and it may be something they don't think about until their oncologist brings it up. They are important discussions to have for sure, though.

TARGETED ONCOLOGY: Are there any next steps to this study you'd like to address?

Yurgelun: We certainly need to look more into the significance of some of these surprise mutations. There are a lot of genes that we are now testing for where I don't think we understand the full spectrum cancer risk that mutations in these genes confer. So understanding the full phenotypic spectrum, as well as the magnitude of risk conferred by some of these mutations, is going to be critically important in providing patients and providers the information they need to understand and interpret these results.

Furthermore, even the genes we think we do understand well, we're learning that the spectrum of cancer risk linked to them may be wider than we traditionally though, and I think we need to do larger studies looking at specifically whether or not these mutations mean the same things when you find them in a non-traditional fashion, such as when we find a BRCA mutation in a colorectal cancer patient.

TARGETED ONCOLOGY: What are the risk factors for colorectal cancer?

Yurgelun: Family history is an important and powerful risk factor. Certainly in the setting of Lynch syndrome and some of the more traditional hereditary colorectal cancer syndromes, that is well-established, but it's also well-established outside of known defined hereditary syndromes that a family history of colorectal cancer is critically important in determining risk. So a patient who knows they have a family history of colorectal cancer probably needs to be screened earlier, more frequently, and it's an important thing for them to consider when creating their own screening guidelines.

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