Tumor mutational signatures in early-onset versus average-onset colorectal cancer

We previously described gene variant-level differences between early-onset colorectal cancer (EOCRC) and average-onset CRC (AOCRC, age >60) to investigate the rising incidence of EOCRC. In this study, we evaluated the tumor mutational signatures in patients with EOCRC versus AOCRC.

The study screened 12470 patients diagnosed with stages I-III colon or rectal cancer who had whole exome sequencing as part of their ctDNA testing (Signatera™, bespoke mPCR-NGS assay). From WES data, tumors were classified into one of six unique mutational signature groups defined by the Catalogue of Somatic Mutations in Cancer (COSMIC): clock-like, mismatch repair (MMR) deficiency, damage by reactive oxygen species (ROS), POLE exonuclease domain mutation, thiopurine chemotherapy, and other (prevalence < 0.2%). The prevalence of each mutational signature was compared between EOCRC and AOCRC groups. Fisher’s exact test was used to test the significance between the groups.

A total of 2697 patients with EOCRC (73.4% colon, 26% rectal, 0.6% unknown) and 9773 patients with AOCRC (81.9% colon, 17.5% rectal, 0.6% unknown) were included, where 8.8%, 37.8%, and 53.4% were AJCC stages I, II, and III, respectively. Early-onset patients compared to average-onset patients had fewer cases of stage II CRC (31.4% vs. 39.4%, p < 0.01) and more cases of stage III CRC (60.3% vs. 51.6%, p < 0.01). Patients with EOCRC were less commonly MSI-H compared to patients with AOCRC (11.5% vs. 17.4%, p < 0.01), or have high tumor mutational burden (16.6% vs. 19.8%, p < 0.01). Fewer patients with EOCRC had clock-like signature compared to AOCRC (69.63% vs. 74%, p < 0.01). MMR deficiency signature was also less common in EOCRC vs. AOCRC (20.7% vs. 22.81%; p < 0.05); notably, EOCRC cases with MMR deficiency signatures were 15.5 times less likely to be associated with BRAF V600E mutation compared to AOCRC (3.1% vs. 48.1%, p < 0.01). Conversely, POLE exonuclease domain mutations signature was 4.2 times more frequent in EOCRC (3.7% vs. 0.9%, p < 0.01). EOCRC was 3.3 times more likely to have a mutational signature consistent with damage from ROS (0.56% vs. 0.15%, p < 0.01).

Patients with EOCRC were less likely to have a MMR deficient signature, but more likely to have mutational signatures consistent with damage by ROS, POLE exonuclease domain mutations. Expectedly, more AOCRC cases harbored clock-like signatures related to age. While EOCRC and AOCRC often do not differ significantly on the single gene variant level, this genomic clustering data suggests that EOCRC may be caused by uniquely different mutagenic processes compared to AOCRC.

The authors.

Has not received any funding.

S. Rivero-Hinojosa: Honoraria (Institution): Natera Inc. V. Aushev: Travel / Accommodation / Expenses: Natera, Inc.; Shareholder / Stockholder / Stock options: Natera, Inc.; Full / Part-time employment: Natera, Inc. M. Liu: Leadership role: Natera; Shareholder / Stockholder / Stock options: Natera; Full / Part-time employment: Natera. A. Jurdi: Shareholder / Stockholder / Stock options: Natera; Full / Part-time employment: Natera. All other authors have declared no conflicts of interest.