Genomic Profiling Uncovers Mutations More Enriched in Early-Onset Colorectal Cancer

Patients with early-onset and late-onset colorectal cancer showed no significant differences in regards to tissue and plasma genomic profiles, but a greater enrichment of the BRCA1 and PTEN mutations were noted in the tissue of those with early-onset disease. Findings were presented at the 2022 ASCO Gastrointestinal Cancers Symposium.

Although colorectal cancer remains rare among younger adults, diagnosis trends exhibit a growing phenomenon with a 51% increase in cases among patients under the age of 50 since 1994. Notably, early-onset colorectal cancer serves as the deadliest cancer for men aged 20 to 49 years, as well as the third most deadliest cancer for women of the same age group.

Seeking to examine and compare the genetic profiles of patients with early-onset and late-onset colorectal cancer, the study authors used Sarah Cannon’s web-based analytics platform that included commercial next-generation sequencing information from oncology practices nationwide.

"Testing performed in oncology practices are routinely extracted and harmonized into the Genospace database," they noted. "Data from colorectal cancer adenocarcinomas were selected; patients with unknown microsatellite instability (MSI) status were excluded."

For the study, only MSI-stable (MSS) tumors were analyzed to reduce the confounding effect of MSI-high hypermutated tumors. Reports generated from archival tissue samples were assessed separately from those generated from plasma, since liquid biopsies were indicated to be more likely conducted during post-treatment.

Overall, next-generation sequencing data of 1477 patients with MSS colorectal cancer were analyzed, of which 1029 were tissue (18.7% early-onset) and 448 plasma (17.8% early-onset) tests. Same sex distribution was shown between both groups, with early-onset patients showing a significantly lower prevalence of Caucasian ethnicity vs late-onset counterparts (43% vs 53%; P < .01).

Of 68 colorectal cancer-related genes examined in tissue, 2 were significantly more enriched in those with early-onset disease vs late-onset—the BRCA1 mutation (7.3% vs 3%; P = .01) and PTEN mutation (6.2% vs 3%; P = .05).

Across panel-wide gene association, 19 genes from tissue were enriched in those with early-onset disease, but none were significant after multiple testing correction. Plasma samples showed significantly higher ATM alterations in patients with late-onset vs early-onset colorectal cancer (17.3% vs. 3.8%; P < .001; false discovery rate = 0.16), which researchers said was likely due to clonal hematopoiesis.

Moreover, no difference in tissue or plasma tumor mutational burden (TMB) was observed:

• TMB in tissue of late-onset patients (median [interquartile (IQ)], 5.04; CI, 3.5-7; TMB > 10, 7%)
• TMB in tissue of early-onset patients (median [IQ], 4.39; CI, 2.5-6.1; TMB > 10, 6%)
• TMB in plasma of late-onset patients (median [IQ], 8.73; 5.7 – 13.4); TMB > 10, 12%)
• TMB in plasma of early-onset patients (median [IQ], 7.19; CI, 2.9-12.6); TMB > 10, 14%)

Tissue and plasma genomic profiles were concordant overall, except for EGFR alterations (4.5% tissue; 21.6% plasma), which researchers said was possibly due to acquired amplification post-EGFR therapy.

“Epigenetic and transcriptional events should be investigated,” concluded the study authors. “Enrichment for BRCA1 and PTEN mutations in early-onset patients may have important screening and therapeutic implications; germline status will be further investigated.”

Reference

Fontona E, Jones C, Misch A, et al. Early-onset colorectal cancer: Real-world genomic data from the community-based Sarah Cannon Cancer Centers Network. Presented at: 2022 ASCO Gastrointestinal Cancers Symposium. Abstract: 198. doi:10.1200/JCO.2022.40.4_suppl.198