Inherited Mutations Play Greater Role in CRC Than Previously Thought

Matthew B. Yurgelun, MD

Nearly 10% of patients with colorectal cancer (CRC) had germline cancer susceptibility gene mutations, according to a study recently published in the Journal of Clinical Oncology. This is much greater than the 3% to 4% previously thought, said lead study author Matthew B. Yurgelun, MD.

The study, which was conducted at the Dana-Farber Cancer Institute, included 1058 patients who were not preselected for age at diagnosis, personal/family history, tumor microsatellite instability (MSI), or mismatch repair (MMR) deficiency. Germline testing was conducted for 25 genes linked to inherited cancer risk.

The results showed that 105 patients (9.9%; 95% CI, 8.2%-11.9%) had at least 1 pathogenic mutation, including 33 patients (3.1%) with Lynch syndrome (LS). Among 29 evaluable LS CRCs, all but 1 showed abnormal MSI/MMR results. Non-LS gene mutations were detected in 74 (7%) patients, including BRCA1/2 mutations in over 1% of patients.

OncLive: Please provide an overview of your study?

In an interview with OncLive, Yurgelun, assistant professor of Medicine, Harvard Medical School, and a researcher at the Dana-Farber Cancer Institute, discussed the study and its implications for patients with CRC and their families.Yurgelun: We analyzed 1058 individuals who had a diagnosis of colon cancer who were seeking care at the Dana-Farber Cancer Institute. As a part of their clinical care here, they consented to have blood drawn for the purposes of research. For this study, we then went on to perform germline testing on all individuals using a commercially available 25-gene panel to look for inherited mutations in genes associated with inherited cancer risk. Some of the genes are linked to inherited CRC risk, and some genes are linked to inherited risk of other cancers, but not necessarily CRC.

For a long time, we’ve known that inherited factors do play a large role in the ideology and risk of CRC, although historically we thought that that accounts for a pretty small fraction of individuals with colorectal cancer, probably around 3% to 4%.

One of the key findings from our study here, however, was that inherited mutations in a cancer susceptibility gene were found in nearly 10% of individuals who we analyzed with this 25-gene panel. These individuals were not specifically selected for factors we traditionally associate with inherited risks of cancer. For example, these individuals were not specifically selected for being young at the time of their colon cancer diagnosis, they were not specifically selected based on factors in their tumor, or based on any sort of family history of cancer.

Was BRCA included in the gene panel?

The fraction of individuals found to have inherited mutations in cancer susceptibility genes was quite a bit higher than what we would have expected in the past. BRCA1 and BRCA2 were analyzed as part of this 25-gene panel, and those are genes that historically have been known to confer particularly high lifetime risks for female breast cancer, ovarian cancer, and to a lesser extent, male breast cancer, pancreatic cancer, and prostate cancer, but have never really been linked to CRC risk.

Within this study, as part of the 25-gene panel, individuals were tested for germline mutations in BRCA1 and BRCA2. We found that over 1% of these individuals, who again, were not specifically selected for any high-risk features, indeed did have inherited mutations in BRCA1 or BRCA2, which is quite a bit higher than what we would expect if we just did testing on random people selected from the general population.

Which patients with CRC should receive molecular testing, and at what point?

To us, this at least suggested that there may be a true link between mutations in these genes and CRC risk, but certainly more studies are needed to tease that out definitively. One of the tricky things from our study is to answer the question of which individuals need germline testing. We’ve historically recommended germline testing for any CRC patient who has a particularly strong family history of colon cancer; any colon cancer patient with a strong family history of endometrial cancer, ovarian cancer, and other cancers linked to Lynch syndrome; and any CRC patient who has a significant number of colorectal adenomas or other polyps.

Our study found that if you look beyond Lynch syndrome, which has historically been known as the most common inherited CRC syndrome, you end up finding a lot of inherited mutations and there doesn’t seem to be, at least from our data, a lot of specific factors that tell us which individuals need germline testing. It raises the question of if we should be performing germline testing on all individuals with CRC, which is a pretty slippery slope.

I think the counterargument to that is that some of these inherited mutations still have a lot of questions behind them, even when we find these mutations, so we’re not quite ready to be recommending germline testing for all individuals with CRC. I think we would come up with as many questions as we do answers if we were to do that.

At the very least, my current recommendation to my patients is to undergo germline testing, certainly if there is any evidence of mismatch repair deficiency (dMMR) in their tumor to suggest Lynch syndrome. If there is any evidence of inherited polyposis due to their personal history of colorectal polyps, or a family history of polyps [they should undergo testing], and furthermore, to undergo germline testing if they’re diagnosed with CRC before the age of 50.

What would you tell a newly diagnosed patient?

Is mismatch repair standard for everyone?

But for individuals who have less striking family histories of other cancers, I think it becomes a situation where we should be thinking about germline testing more broadly and have a much more liberal threshold for such testing than we traditionally do. I think one thing that the literature is showing us we should be moving toward is testing in early-onset individuals. Even if they don’t have some of these traditional features such as dMMR in their tumor, even if they don’t have an obvious family history of colorectal or other cancers, and even if they don’t have a personal history of significant polyposis, that young age of diagnosis in particular is something that we should be thinking about for germline testing even if these other factors aren’t present. Current guidelines recommend dMMR testing or MSI testing—they’re essentially interchangeable. But current guidelines recommend that type of testing for all CRC patients. Certainly, it has been recommended in particular for patients in the metastatic setting to help guide immunotherapy use, such as the use of checkpoint inhibitors, but we have had data in the literature now for several years saying that dMMR testing really should be standard for all CRC patients, specifically to screen for Lynch syndrome.

What kind of questions should patients be asking their healthcare team?

Our study showed that if you go 1 or 2 steps beyond that and you start looking for other syndromes, you do indeed find them. Lynch syndrome is far and away the most common inherited syndrome, but our data showed it’s not the only syndrome we should be looking for. It’s certainly important for patients who have had prior genetic testing to readdress that with their healthcare team. Patients with a prior history of CRC who maybe underwent germline testing in the past and were found to have no abnormalities may want to reconsider testing now that there are tests available that can test a little bit more broadly, especially if they had particularly concerning personal or family histories of cancer. The testing has become more sophisticated over the past several years and we’re finding patients who we tested in the past and now go back and retest with these broader panels where we do indeed find explanations for their high-risk histories.

For patients who are newly diagnosed or who have never had testing in the first place, I think it’s important that patients bring up the notion of familial risk. Many cancer patients, especially those with more advanced disease, have a lot on their plate, and their healthcare providers are often distracted by making sure they’re getting the right chemotherapy, the right social support, the right symptomatic support, and unfortunately, genetics often fall a little bit further down in priority in some cases.

What would you suggest if the patient doesn’t know they have a history?

Right now, there are no therapies that directly target the susceptibility genes. What is in the works in this area?

I certainly encourage patients to advocate for themselves about any concerns they might have about inherited risks, especially as it applies to family members, because the testing is quite widely available at this point, and it is something that many patients should be considering. For patients who don’t know their family history, there still can be reasons to consider germline testing. If they have certain features in their tumor, such as dMMR or MSI, then that would absolutely be a reason to consider germline testing. If they have a history of other cancers, or a history of significant degrees of colorectal polyps, they should be considering testing regardless of whether or not they know their family history. Certainly, patients with CRC who are diagnosed at a young age should consider germline testing even if they have an unknown family history. Family history is a big part of how we access risk, it’s not the only piece though. As far as interventions that we consider for individuals found to have certain types of inherited susceptibility, screening is an incredibly powerful tool. In the setting of Lynch syndrome, for example, individuals are typically recommended to undergo colonoscopies every 1 to 2 years. I often recommend every year, usually beginning in their early 20s, if they have a diagnosis of Lynch syndrome. The reason for such an aggressive recommendation is because we know it works. We know that colonoscopies are an incredibly powerful tool, not just at early detection, but also as CRC prevention.

We have recently seen a rise in young adults diagnosed with colon cancer. What are your thoughts on what might be contributing to this and what recommendations do you have for prevention?

One of the key benefits to making a genetic diagnosis in somebody who has a degree of inherited risk is that it helps us understand what the risks are, and just as importantly, how to manage them, how to prevent cancers. It’s more than early detection. For individuals with these types of inherited risks, beginning colonoscopies at a young age can be incredibly powerful at truly preventing a cancer from developing in the first place.Certainly, we have seen an increase in the incidence of young adults with CRC, particularly rectal cancer, and particularly in individuals in their 40s and late 30s. It doesn’t seem that genetics is a driving force behind that increasing incidence. We would assume that genetic factors should be remaining relatively stable throughout the generations, so I think the assumption has been that it’s lifestyle factors, environmental factors, or interplays between the 2, and maybe interplays with some more subtle genetic factors that we haven’t come to understand just yet.

Yurgelun MB, Kulke MH, Fuchs CS, et al. Cancer susceptibility gene mutations in individuals with colorectal cancer. J Clin Oncol. 2017;35(10):1086-1095. doi: 10.1200/JCO.2016.71.0012.