Tumor Mutational Signatures Among Patients With Early-Onset Versus Average-Onset Colorectal Cancer

At the 2023 World Congress on Gastrointestinal Cancers in Barcelona, Spain, Eric Lander, MD, Vanderbilt University Medical Center, Nashville, Tennessee, presents novel data regarding tumor mutational signatures among patients with early-onset versus average-onset colorectal cancer.

Dr Lander concluded, “While [early-onset colorectal cancer] and [average-onset colorectal cancer] often do not differ significantly on the single gene variant level, this genomic clustering data suggests that [early-onset colorectal cancer] may be caused by uniquely different mutagenic processes compared to [average-onset colorectal cancer].”

Transcript:

Hi everyone. My name is Eric Lander. I'm finishing up my fellowship at Vanderbilt University Medical Center in Nashville, Tennessee in the United States, and I'm having a focus on GI medical oncology throughout my training. I'm honored to be at the World Congress of GI Cancers this year, presenting my research. We focused on tumor mutational signatures in early onset versus average onset colorectal cancer.

So, as you may or may not know, more and more young people are getting colorectal cancer throughout the world, and we did not know why, and it's becoming a larger and larger problem throughout the world. And so, our data that we had already presented at ASCO this year looked at somatic gene mutations between patients with early onset disease, which we defined as an age less than 50, versus average onset disease, which we defined as an age greater than 60, who had colorectal cancer. And while we didn't find mutational differences in the  [microsatellite stable] (MSS) [tumor mutational burden] (TMB) low subpopulation, we did find numerous differences in the [microsatellite instable] MSI high TMB high and the MSS TMB high subpopulations. I encourage you to look at our abstract presented by ASCO this year in June.

Now, during that presentation, what unfortunately we found was that, like I said, there were not significant differences in the MSS TMB low group, and this is where we hoped that tumor mutational signatures might be able to underscore differences existing in that subpopulation. So, while that previous analysis was specific genes being mutated, tumor mutational signatures look at clusters of mutations or the whole signature of a tumor genome, and trying to identify whether the signature of genomes in younger patients is unique compared to older patients with colorectal cancer. 

Our study was the largest, and I think the first of its kind. Looking at tumor mutational signatures, we had 12,470 patients from the US with colon or rectal cancer, over 2000 cases of early onset disease. And when we looked at tumor mutational signatures in the cosmic database between these age groups, stratified by TMB and MSI status, we found that in patients with early onset disease, there were some unique signatures that stood out. While most signatures, regardless of age, were due to clocklike, or what we consider related just to age and endogenous mutational differences that occur over time, or the [mismatch repair] (MMR) deficiency signature, we did find specific signatures that were most common in early onset disease.

To summarize it, we found that early onset had far greater proportion of patients with POLE mutations, about 4% of the population. About 3% of patients had a signature consistent with prior receiving of thiopurine chemotherapy. Remember that thiopurine chemotherapies such as azathioprine are often used to treat inflammatory bowel disease, and so we don't necessarily know for sure if all the patients in our cohort had received those treatments, but it's certainly hypothesis-generating to consider whether or not, if you receive a thiopurine chemotherapy, if perhaps that's predisposing to more cases of colon cancer in the early onset group. And then we found this also unique but rare signature of reactive oxygen species being more common in early onset, and that held even in the MSS TMB low subpopulation.

In conclusion, we did see a lot of differences. Generally, the profiles were similar between early and average onset, but I encourage you to look at our data because it does highlight unique differences between age groups and underscores the need for NGS testing in all early onset cases, because I'm hoping that we can start to target clinical trials and future therapeutics to early onset and better underscore what is causing more and more patients getting colorectal cancer at an early age.

Source:

Lander E, Rivero-Hinojosa S, Aushev V, et al. Tumor mutational signatures in early-onset versus average-onset colorectal cancer. Presented at the 2023 World Congress on Gastrointestinal Cancers; June 28-July 1, 2023; Barcelona, Spain. Abstract SO-21