Rachel Pearlman, MS, LGC, Discusses Fine Tuning Genetic/Germline Testing for CRC


In an interview with CancerNetwork® during National Colorectal Cancer Awareness Month, Rachel Pearlman, MS, LGC, highlights recent updates in genetic testing in colorectal cancer and where the field needs to head to provide individuals with better options.

A necessary shift is on the horizon for colorectal cancer (CRC) genetic testing guidelines, which are likely to move away from testing based solely on mismatch repair (MMR) status to broad implementation for all patients with a diagnosis, according to Rachel Pearlman, MS, LGC.

“It’s important for practitioners to think outside of the box. Decisions for germline testing [in CRC] should not be made solely on MMR status. Yes, universal tumor screenings still need to be done because it drives immunotherapy options for treatment, but it shouldn’t necessarily drive who gets gene testing anymore. We know that tumor screening won’t catch all [Lynch syndrome–associated] cases and an appreciable portion have non–MMR variants anyways. Also, germline testing has come down considerably in cost, too. [Therefore], germline [pan-cancer] panels are much more affordable and informative nowadays than what they used [be],” Pearlman said.

In an interview with CancerNetwork® during National Colorectal Cancer Awareness Month, Pearlman, a licensed genetic counselor with the Clinical Cancer Genetics Program at the Ohio State University Comprehensive Cancer Center, also discussed her efforts as the project manager of the Ohio Colon Cancer Prevention Initiative.

What do you think is on the horizon for genetic testing in CRC?

Coming up on the horizon, genetic testing or germline genetic testing will hopefully be recommended for all individuals with colon cancer, which is a big shift from our current guidelines based mostly on MMR deficiency (MMRd) status, age of diagnosis, or family history criterion. There’s a lot of burden on the practitioner trying to figure out who is the appropriate person to offer genetic testing to. Once germline genetic testing is recommended for all [patients with] colon cancer—or if that were to happen—that would certainly eliminate a lot of the burden of trying to figure out who is the right person to test [if] we know that everybody who has colon cancer is appropriate for testing.

Last year, you were an author on a study focused on universal screenings for hereditary CRC as part of a prevention initiative. Could you speak to the Ohio Colorectal Cancer Prevention Initiative (OCCPI)?

Several years ago, some of my collaborators had completed a prior study of just the Columbus, Ohio area where we learned the prevalence of Lynch syndrome in individuals with colon cancer and that tumor screening for Lynch syndrome was effective. But what was needed was a dissemination and implementation project that would make universal tumor screening accessible to everyone. We were able to get a large grant from Pelotonia, which is our annual grassroots bike ride where 100% of the money raised goes towards cancer research at [The Ohio State University Comprehensive Cancer Center – James Cancer Hospital]. We were able to get a large grant from them and bring universal tumor screening to the whole state.

The OCCPI study was a statewide initiative in Ohio, that was created to prevent colon cancer. Obviously, we know that individuals who are born with a germline pathogenic variant in a cancer predisposition gene have increased risk to develop specific types of cancer. The types of cancer depend on which gene isn’t working correctly but we know that by identifying individuals with colon cancer who have these germline pathogenic variants, we could then hopefully prevent them from getting different cancers in the future, and we could help their family members reduce their risk for cancers too.

With the OCCPI study, we built a statewide network of 51 different hospitals throughout the state of Ohio, and it consisted of a mix of both large and small community hospitals. The OCCPI study is the largest study to date that performed universal tumor screenings, with both microsatellite instability testing and immunohistochemistry for MMRd on everyone in the study. We also did germline genetic testing with multigene pan-cancer panels for those who met our germline testing criteria. We did tumor sequencing for those with unexplained MMRd. We also provided genetic counseling locally for those who tested positive for a germline pathogenic variant and no-cost cascade testing and genetic counseling for the relatives of those found to have Lynch syndrome.

What were some of the key highlights from that research?

Importantly, we found that 1 in 14, or 7.1%, of individuals with colon cancer will have at least 1 [pathogenic germline variant], increasing cancer risk. We know that this is an underestimate of the true prevalence because only our patients [who were at] high risk received germline testing in our study. The true prevalence is probably closer to 10% to 15%, as shown by some other studies. We also found that 1 in 25, or a little bit over 4%, of [patients with] colon cancer have Lynch syndrome, which is a higher frequency than what we had previously reported likely due to improved technology with both the universal tumor screening and germline testing. It [is] universally being done on all-comers rather than targeted based your diagnosis or family history.

Importantly, we found that 3.1% had a pathogenic variant in a non–Lynch syndrome gene, the most common being in ATM, which was [thought to be] a breast and pancreas gene; CHEK2, which is thought of as a breast and colon gene; APC, which is known to cause polyposis; and also interestingly, BRCA1/2, which increases risk for breast and ovarian cancer. We were finding gene mutations in individuals [who] we weren’t necessarily expecting based on their colon cancer diagnosis. For some of them, we weren’t expecting them based on the family history either.

We also have some interesting data in our young onset cohort. We found that 16% of individuals diagnosed with colon cancer under the age of 50 years had at least 1 gene mutation. About 8% of those individuals have Lynch syndrome and 8% had no different hereditary syndrome. Most important to come out of this research was that if universal tumor screening, which is recommended for every person who’s diagnosed with colon cancer, [was] the only method used to screen for hereditary cancer syndrome, then 38.6% of our patients identified as having a mutation would have been missed, including 6.3% of those who are identified to have Lynch syndrome. We found that we’re missing Lynch syndrome and MMR proficient patients, and we found unexpected mutations in [patients who had] proficient and efficient MMR [disease].

How has this research impacted the CRC landscape and how might it affect future efforts?

Certainly, there has been a lot of focus on immunotherapy treatment options in individuals with MMRd colon cancer. In terms of the genetic aspect of these recent studies that have come out over the last few years, ours included, [results] have helped us to understand the prevalence and spectrum of hereditary syndromes in individuals with colon cancer in a way that wasn’t known previously.

We published a separate paper looking at our early onset cohort, and we determined that about a third of colon cancers [in young individuals] were potentially preventable had they known about their genetic predisposition or their family history and followed those recommended surveillance guidelines. The problem is that people don’t know that they have a genetic predisposition prior to being diagnosed with cancer. Sadly, even once they get diagnosed, they aren’t always offered testing. With Lynch syndrome specifically, 95% of individuals with Lynch syndrome don’t know that they have it. We continue to spread awareness about high frequency in this population. We hope that by identifying individuals with cancer who have a hereditary predisposition, we can then rewrite the script in that family and focus on preventing their cancers all together [as well as in] the relatives who also have the gene mutation but haven’t developed cancer.

Are you currently participating in any other kind of clinical research that you want to highlight?

We’re currently finishing up a similar study utilizing the statewide network that we have established with the OCCPI study but we’re doing it [in patients with] endometrial cancer. It’s called the Ohio Prevention and Treatment for Endometrial Cancer. We’re doing germline multigene panel testing and up-front tumor sequencing. We had ended accrual in December and the results were recently published in Journal of Clinical Oncology Precision Oncology.


Pearlman R, Frankel WL, Swanson BJ, et al. Prospective statewide study of universal screening for hereditary colorectal cancer: The Ohio Colorectal Cancer Prevention Initiative. JCO Precis Oncol. 2021;5:PO.20.00525. doi:10.1200/PO.20.00525.

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